SSRI induced serotonin transporter degradation - now reversible

[PeskyPeater]

This is about formula of Chinese medicine that can reverse damage from SSRI and can be used for treating HSP high Sensitive Person with the short allele of serotonin transporter gene. With possible recovery of sexual function or anhedonia.

Abstract
Ethnopharmacological relevance: Zuojin Pill (ZJP), a traditional Chinese medicinal decoction, contains two herbal drugs: Coptis chinensis Franch. and Evodia rutaecarpa (Juss.) Benth. in the ratio of 6:1 (w/w). Previous pharmacological studies have shown that two herbs in ZJP have the antagonistic effects on catecholamine secretion in bovine adrenal medullary cells. Furthermore, the alkaloids from the two herbs in ZJP may provide a protective effect for depression in individuals with a low expressing 5-HTT allele by increasing receptor concentration in serotonergic neurons. However, antidepressant effect has not been reported before and has not been fully clarified.

Our previous pharmacological studies have shown that seven alkaloids, epiberberine, jatrorrhizine, coptisine, palmatine, berberine, evodiamine, rutaecarpine in the ethanol extract of ZJP, and the quantification of seven alkaloids in the ethanol extracts of ZJP was 32.65, 13.59, 110.64, 61.20, 153.0, 1.89, 1.47 mg/g, respectively, furthermore, the results showed that the alkaloids from the ethanol extract of ZJP have the anti-inflammatory (Wang et al., 2012) and two herbs in ZJP have the antagonistic effects on catecholamine in secretion in bovine adrenal medullary cells (Zhao et al., 2010). Furthermore, the evidence showed that the combination of berberine and evodiamine (the main bioactive ingredients in the herb of Rhizoma Coptidis and Fructus Evodiae respectively) might provide a protective effect for depression in individuals with a low expressing 5-HT transporter (5-HTT) allele by increasing receptor concentration in serotonergic neurons which could have more potential as an antidepressant or foodintake inhibitor than berberine or evodiamine alone (Hu et al., 2011). The 5-HTT regulates 5-HT transmission, which in turn modulates mood, emotion and appetite (Camarena et al., 2002). The 5-HTT is also well documented as the pharmacological target of selective 5-HT reuptake inhibitors, and its expression has been reported to be down-regulated by the antidepressants fluoxetine and sertraline (Johnson et al., 2009; Zhao et al., 2009).

source - direct link PDF

- Information about HSP high sensitive person 5-HTTLPR_ShortShort_Genotype Full

Abstract​

Associations between the common polymorphism in the serotonin transporter (5-HTT) promoter 5-HTTLPR and the personality traits Neuroticism and Harm Avoidance are equivocal. The temperamental trait Sensory Processing Sensitivity (SPS), which is characterized by increased sensitivity to environmental stimuli (Aron and Aron, 1997) and is related to Neuroticism and Openness (Smolewska et al., 2006), may describe an underlying characteristic more directly associated with 5-HTTLPR genotype. High levels of SPS are found in 15-20% of the population and have in fMRI studies been associated with enhanced neural processing of detailed visual stimuli (Jagiellowicz et al., 2011) and increased neural activation in response to happy and sad faces (Acevedo et al., 2010). Several defining characteristics of SPS, as reflected by items on the self-report questionnaire, are similar to physiological characteristics found in 5-HTTLPR short allele carriers, including increased brain activation in response to emotional stimuli (Canli et al., 2005), increased acoustic startle response (Brocke et al., 2006), and increased cortisol response to social evaluation (Way et al., 2010). High levels of SPS may reflect an endophenotype associated with the 5-HTTLPR short/short genotype

 

[LeeLemonoil]

Thanks for sharing. Interesting. Good to see researchers knowing what they’re doing

 

[JCastro]

Great share. That Sensory Processing Sensitivity study is very interesting too.

Are PSSD and post-SSRI anhedonia things you deal with? Let us know if you see results with these herbs.

There was a report of a person with PSSD and blunted perception after SSRIs who profoundly improved with high-dose inositol. He said it made his vision have depth again, colors saturated again, butterflies in stomach again, plus the relief of PSSD.

Berberine seems to have great benefits alone, so this combination is intriguing.

 

[PeskyPeater]

Great share. That Sensory Processing Sensitivity study is very interesting too.

Are PSSD and post-SSRI anhedonia things you deal with? Let us know if you see results with these herbs.

There was a report of a person with PSSD and blunted perception after SSRIs who profoundly improved with high-dose inositol. He said it made his vision have depth again, colors saturated again, butterflies in stomach again, plus the relief of PSSD.

Berberine seems to have great benefits alone, so this combination is intriguing.

Yes, I do. Apathy mainly and anhedonia, but no other erectile issues. And indeed I know about that inositol treatment from PSSD forum, no experience with it, but it seem not to work for everybody so haven't focused on that. I have tried berberine before but that is not working. And I think the combination and additional substance in these herbs are going to be synergistic and could have much better effect.

The thing to be aware of, I have learned now, is that when trying to increase the expression of serotonin transporters, you are effectively lowering the levels or depleting it and as reaction the neuron will upregulate itself. Meaning you can't take anything that increases serotonin like MAO-A in the meantime of using this chinese medicine or any other, for that will interfere with the process. Inducing serotonin is going to downregulate it's functions. Here is a study about that:

External 5-HT Down-regulates All Serotonergic Functions Induced along the Serotonergic Differentiation Program​

The onset of serotonergic functions during the 1C11 serotonergic program follows a well defined kinetic pattern as well (TableIII). Since 5-HT2B and 5-HT1B/D receptors were present on 1C11*/5HTcells as early as day 2 of the serotonergic differentiation program, we wondered whether these receptors could modulate the serotonergic functions, similarly to what we observed for the catecholaminergic pathway. Because standard 10% FCS-supplemented medium contains 0.5 to 1 μm 5-HT, the culture medium was dialyzed, and the 5-HT level was reduced to less than 1 nm. The parameters for serotonergic differentiation were assessed for 1C11*/5HTcells grown in 5-HT-depleted medium. Under these new culture conditions, the time sequence of acquisition of serotonergic functions remained unchanged. However, at day 4, 5-HT cellular content (×2.8), tryptophan hydroxylase activity (×9.3), and the apparentV max of 5-HT transport (×7.7) were higher than the values obtained with 1C11*/5HT cells grown in 10% FCS medium (Table III). These phenotypic changes specifically resulted from 5-HT starvation. Indeed, the values again became very close to those obtained under standard culture conditions if 5-HT concentration in the dialyzed medium was increased to 0.5 μm at day 0 of the serotonergic program (Table III). This experiment interestingly indicates a negative feedback of extracellular 5-HT on the extent of 5-HT synthesis and storage as well as on the 5-HT transport system itself.

 

[PeskyPeater]

That specific research about 1C11 neurons quoted above is connected with the research behind the actual mechanism of SSRI 'effects' on the brain or maybe we should call it 'damage' as the same mediator is seen in neuro degeneration in Alzheimers Disease and abnormalities in Down's syndrome.

"Abstract
S100 beta is a multifunctional protein that is found in large amounts in astrocytes and a number of other tissues. In the developing nervous system, S100 beta is secreted from proliferating astrocytes during the time of neurite outgrowth from cortical neurons. The secreted form has neurotrophic activity on primary neurons and neuroblastoma cells. The neurotrophic activity is sensitive to reduction of disulfide bonds, and appears to be a disulfide dimer of S100 beta. The accumulation of S100 beta in mature glial cells is associated with microtubule network. The transfection and expression of cDNA for S100 beta in mammalian cells confers neurotrophic activity on extracts of these cells. Based on our observations of a neurotrophic activity for S100 beta, the occurrence of the gene for S100 beta on human chromosome 21 (Allore et al., 1988) and the elevated levels of S100 beta-containing cells in AD and DS brains (Griffin et al., 1989), we suggest that S100 beta plays a role in the abnormal development of the nervous system in DS and the degeneration of central neurons in AD. It is essential at the present stage to demonstrate the action of S100 beta in vivo, and to construct animal models, such as transgenic mice, that overexpress S100 beta. Such models will allow the dissection of the role of S100 beta in the developing and degenerating central nervous system. "
S100 beta as a neurotrophic factor - PubMed

https://www.sciencedirect.com/science/article/abs/pii/S0165572811003389
iNOS and TNF-α increase in astrocytes after treatment with micromolar concentrations of S100B

- Then here is a review about the SSRI inducing also s100 beta in serotonin and also other brain regions of norepinephrine 1C11 neurons

A new mechanism of action for Selective Serotonin Reuptake Inhibitors (SSRIs)?: Pharm 551A, Baudry et al., 2010
"The question then arises of how the response of serotonergic neurons to fluoxetine treatment is relayed to noradrenergic neurons in vivo. Reciprocal connections exist between these two brainstem monoaminergic nuclei, thus supporting communication between the two systems (16). Recently, the expression of miR-16 in monocytes was shown to be down-regulated by S100β (17), a neurotrophic protein that is up-regulated by fluoxetine treatment (18). We therefore hypothesized that the secretion of S100β increases upon exposure of raphe to fluoxetine and that this protein acts as a paracrine factor to promote the reduction in miR-16 in the locus coeruleus, in turn unlocking the expression of serotonergic functions. We first exposed 1C115-HT cells to fluoxetine and observed an accumulation of S100β in the culture medium (Fig. 4A). Although the addition of S100β slightly decreased miR-16 levels in these serotonergic cells (Fig. 4B), it did not affect SERT expression (Fig. 4C), which is in agreement with the lack of impact of miR-16 silencing on SERT in 1C115-HT cells (Fig. 1B). A larger decrease (43% of control level) of miR-16 was seen in 1C11NE cells exposed to S100β (Fig. 4B), which correlated with the appearance of SERT (Fig. 4C). In addition, after S100β treatment, 1C11NE cells acquired the ability to synthesize and store 5-HT (Fig. 4, D and E) and to express 5-HT2B receptors (Fig. 4F). These data thus validate our working hypothesis on an in vitro level. We then measured the level of S100β in raphe upon infusion of fluoxetine. Fluoxetine up-regulated S100β levels in serotonergic nuclei (133% versus control) (Fig. 5A). Further, injection of S100β into the locus coeruleus decreased (by 22.4%) miR-16 levels and turned on the expression of SERT (Fig. 5, B and C). Finally, antibody-mediated neutralization of S100β in the locus coeruleus prevented the decrease in miR-16 levels observed upon infusion of fluoxetine in raphe (Fig. 5D). In addition, the decrease in miR-16 and the onset of SERT expression observed in the locus coeruleus, upon systemic fluoxetine treatment, were both eliminated by small interfering RNA–mediated knockdown of S100β in raphe (fig. S8, A and B). The data from 1C115-HT cells (Fig. 4A) and the innervation of the locus coeruleus by raphe fibers (16) strengthen the hypothesis that secretion of S100β by serotonergic neurons, at the locus coeruleus, mediates the action of fluoxetine. Secretion of S100β by glial cells in the raphe is less likely to promote a long-range action on the locus coeruleus."
...
"This leaves us with the following model for a novel mechanism of action for SSRIs:
1) SSRIs suppress WNT signaling in the raphe leading to a maturation of miR-16. This causes an increase in expression of S100beta and a decrease in SERT expression in these 5HT neurons.
2) SSRIs increase S100beta release in the locus ceruleus causing a decrease in miR-16 expression in these NE neurons. That decrease in miR-16 expression releases a suppression of 5HT function in those neurons leading to an increase in 5HT synthesis, increased SERT expression and 5HT2B receptor expression.
3) Presumably this causes a sort of double whammy for brain 5HT levels. Less SERT expression in the raphe leads to greater 5HT levels because reuptake mechanisms are decreased. In combination with this, locus ceruleus neurons take on a 5HT phenotype thereby increasing 5HT levels through the activation of a novel 5HT pathway in the CNS. "

 

[PeskyPeater]

Here we see the chronic effects on the brain's serotonin system where the feedback 5-HT1A is internalized/desensitized and damaged by uncoupling from it's g-protein and losing part of it's function. But these recover after discontinuation, only the transporter SERT is actually degraded over time and does not restore. The situation that is somewhat similar as having a genetic short allele and low expression of SERT.

Effects of the antidepressant fluoxetine on the subcellular localization of 5-HT1A receptors and SERT

ABSTRACT​

Serotonin (5-HT) 5-HT1A autoreceptors (5-HT1AautoR) and the plasmalemmal 5-HT transporter (SERT) are key elements in the regulation of central 5-HT function and its responsiveness to antidepressant drugs. Previous immuno-electron microscopic studies in rats have demonstrated an internalization of 5-HT1AautoR upon acute administration of the selective agonist 8-OH-DPAT or the selective serotonin reuptake inhibitor antidepressant fluoxetine. Interestingly, it was subsequently shown in cats as well as in humans that this internalization is detectable by positron emission tomography (PET) imaging with the 5-HT1A radioligand [18F]MPPF. Further immunocytochemical studies also revealed that, after chronic fluoxetine treatment, the 5-HT1AautoR, although present in normal density on the plasma membrane of 5-HT cell bodies and dendrites, do not internalize when challenged with 8-OH-DPAT. Resensitization requires several weeks after discontinuation of the chronic fluoxetine treatment. In contrast, the SERT internalizes in both the cell bodies and axon terminals of 5-HT neurons after chronic but not acute fluoxetine treatment. Moreover, the total amount of SERT immunoreactivity is then reduced, suggesting that SERT is not only internalized, but also degraded in the course of the treatment. Ongoing and future investigations prompted by these finding are briefly outlined by way of conclusion.

 

[PeskyPeater]

So that is what the above Zuo Ji is for, it can increase the serotonin transporter systems probably by reducing brain serotonin.
But how can we address the changes made by SSRI in the locus coeruleus (LC) the part were norepinephrine is highly expressed without depleting it or using transporter inhibitors that can make things worse.

First we have to look at what other functions are expressed in the LC.
After some diggin it seems that GABA neurons are located there but are not expressed in the same fashion in human as in rodents, the lab rats they use to test SSRI on. Go figure. Another scandalous piece of work of the pharma industry. Seem they didn't really knew what they were doing or the repercussions it had for humans.

Human locus coeruleus neurons express the GABAA receptor γ2 subunit gene and produce benzodiazepine binding

Abstract​

Noradrenergic neurons of the locus coeruleus project throughout the cerebral cortex and multiple subcortical structures. Alterations in the locus coeruleus firing are associated with vigilance states and with fear and anxiety disorders. Brain ionotropic type A receptors for γ-aminobutyric acid (GABA) serve as targets for anxiolytic and sedative drugs, and play an essential regulatory role in the locus coeruleus. GABAA receptors are composed of a variable array of subunits forming heteropentameric chloride channels with different pharmacological properties. The γ2 subunit is essential for the formation of the binding site for benzodiazepines, allosteric modulators of GABAA receptors that are clinically often used as sedatives/hypnotics and anxiolytics. There are contradictory reports in regard to the γ2 subunit’s expression and participation in the functional GABAA receptors in the mammalian locus coeruleus. We report here that the γ2 subunit is transcribed and participates in the assembly of functional GABAA receptors in the tyrosine hydroxylase-positive neuromelanin-containing neurons within postmortem human locus coeruleus as demonstrated by in situ hybridization with specific γ2 subunit oligonucleotides and Autoradiographic assay for flumazenil-sensitive [3H]Ro 15-4513 binding to benzodiazepine sites. These sites were also sensitive to the α1 subunit-preferring agonist zolpidem. Our data suggest a species difference in the expression profiles of the α1 and γ2 subunits in the locus coeruleus, with the sedation-related benzodiazepine sites being more important in man than rodents. This may explain the repeated failures in the transition of novel drugs with a promising neuropharmacological profile in rodents to human clinical usage, due to intolerable sedative effects.

 

[PeskyPeater]

Then focusing on the GABA system in locus coeruleus, how do we put things in perspective as to be able to find solutions?
We can look at effects of alternative medicine, Traditional Chinese medicine on these parts of the brain.

For example:

Xiao Yao San Improves Depressive-Like Behaviors in Rats with Chronic Immobilization Stress through Modulation of Locus Coeruleus-Norepinephrine System​

Abstract​

Most research focuses on the hypothalamic-pituitary-adrenal (HPA) axis, hypothalamus-pituitary-thyroid (HPT) axis, and hypothalamus-pituitary-gonadal (HPGA) axis systems of abnormalities of emotions and behaviors induced by stress, while no studies of Chinese herbal medicine such as Xiao Yao San (XYS) on the mechanisms of locus coeruleus-norepinephrine (LC-NE) system have been reported. Therefore, experiments were carried out to observe mechanism of LC-NE system in response to chronic immobilization stress (CIS) and explore the antidepressant effect of XYS. Rat model was established by CIS. LC morphology in rat was conducted. The serum norepinephrine (NE) concentrations and NE biosynthesis such as tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DBH), and corticotrophin-releasing-factor (CRF) in LC were determined. Results showed that there were no discernible alterations in LC in rats. The serum NE concentrations, positive neurons, mean optical density (MOD), and protein levels of TH, DBH, and CRF in model group were significantly increased compared to the control group. But XYS-treated group displayed a significantly decreased in NE levels and expressions of TH, DBH, and CRF compared to the model group. In conclusion, CIS can activate LC-NE system to release NE and then result in a significant decrease in rats. XYS treatment can effectively improve depressive-like behaviors in rats through inhibition of LC-NE neurons activity.

- And when we analyze these herbs used in this ancient concoction, it becomes clear that most of them have effects on the norepinephrine and related dopamine systems via modulating the GABA system and MOA-B inhibition but amazingly not norepinephrine directly.
This give rise to the possibility of using a companion with Zuo Jin to address the changes made from SSRI in both serotonin neurons and the norepinephrine and downstream GABA/glutamic systems.

2.2. Preparation of Xiao Yao San​

The herbal formula of XYS comprises the following drugs: Angelicae sinensis Radix (root of Angelica sinensis (Oliv.) Diels), Paeoniae Radix Alba (root of Paeonia lactiflora Pall.), Bupleuri Radix (root of Bupleurum chinese DC), Atractylodis Macrocephalae Rhizoma (root and rhizome of Atractylodes macrocephala Koidz), Glycyrrhizae Radix et Rhizoma (root and rhizome of Glycyrrhiza uralensis Fish), Poria (fungus nucleus of Poria cocos (Schw.) Wolf), Zingiberis Rhizoma Recens (root and rhizome of Zingiber officinale Rosc.), and Menthae Haplocalycis Herba (overground parts of Mentha haplocalyx Briq.) (the ratio is 6 : 6 : 6 : 6 : 6 : 2 : 2 : 3).

 

[LeeLemonoil]

@PeskyPeater

Good work, thanks for sharing

 

[Cfgalak]

This is about formula of Chinese medicine that can reverse damage from SSRI and can be used for treating HSP high Sensitive Person with the short allele of serotonin transporter gene. With possible recovery of sexual function or anhedonia.

Abstract
Ethnopharmacological relevance: Zuojin Pill (ZJP), a traditional Chinese medicinal decoction, contains two herbal drugs: Coptis chinensis Franch. and Evodia rutaecarpa (Juss.) Benth. in the ratio of 6:1 (w/w). Previous pharmacological studies have shown that two herbs in ZJP have the antagonistic effects on catecholamine secretion in bovine adrenal medullary cells. Furthermore, the alkaloids from the two herbs in ZJP may provide a protective effect for depression in individuals with a low expressing 5-HTT allele by increasing receptor concentration in serotonergic neurons. However, antidepressant effect has not been reported before and has not been fully clarified.



source - direct link PDF

- Information about HSP high sensitive person 5-HTTLPR_ShortShort_Genotype Full

Abstract​

Associations between the common polymorphism in the serotonin transporter (5-HTT) promoter 5-HTTLPR and the personality traits Neuroticism and Harm Avoidance are equivocal. The temperamental trait Sensory Processing Sensitivity (SPS), which is characterized by increased sensitivity to environmental stimuli (Aron and Aron, 1997) and is related to Neuroticism and Openness (Smolewska et al., 2006), may describe an underlying characteristic more directly associated with 5-HTTLPR genotype. High levels of SPS are found in 15-20% of the population and have in fMRI studies been associated with enhanced neural processing of detailed visual stimuli (Jagiellowicz et al., 2011) and increased neural activation in response to happy and sad faces (Acevedo et al., 2010). Several defining characteristics of SPS, as reflected by items on the self-report questionnaire, are similar to physiological characteristics found in 5-HTTLPR short allele carriers, including increased brain activation in response to emotional stimuli (Canli et al., 2005), increased acoustic startle response (Brocke et al., 2006), and increased cortisol response to social evaluation (Way et al., 2010). High levels of SPS may reflect an endophenotype associated with the 5-HTTLPR short/short genotype

Where can I find this? I wanted to try it for my PSSD!

 

[PeskyPeater]

SSRI induced brainzaps - Possible treatment Found

Brain Zaps: Causes & Treatments For Electrical Shock Sensations
Brain zaps are commonly reported electrical shock sensations that are often experienced during discontinuation of antidepressant medications. Other common names for brain zaps include: brain shivers, electrical shocks, and brain shocks. People often describe them as feeling electrical current uncontrollably zapping their brains, which can be extremely frightening and uncomfortable. A person experiencing these zaps may get dizzy, feel minor pain, and high levels of discomfort.

Do these head zaps sound like mini seizures?

Hi,

I am a 20 y/o female. Over the last 3 - 4 weeks I have been having what I can only describe as 'head zaps' . They started suddenly whilst I was at the airport about to go on holiday and have been happening around 10 - 30 times a day since. They feel like sudden jolts of electricity going through my head.. As well as this I have been feeling quite lethargic and having 'brain fog'.

I went to the GP last week and he said it sounds like a pinched nerve in my neck. I told him I'm worried it's some kind of seizure and he laughed and reassured me it wasn't. However, the only websites online reporting this symptom are either to do with SSRI withdrawal (I have never taken anti depressants) or epilepsy.

I am at a loss of what to do.. but they are really starting to affect my every day life.

Hi there,
I'm so glad i read your message. You're not alone. Since 2004 (im 32 now) I've been having these "jolt like" sensations or I usually describe it like if you get shocked from the vacuum after walking across the rug. It's different than a regular seizure. I have diagnosed epilepsy too, with absence seizures. What type do you have? I've yet to find someone who has experienced the same thing as me, yet my neurologist is starting to come to some conclusions now. I'd love to talk to you more about this. I hope you're doing okay. You're right. They interfere with everything.

First Evidence of Kv3.1b Potassium Channel Subtype Expression during Neuronal Serotonergic 1C11 Cell Line Development

The Kv3 channels family presents four subtypes—Kv3.1, Kv3.2, Kv3.3, and Kv3.4—that are distinguished from the other mammalian Kv families by their typical opening at positive potentials and by their rapid activation and deactivation kinetics [4–7]. Otherwise, the Kv3.1 channel subtype is highly sensitive to 4-aminopyridine (4-AP) and to tetraethylammonium TEA [6,8] and is inhibited by fluoxetine, an antidepressant drug known as Prozac [9].
Kv3.1 is involved in neurologic epilepsy [15] and neurodegenerative diseases such as multiple sclerosis [16] and Alzheimer’s [13], in cancer tumor hypoxia [17] and in behavior disorders such as bipolar disorder [18] and schizophrenia [19]. Kv3.1 dysfunction was also reported in cases of circadian cycle disturbance, sleep loss [20,21] and depression [22]. Most neuropsychiatric diseases, including schizophrenia and depression, are currently treated with medications that have a high affinity for serotonin receptors 5HT [23]. In fact, during depression, selective serotonin reuptake inhibitors like fluoxetine (SSRIs) are the most commonly prescribed drugs [24]. Fluoxetine interacts with the channel open state [9] and blocks, at micromolar concentrations, several potassium channel subtypes, as Kv1.1, Kv1.3, Kv1.4, Kv1.5, Kv3.1, Kv4.3, hERG and TREK-1 [25–28].
Moreover, a recent study reports that changes in neuronal cells activity during acute and/or chronic SSRI treatment correlates with the changes in the function of the Kv3.1 channel. In neuronal circuits, Kv3.1 is differentially regulated: antipsychotic treatment elevates the Kv3.1 level in the cortex but, in the hippocampus, chronic antidepressant drug use resulted in reduced activity of this channel [30]. For these reasons, we propose in this study to define the relationship between the expression of the Kv3.1b and the serotonergic activity of the 1C11 cell line, using fluoxetine, their common modulator. 1C11 is a murine serotonergic cell line from neuronal stem cells and may undergo either serotoninergic or noradrenergic differentiation upon induction [31].

Saikosaponin a Enhances Transient Inactivating Potassium Current in Rat Hippocampal CA1 Neurons​

Abstract​

Saikosaponin a (SSa), a main constituent of the Chinese herb Bupleurum chinense DC., has been demonstrated to have antiepileptic activity. Recent studies have shown that SSa could inhibit NMDA receptor current and persistent sodium current. However, the effects of SSa on potassium (K+) currents remain unclear. In this study, we tested the effect of SSa on 4AP-induced epileptiform discharges and K+ currents in CA1 neurons of rat hippocampal slices. We found that SSa significantly inhibited epileptiform discharges frequency and duration in hippocampal CA1 neurons in the 4AP seizure model in a dose-dependent manner with an IC50 of 0.7 μM. SSa effectively increased the amplitude of I Total and I A, significantly negative-shifted the activation curve, and positive-shifted steady-state curve of I A. However, SSa induced no significant changes in the amplitude and activation curve of I K. In addition, SSa significantly increased the amplitude of 4AP-sensitive K+ current, while there was no significant change in the amplitude of TEA-sensitive K+ current. Together, our data indicate that SSa inhibits epileptiform discharges induced by 4AP in a dose-dependent manner and that SSa exerts selectively enhancing effects on I A. These increases in I A may contribute to the anticonvulsant mechanisms of SSa.

Under physiological conditions, voltage-gated potassium (K+) currents are key regulators of neuronal excitability [7], such as resting membrane potential, action potential waveform, and firing frequency [8, 9]. Alterations in their electrical function are related to hyperexcitability and epilepsy [10, 11]. Several animal models of epilepsy have been developed by using K+ channel blockers, such as 4-aminopyridine (4AP) [12], dendrotoxin I [13], tityustoxin-K, and pandinustoxin-K [14]. In addition, mice with induced deletions of various K+ current genes exhibit seizures [15, 16]. K+ currents were decreased in hippocampal CA1 pyramidal neuron dendrites in several animal models of seizure [17, 18]. Drugs that enhance K+ currents activity possess antiepileptic action [19, 20]. Thus, K+ currents may play an active role in controlling epileptic synchronization [21, 22].​

 

[Lokzo]

Following thread.

Nice research OP.

I may have to trial this at some stage.

 

[PeskyPeater]

More about the SSRI Fluoxetine and it's alterations of glutamate and GABA neuronal systems- similarities with Parkinson's Disease. And another candidate of a Chinese herbal treatment. With the discovery of, not inhibitors, but actual AcetylcholinEsterase (AChE) enhancers that breakdown acetylcholine involved in learned helplessness, see the article by Dr Ray Peat...

Fluoxetine Suppresses Glutamate- and GABA-Mediated Neurotransmission by Altering SNARE Complex

Abstract​

Major depressive disorder is one of the most common neuropsychiatric disorders worldwide. The treatment of choice that shows good efficacy in mood stabilization is based on selective serotonin reuptake inhibitors (SSRIs). Their primary mechanism of action is considered to be the increased synaptic concentration of serotonin through blockade of the serotonin transporter (SERT). In this study, we described an alternative mode of action of fluoxetine (FLX), which is a representative member of the SSRI class of antidepressants. We observed that FLX robustly decreases both glutamatergic and gamma-Aminobutyric acid (GABA)-ergic synaptic release in a SERT-independent manner. Moreover, we showed that this effect may stem from the ability of FLX to change the levels of main components of the SNARE (solubile N-ethylmaleimide-sensitive factor attachment protein receptor) complex. Our data suggest that this downregulation of SNARE fusion machinery involves diminished activity of protein kinase C (PKC) due to FLX-induced blockade of P/Q type of voltage-gated calcium channels (VGCCs). Taken together, by virtue of its inhibition at SERT, fluoxetine increases extracellular serotonin levels; however, at the same time, by reducing SNARE complex function, this antidepressant reduces glutamate and GABA release.

​

To investigate whether the inhibitory action of FLX is only transient or has a long-lasting effect, the cells were treated with FLX for 90 min, but presynaptic activity was measured 24 h later. As seen in Figure 2I, washing out the drug for 24 h did not rescue its effect on synaptic vesicle (SV) recycling.

...treatment of primary neurons with FLX significantly upregulated the level of α-synuclein, a protein which is highly implicated in several neurodegenerative disorders, including Parkinson’s disease.

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Alpha-synuclein (α-Syn) is a key protein involved in Parkinson's disease (PD) pathology. PD is characterized by the loss of dopaminergic neuronal cells in the substantia nigra pars compacta and the abnormal accumulation and aggregation of α-Syn in the form of Lewy bodies and Lewy neurites..

Modeling Parkinson’s Disease With the Alpha-Synuclein Protein​

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-Another candidate:

Xiao Chai Hu Tang Wan​

Composition:
Bupleurum chinensis root (Chai Hu)
Pinellia ternata rhizome (Fa Ban Xia) - (1) Modulate GABAergic system (2) Upregulate GABAA receptors
Codonopsis pilosula root (Dang Shen) - Phytochemical and Pharmacological Review
Scutellaria baicalensis root (Huang Qin) - increasing the counts of dopaminergic neurons, reducing acetylcholine.
Ziziphus jujuba fruit (Da Zao) - Increase AChE and BChE activity
Glycyrrhiza uralensis root (Gan Cao)
Zingiber officinale rhizome (Sheng Jiang) - restoring the balance between GABA and GLUTAMATE

Chinese Herbal Medicine for Treating Epilepsy
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Scutellaria baicalensis root (Huang Qin)

In vivo, baicalein exerted neuroprotective action through reducing behavioral damage and the depletion of dopaminergic neurons in rotenone-induced PD model (Zhang et al., 2017a). Moreover, other studies have shown that treatment with baicalein significantly attenuated the dopamine (DA) content in striatum induced by 1-methyl-4-phenylpyridinium (MPP+) (Hung et al., 2016) and increased the numbers of tyrosine hydroxylase (TH) neurons in PD rat model induced by 6-hydroxydopamine (6-OHDA) (Mu et al., 2009). All these data indicated that baicalin can be used as an effective drug to prevent or treat neurodegenerative diseases such as PD Parkinson's disease.

Inhibitory effect of baicalein on mice tremor induced by oxotremorine and mechanisms | Chinese Journal of Pharmacology and Toxicology;(6): 1007-1007, 2017. | WPRIM

After 7, 14, 21 and 28 d of continuous administration, the latency, duration and tremor frequency of tremor mice were significantly shortened, the levels of acetylcholine were significantly decreased, the changes of DOPAC and DA neurotransmitters in the brain of model group were recovered, regulate the dynamic balance of acetylcholine and dopamine in the brain.​

https://sci-hub.st/10.1016/j.neulet.2008.05.116

...The protective effect may be caused by increasing the levels of DA and 5-HT in the striatum, increasing the counts of dopaminergic neurons, inhibiting oxidative stress and the astroglia response. These results suggest that baicalein possesses potent neuroprotective activity and may be a potential anti-Parkinson’s disease drug that is worthy of further study.

MPTP caused a partial lesion of the substantia nigra and a significant reduction in striatal dopamine levels. Our results suggested that baicalein could attenuate the decrease in the levels of DA and 5-HT in the striatum of MPTP-lesioned mice. Moreover, the present data suggested that baicalein may alter MAO activity in our experimental paradigm since the DOPAC/DA and HIAA/5-HT were changed by baicalein. MAO, a key enzyme in catecholamine metabolism, catalyzes the oxidative deamination of biogenic amines, such as DA, 5-HT, and norepinephrine [24]. The regulation of MAO activity is important for the treatment of Parkinson’s disease. These results suggested that baicalein could partly inhibit the activity of MAO, but this required further study. By using tyrosine hydroxylase immunohistochemistry, we were able to demonstrate that baicalein reduced the MPTP-induced loss of dopaminergic neurons in the mice substantia nigra. Moreover, dopaminergic neurons not only appeared to have more cellular counts but also have more developed and longer processes in baicalein pretreated mice. These results suggest that baicalein could protect dopamine neurons against MPTP-induced toxicity.

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6-Gingerol, a Major Constituent of Zingiber officinale Rhizoma, Exerts Anticonvulsant Activity in the Pentylenetetrazole-Induced Seizure Model in Larval Zebrafish

Abstract:
Zingiber officinale is one of the most frequently used medicinal herbs in Asia. Using rodent seizure models, it was previously shown that Zingiber officinale hydroethanolic extract exerts antiseizure activity, but the active constituents responsible for this effect have not been determined. In this paper, we demonstrated that Zingiber officinale methanolic extract exerts anticonvulsant activity in the pentylenetetrazole (PTZ)-induced hyperlocomotion assay in larval zebrafish. Next, we isolated 6-gingerol (6-GIN)—a major constituent of Zingiber officinale rhizoma. We observed that 6-GIN exerted potent dose-dependent anticonvulsant activity in the PTZ-induced hyperlocomotion seizure assay in zebrafish, which was confirmed electroencephalographically. To obtain further insight into the molecular mechanisms of 6-GIN antiseizure activity, we assessed the concentration of two neurotransmitters in zebrafish, i.e., inhibitory γ-aminobutyric acid (GABA) and excitatory glutamic acid (GLU), and their ratio after exposure to acute PTZ dose. Here, 6-GIN decreased GLU level and reduced the GLU/GABA ratio in PTZ-treated fish compared with only PTZ-bathed fish. This activity was associated with the decrease in grin2b, but not gabra1a, grin1a, gria1a, gria2a, and gria3b expression in PTZ-treated fish. Molecular docking to the human NR2B-containing N-methylD-aspartate (NMDA) receptor suggests that 6-GIN might act as an inhibitor and interact with the amino terminal domain, the glutamate-binding site, as well as within the ion channel of the NR2Bcontaining NMDA receptor. In summary, our study reveals, for the first time, the anticonvulsant activity of 6-GIN. We suggest that this effect might at least be partially mediated by restoring the balance between GABA and GLU in the epileptic brain; however, more studies are needed to prove our hypothesis

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Chinese Herbal Medicine for Treating Epilepsy

Ziziphus jujuba ​

Ziziphus jujuba is usually used to treat insomnia in traditional Chinese medicine. A study designed with the MES model and the PTZ model of rats indicated that Z. jujuba achieves anticonvulsant effects by increasing acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity and the latency of myoclonic jerks, thereby preventing seizure attacks (Pahuja et al., 2011). The additional usage of hydroalcoholic extract of Z. jujuba can enhance the anticonvulsant effects of phenytoin and phenobarbitone but not carbamazepine that is evaluated in MES-induced seizure rats (Pahuja et al., 2012).

Pinellia ternata ​

Pinellia ternata is mostly used to treat ailments of the respiratory and gastrointestinal systems. A component of P. ternate, pinellia total alkaloids, is involved in the modulation of GABAergic systems through its increase of GABA and GAD65 expression, reduction of GABA transporter-1 (GAT-1) and GABA transaminase (GABA-T) expression, and upregulation of GABAA receptor α5, δ, α4, and γ2 subunits in the hippocampal formation. Research in 2020 indicated that pinellia total alkaloids (PTA) may exert antiepileptogenic effects that reduce the occurrence of spontaneous recurrent seizures in pilocarpine-induced epileptic rats, and PTA 800 mg/kg group has the lowest frequencies of spontaneous recurrent seizures compared to PTA 400 mg/kg group and Topiramate 60 mg/kg group (Deng et al., 2020).

 

[PeskyPeater]

[edit]

Obligatory roles of dopamine D1 receptors in the dentate gyrus in antidepressant actions of a selective serotonin reuptake inhibitor, fluoxetine

Abstract​

Depression is a leading cause of disability. Current pharmacological treatment of depression is insufficient, and development of improved treatments especially for treatment-resistant depression is desired. Understanding the neurobiology of antidepressant actions may lead to development of improved therapeutic approaches. Here, we demonstrate that dopamine D1 receptors in the dentate gyrus act as a pivotal mediator of antidepressant actions in mice. Chronic administration of a selective serotonin reuptake inhibitor (SSRI), fluoxetine, increases D1 receptor expression in mature granule cells in the dentate gyrus. The increased D1 receptor signaling, in turn, contributes to the actions of chronic fluoxetine treatment, such as suppression of acute stress-evoked serotonin release, stimulation of adult neurogenesis and behavioral improvement. Importantly, under severely stressed conditions, chronic administration of a D1 receptor agonist in conjunction with fluoxetine restores the efficacy of fluoxetine actions on D1 receptor expression and behavioral responses. Thus, our results suggest that stimulation of D1 receptors in the dentate gyrus is a potential adjunctive approach to improve therapeutic efficacy of SSRI antidepressants.

​

Potential Antidepressant Effects of Scutellaria baicalensis, Hericium erinaceus and Rhodiola rosea​

S. baicalensis primarily targets alterations of the DA system, which are implicated in various neurological and mental disorders, and also in their comorbidity [92].
Immediately after intravenous administration, total flavonoids from Scutellariae radix are able to cross the BBB, with the striatum and hippocampus being the most prominent targets [88].
Remarkably, baicalin distributes most specifically to the DA system and it induces an increase in DA levels in the rat striatum, hippocampus and cortex [88,89,93].
Accordingly, recent studies suggest that baicalin and baicalein may induce beneficial effects in DA-related brain disorders by increasing DA levels in the brain besides protecting dopaminergic neurons from mitochondrial- and oxidative-related toxicity [6,7,94].
In fact, baicalein fully prevents 6-OHDA- and MPTP-induced behavioral alterations by preventing reductions of striatal DA levels, the increase in DOPAC/DA and HVA/DA ratios and the loss of striatal tyrosine hydroxylase (TH) [6,7].
Similarly, baicalin prevents methamphetamine (METH)-induced alterations, namely the loss of DA and DA transporter (DAT) in the striatum, which play an important role in the pathogenesis of mental disorders [94].
Baicalin also ameliorates synaptogenesis and memory-related dysfunctions which are associated with GABAA receptor downregulation following abnormal stimulation of DA D1 receptors (D1Rs) [95].
In detail, baicalin prevents the reduction of GABAA-induced currents which occurs following the in vivo administration of exogenous DA and abnormal stimulation of D1Rs [95].
Mechanistically, baicalin fosters the interaction of GABAAR with tyrosine kinase receptor B (TrkB) and AKT thus reversing the DA-induced decrease in the expression of GABAAR/TrkB/AKT pathway. Thus, baicalin plays a key role in modulating the GABAergic system. This is supported by the emerging role of baicalin as a potential anxiolytic by acting as a partial, subtype-selective GABAA receptor ligand [9].
These findings are in line with increasing evidence centered on the neuroprotective and nootropic action of Scutellariae radix extracts in substance-induced addiction, attention deficit hyperactivity disorders, depression and anxiety [93,95,96].

 

[PeskyPeater]

Now addressing the sexual anhedonia issue from chronic SSRI administration with the focus on oxytocin [OXT] and the role of GABA - glutamate and the neurosteroids, which is not yet completely understood, but let's see what clues are to be found to help put things into perspective...

As we know:

...fluoxetine increases extracellular serotonin levels; however, at the same time, by reducing SNARE complex function, this antidepressant reduces glutamate and GABA release.

- The following excerpts are taken from:

THE OXYTOCIN RECEPTOR: FROM INTRACELLULAR SIGNALING TO BEHAVIOR
Benjamin Jurek and Inga D. Neumann
Department of Behavioural and Molecular Neurobiology, Institute of Zoology, University of Regensburg, Regensburg, Germany

... SNARE proteins seem to be generally required for dendritic neuropeptide release, the detailed contribution of various proteins to the molecular machinery essential for somato-dendritic OXT release within the hypothalamus and from neurohypophysial terminals may substantially differ. ...

In both males and females, mating and sexual stimulation have been linked to an increased OXT system activity, as reflected by increased OXT secretion into blood in various mammalian species ..
Also, increased plasma OXT concentrations have been found in sexually aroused men and women during sexual self-stimulation, with peak OXT concentrations found during ejaculation and orgasm, respectively ...
Plasma Oxytocin Increases in the Human Sexual Response*
Changes In Oxytocin and Vasopressin Secretion During Sexual Activity in Men

- Axon terminal release of OXT

After axonal transport to neurohypophysial terminals and local storage, the release of OXT follows general mechanisms of neuronal exocytosis [Exocytosis is a form of bulk transport] ... Magnocellular terminals build close anatomical contacts with these capillaries, so-called neuro-hemal contacts, which lack a blood-brain barrier and thus are characterized by fenestrated contacts between capillary endothelial cells (427). As for all other neuroendocrine systems, such as AVP or CRF and other hypothalamicreleasing hormones into the portal blood circulation of the eminentia mediana, this allows diffusion of OXT into the circulation.

For terminal Exocytosis of neuropeptidergic (as well as other) vesicles, the interaction of multiple vesicle- and membrane-associated proteins is essential in forming a complex known as the
soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complex.
The SNARE complex largely consists of the vesicle-associated membrane protein 2 (VAMP-2), syntaxin-1, and soluble N-ethylmaleimide attachment protein-25 (SNAP-25), and a number of regulatory proteins such as synaptotagmins, munc-18, and Ca2-dependent activator protein for secretion (CAPS-1), which are described in detail elsewhere ...
This entire exocytosis machinery has also been identified in neuropeptidergic terminals of the posterior pituitary


- Intracerebral OXT release in a nonsynaptic fashion

Despite the presence of oxytocinergic axons in various brain regions (see FIGURE 6 and sect. IVB), evidence for presynaptic release, as shown in the neurohypophysis, is still missing. Therefore, intracerebral release of OXT was hypothesized to occur non-synaptically, from either axons or axon collaterals of magnocellular PVN (and SON) neurons projecting to forebrain and other limbic regions, as well as from dendrites and somata within the hypothalamic PVN and SON. As such, OXT may rather act as a neuromodulator than as a classical neurotransmitter on nearby and also distant neuronal structures ...

This view is supported by the spatial distribution of large dense-core vesicles containing OXT, which are not located in the active zones of pre-synapses in the few OXT synapses found in the SON (1002) and ventromedial hypothalamic nucleus (394). Moreover, OXTR could not be attributed to postsynaptic membranes so far. Furthermore, the onset of electrophysiological responses to OXT is delayed, thereby exceeding the time typically needed for synaptic transmission (1–10 ms) and ranging within seconds in the central amygdala (544, 545) or other brain regions. A similar second-range delay of cellular responses was recently demonstrated after evoked somato-dendritic release of AVP from magnocellular PVN neurons, pointing toward a similar non-synaptic, diffusion-like neuropeptide action that allows for inter-populational cross talk within ~100- m distance (967).
However, this view is challenged by the finding that the OXT agonist TGOT depolarized small hilar interneurons in hippocampal slices and facilitated subsequent GABA release not only onto pyramidal cells but also onto mossy cells of the granular layer of the dentate gyrus...

The non-synaptic mode of release should be further confirmed by time-lapse imaging, implementing recently developed techniques for monitoring, docking, and release of large dense-cored vesicles (1042). These techniques should also allow dissection of the role of glutamate- or GABAcontaining synaptic vesicles in OXT neurons (458), which remain enigmatic since fast synaptic transmission from axons of magnocellular OXT neurons either in the hypothalamus or extrahypothalamic places could not be shown so far ...

The overall OXTR expression level in the PVN of mice, humans, or common marmosets is relatively low (499, 635, 920) and is only detectable by highly sensitive methods, such as single cell RT-PCR (220), or by prior upregulation of the expression using an OXTR antagonist (357). Although expression levels of the Oxtr gene in the brain are modulated by sex steroids (65, 1120; and sect. V), OXTR expression in the hypothalamic PVN is similar between males and virgin females (702), and seems to be stable over the estrous cycle and during early to mid-pregnancy (days 13–15) (1120). However, an increase of Oxtr mRNA in the rat PVN at mid-gestation (day 15) and late gestation (day 20) has been detected (65). Interestingly, OXTR-expressing neuronal populations within the hypothalamic PVN are not uniform, but are comprised of neurons with separate electrophysiological and transcriptional characteristics, causing differential responses to OXT (220, 221, 1067). For example, the majority of oxytocinergic and vasopressinergic magnocellular neurons in the PVN do not express the OXTR, but the small population that do express the OXTR divide into 40% corticotropin releasing factor (CRF)-positive and 60% CRF-negative neurons (221). In contrast, OXTR-positive parvocellular neurons are exclusively of the non-CRF type. In addition, OXTR-expressing neurons in the PVN are exclusively glutamatergic, whereas OXTR neurons in the BNST are GABAergic, as indicated by GAD67 (for GABA) or VGLUT2 (for glutamate) expression, respectively (221).
-------

Neurosteroids

... studies revealed that the key elements in the gene promoters that regulate their cell-type-specific expression in magnocellular neurons of the SON are located in the 5=-flanking regions of both promoters. In the case of the Oxt gene, the regulatory DNA sequence appeared to reside in the 216 to 100 bp upstream of the transcription start site (335), where a celltype-specific activator of transcription may operate. Evidence for specific suppressors of AVP expression in OXT cells (or vice versa) could not be identified so far (334). In this 5=-flanking region in the Oxt promoter, functional estrogen/retinoic acid receptor-like transcription factor binding sites have been localized, which were described as the composite hormone response element (8). This element has the capacity to bind various classical and orphan nuclear hormone receptors (132), such as estrogen receptor β (ER β) (868, 947). Some of these nuclear hormone receptors are also present in magnocellular neurons (463), where they may activate or inhibit OXT promoter gene expression (187, 868). Sharma and co-workers found that the ER β is activated by the dihydrotestosterone metabolite 5-androstane-3β,17β-diol, leading not only to ER β occupancy of the estrogen responsive element of the OXT promoter but also to increased binding of the transcription factor CREB and to acetylation of histone H4. These three components form a functional complex that drives OXT expression by activated transcription factors and loose chromatin structure (929) (FIGURE 5).

- Note: 5-androstane-3β,17β-diol is metabolite of DHEA and DHT

3. Progesterone
In general, there is limited evidence for a role of progesterone in the regulation of Oxtr expression. Progesterone, which is mainly synthesized in the corpus luteum, adrenals, brain, and, during pregnancy, placenta, helps to maintain uterine quiescence during pregnancy and is, therefore, in clinical use to prevent preterm birth. Progesterone exists in two major isoforms, progesterone A and progesterone B, with the latter being the long form of progesterone, whereas progesterone A is truncated and mainly acts as transactivation repressor of progesterone B (533). In human myometrium samples, the progesterone A-to-progesterone B ratio correlates with the level of OXTR mRNA, indicating a transcriptional regulation of OXTR by progesterone B. On a behavioral level, progesterone induces female mating behavior within a time frame of 30 min via the expression of Oxtr in the posterior ventromedial hypothalamus (922).

- In other words, in theory we could use DHEA with progesterone to restore SSRI induced altered expressions of the oxytocin complex and the sensitivity of sexual function.

 

[PeskyPeater]

Testosterone metabolite 3β-diol (5-androstane-3β,17β-diol) is indirectly a neuronal seratonin antagonist via oxytocin. Also able to reduce an overactive HPA-axis in the stressed brain reducing anxiety and depression.. 3β-diol can upregulate / modulate the expression of the oxytocin complex via estrogen Beta, improving structure and energy.

Switching brain serotonin with oxytocin

Discussion​

These findings show that OXT modulates the serotoninergic system. If the interaction between these neuromodulators has been shown in the past by animal research, to our knowledge, this is the first study to reveal similar effects in the human brain. The finding that OXT regulates 5-HT1A network suggests that OXT interferes with 5-HT neurotransmission. In accordance with occupancy models, an increase of MPPF Binding Potential means that more space is available for the antagonist to bind at the 5-HT1A receptor, and this in turn reflects depletion of 5-HT in the extracellular space (18). We show that OXT exerts an action at the very root of the 5-HT system, as demonstrated by the increase of MPPF Binding Potential in the DRN, the main locus of 5-HT synthesis (20). In line with this, increased 5-HT concentration induced by the 5-HT reuptake inhibitor fluoxetine reduces MPPF Binding Potential in the DRN (27). Consequently, the increase of MPPF Binding Potential observed here could be interpreted as an inhibitory effect of OXT on 5-HT activity. Along the same line, rats treated with a 5-HT agonist (5-methoxytryptamine), which causes hyperserotonemia, exhibit a decrease of OXT in the paraventricular nucleus of the hypothalamus and a form of “autistic-like” behavior (28), suggesting the existence of mutual interactions between the 5-HT and OXT systems.

... In view of these findings, we propose that OXT is linked to 5-HT by a reciprocal and coordinated functional relation similar to the links previously evoked between OXT and cortisol (47) or OXT and estrogen (48). This may be of relevance to psychiatric research. Indeed, the therapeutic potential of OXT has been demonstrated in autism (49), social anxiety disorders, impulse aggressivity, and depression (1, 4). Interestingly, decrease of 5-HT1A receptor Binding Potential is a core biomarker of these pathologic conditions (3, 22). Therefore, OXT effect on the serotoninergic system expressed as an increase of 5-HT1A receptors Binding Potential might be crucial for predicting adaptive responses to social environments. Given the two neuromodulators’ implication in emotion-based behavior and psychiatric disorders, OXT and 5-HT systems should probably be considered jointly as targets of future therapeutic interventions.
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Oxytocin and Estrogen Receptor β in the Brain: An Overview​

Regulation of Oxytocin Function by Steroid Hormones​

...
Understanding oxytocin [OT] regulation by sex steroids is important since anxiety and depressive disorders show a larger gender disparity (38), which may be related to circulating steroid hormone levels. Testosterone has been shown to decrease HPA axis activity (59, 60), whereas estrogens can both increase (60, 61) or decrease (62, 63) HPA axis activity, and these alterations may in part be through modulations of OT activity. The differences in the observed effects of estrogens on behavior and neuroendocrine responses to stress may relate to its differential activity on ERα and ERβ. Activation of ERα can increase HPA axis activity, whereas activation of ERβ has the opposite effect (61, 64). Although ERα-mediated activity modulates OTR transcription, ERβ-mediated activity has been found to alter Ot mRNA levels (65, 66). Moreover, androgen modulation of OT appears to be mediated in part by the testosterone metabolite 3β-diol, which activates ERβ to allow binding to the Ot promoter to increases Ot mRNA (67).

Estrogen Receptor β and Oxytocin Interactions in Regulation HPA Axis and Anxiety-Related Behaviors​

...
Recent studies have begun to investigate the complex interaction between ERβ and the Ot promoter. Using a mouse hypothalamic cell line expressing ERβ and OT, Sharma et al. (74) demonstrated Ot promoter occupancy by ERβ. The Ot promoter has a composite hormone response element, which allows for steroid receptor binding and Ot gene transcription regulation by ERs and other members of the nuclear receptor family but not the other steroid hormone receptors (75). Treatment of a neuronal cell line with the ERβ agonists, 3β-diol, DPN, or estradiol, elicited increases in Ot mRNA levels and Ot promoter occupancy (67, 74). In tandem with ERβ occupancy of the Ot promoter, cAMP response element-binding protein (CBP) and steroid receptor coactivator (SRC)-1 were found to occupy the Ot promoter, leading to increased acetylation of histone H4 in the presence of 3β-diol. Taken together, the data suggest that in the presence of 3β-diol, ERβ binds the Ot promoter and recruits ligand-dependent coactivator SRC-1, which binds CBP, and forms a functional complex that acetylates histone H4 to drive Ot gene expression (74). The role of ERβ related to OT signaling at the molecular level and its larger role in OT signaling throughout the brain are summarized in Figure 1. Further studies are needed to determine the extent of the binding of ERβ to the Ot promoter, the co-activators recruited, and how this interaction modulates HPA axis function in vivo.

 

[HealthisWealth]

will study this to help someone.

 

[PeskyPeater]

...treatment of primary neurons with FLX [fluoxetine] significantly upregulated the level of α-synuclein, a protein which is highly implicated in several neurodegenerative disorders, including Parkinson’s disease.

Anti-aggregation and fibril-destabilizing effects of sex hormones on α-synuclein fibrils in vitro

Abstract
The α-synuclein aggregation in the brain is the hallmark of Lewy body diseases, including Parkinson's disease and dementia with Lewy bodies, and multiple system atrophy. Some epidemiological studies have revealed that estrogen therapy reduces the risk of Parkinson's disease in females. We examined the effects of estriol, estradiol, estrone, androstenedione, and testosterone on the formation and destabilization of α-synuclein fibrils at pH 7.5 and 37 °C in vitro, using fluorescence spectroscopy with thioflavin S and electron microscopy. These sex hormones, especially estriol, significantly exert anti-aggregation and fibril-destabilizing effects; and hence, could be valuable preventive and therapeutic agents for α-synucleinopathies.

...We recently showed that antioxidant compounds, including nordihydroguaiaretic acid (NDGA), and antiparkinsonian agents, nicotine and non-steroidal anti-inflammatory drugs (NSAIDs) inhibited the formation of αS fibrils (fαS) in a dose dependent manner and destabilized preformed fαS ...


Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro - PubMed

Abstract
The aggregation of alpha-synuclein (alphaS) in the brain has been implicated as a critical step in the development of Lewy body diseases (LBD) [Parkinson's disease (PD)/dementia with Lewy bodies (DLB)] and multiple system atrophy (MSA). The involvement of neuroinflammation and microglial activation has been emphasized in the pathogenesis of PD. Recent epidemiological studies have revealed that therapeutic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing PD. Here, we examined the effects of NSAIDs, such as ibuprofen, aspirin, acetaminophen, meclofenamic acid sodium salt, sulindac sulfide, ketoprofen, flurbiprofen, diclofenac sodium salt, naproxen, and indomethacin, on the formation and destabilization of alphaS fibrils (falphaS) at pH 7.5 and 37 degrees C in vitro, using fluorescence spectroscopy with thioflavin S and electron microscopy. All examined NSAIDs, except for naproxen and indomethacin, inhibited the formation of falphaS in a dose-dependent manner. Moreover, these molecules dose-dependently destabilized preformed falphaS. The overall activity was in the order: ibuprofen approximately aspirin approximately acetaminophen approximately meclofenamic acid sodium salt approximately sulindac sulfide>ketoprofen approximately flurbiprofen approximately diclofenac sodium salt>naproxen approximately indomethacin. These findings indicate that NSAIDs could be key molecules for the development of therapeutic or preventive agents for LBD and MSA.

 

[PeskyPeater]

Alterations in the sensitivity of 5(th) receptor subtypes following chronic asvagandha treatment in rats​

Abstract
Asvagandha (Withania somnifera) is an important antistress drug has now been sown to have an antidepressant action in clinically depressive patients, However, the mechanism of its antidepressant action has not been studied. Normal rats fed with asvagandha root extract (100mg/kg orally) for 4 and 8 weeks showed enhanced open field behavior and emotional stability along with a moderate but significant enhancement in the functional sensitivity of 5 HT2 receptors in the brain and a reciprocal subsensitivity of the 5HT1A receptors chronic asvagandha treatment (propylactically) was effective in preventing the behavioral deficit in open field activity in an animal model of depression. This was accompanied by an adaptive supersensitivity of the postsynaptic 5HT2 receptors in the brain. The effect of chronic Asvagandha on 5HT receptor subtypes is similar to the action of chronic ECT treatment and several antidepressant drugs.

 

[PeskyPeater]

Somehow I did not get erectile dysfunction when using SSRI for a couple of years. Was I just lucky or did I do something that had any influence?
Before I was on fluoxetine I remember having used aswagandha with curcumin, I thought this was good for serotonin and mood. They have antidepressant effects and work on the serotonin complex, don't seem to do anything specific for penile function, although they can improve hormones somewhat. curcumin effect on hormones

Another combination that's more interesting that I used was:
Horny Goat Weed with Acetyl-L Carnitine with the intention of strengthening my pelvic nerves and penile function.

Acetyl-L-carnitine plus propionyl-L-carnitine improve efficacy of sildenafil in treatment of erectile dysfunction after bilateral nerve-sparing radical retropubic prostatectomy​

Horny goat weed or Epimedium is actually an important part of TCM treatments of ED.
Let's see what's it all about:

In short:
Horny Goat Weed Research Breakdown

Secondary to PDE5 inhibition, Icariin appears to be a potent pro-erectile agent. It is clearly outperformed by Viagra

Icariin may also promote Nitric Oxide signalling via increasing expression of NOS enzymes, which may work synergistically with the PDE5 inhibition

Beneficial effects on neurons may extend to the pelvis

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The Stimulative Effect of Yangjing Capsule on Testosterone Synthesis through Nur77 Pathway in Leydig Cells​

Abstract​

Yangjing Capsule (YC), an innovative Chinese medicine based on traditional prescription, promotes testosterone synthesis by upregulating the expression of steroidogenic enzymes. Nur77 as a nuclear receptor is known to regulate the expression of many steroid synthetases. This study aimed to explore the potential mechanisms by which YC regulates testosterone synthesis in Leydig cells. Real-time PCR and Western blot analysis were employed to assess the expressions of steroidogenic enzymes and Nur77 after treating MLTC-1 cells with YC. The luciferase reporter gene assay was performed to detect the activity of Nur77 gene promoter. Also, the expressions of steroid synthases were detected after Nur77 gene was knocked down. YC significantly stimulated Nur77 production and upregulated StAR and HSD3B expression, and this agrees with the activity of Nur77 gene promoter that was significantly enhanced by YC. Interestingly, knockdown of Nur77 blocked the above YC’s effects and consequently inhibited testosterone synthesis in MLTC-1 cells. YC promotes StAR and HSD3B expression and upregulates testosterone synthesis in Leydig cells, which is mediated by Nur77 pathway.

YC is composed of Herba Epimedii Brevicornus, Radix Rehmanniae Preparata, Rhizoma Polygonati Sibirici, Placenta Hominis, Angelica Sinensis, and other components. It has been shown that YC promotes testosterone synthesis via steroidogenic enzymes (CYP11A1 and HSD3B) and StAR and can be used for the treatment of male infertility and sexual dysfunction [14, 15]. However, the molecular mechanisms by which YC affects the expression of steroidogenic enzymes and promotes testosterone synthesis remain unclear.

In the present study, we demonstrated that YC promotes testicular steroidogenesis, at least in part, by upregulating the orphan nuclear receptor Nur77. These findings provide a molecular mechanism for YC-mediated induction of testosterone production in testicular Leydig cells.

2.2. Preparation of YC and Cells​

YC was prepared as previously described [15]. *

*-let's see what the constituents are exactly and analyze it:

Effects of the Yangjing Capsule Extract on Steroidogenesis and Apoptosis in Mouse Leydig Cells​

2.2. The Yangjing Capsule Extract

The Yangjing capsule is composed of 11 traditional Chinese drugs: 13.3% Herba Epimedii Brevicornus, 6.7% Rhizoma Polygonati Sibirici, 6.7% Radix Rehmanniae preparata, 10% Radix Astragali Mongolici, 6.7% Placenta Hominis, 6.7% Semen Astragali Complanati, 10% Radix Angelicae Sinensis, 6.7% Hirudo, 6.7% Semen Litchi, 13.3% Semen Vaccariae Segetalis, and 13.3% Concha Ostreae (calcined).

Radix Astragali Mongolici / Astragalus , it has similar effects as Radix Rehmanniae preparata and also Panax Notoginseng in that they increase angiogenisis or the growth of bloodvessels.

The combination of these two herbs in a 2:1 ratio of Astagalus:Rehmanniae appears to be effective in producing angiogenesis in vivo and aids in wound healing - source

....and
Panax notoginseng saponins promote endothelial progenitor cell angiogenesis via the Wnt/β-catenin pathway

Background​

Distraction osteogenesis (DO) is an effective treatment in craniomaxillofacial surgery. However, the issue of sufficient blood supply at the regeneration tissue has limited its wide application. Panax notoginseng saponins (PNS) is a Traditional Chinese Medicine that is commonly used to treat a range of angiogenic diseases. However, the mechanisms whereby PNS alters angiogenesis in endothelial progenitor cells (EPCs) have yet to be clarified.

Methods​

EPCs were identified by immunofluorescence, confirmed by their uptake of fluorescently labeled Dil-ac-LDL and FITC-UEA-1. EPCs were treated with different concentrations of PNS, and the effects of PNS on cell proliferation were measured on the optimal concentration of PNS determined. The effects of PNS on angiogenesis and migration, angiogenic cytokines mRNA expression and the proteins of the Wnt pathway were investigated. Then knocked down β-catenin in EPCs and treated with the optimum concentrational PNS, their angiogenic potential was evaluated in tube formation and migration assays. In addition, the expression of cytokines associated with angiogenesis and Wnt/β-catenin was then assessed via WB and RT-qPCR.

Results​

We were able to determine the optimal concentration of PNS in the promotion of cell proliferation, tube formation, and migration to be 6.25 mg/L. PNS treatment increased the mRNA levels of VEGF, bFGF, VE-Cadherin, WNT3a, LRP5, β-catenin, and TCF4. After knocked down β-catenin expression, we found that PNS could sufficient to partially reverse the suppression of EPC angiogenesis.

Conclusions​

Overall, 6.25 mg/L PNS can promote EPC angiogenesis via Wnt/β-catenin signaling pathway activation.

Wnt/β-catenin pathway is also important in inflammation involving the NF-kB pathway and network together or are somewhat interchangeable:

Crosstalk between Wnt/β-Catenin and NF-κB Signaling Pathway during Inflammation​

Besides its important role in embryonic development and homeostatic self-renewal in adult tissues, Wnt/β-catenin signaling exerts both anti-inflammatory and proinflammatory functions. This is, at least partially, due to either repressing or enhancing the NF-κB pathway. Similarly, the NF-κB pathway either positively or negatively regulates Wnt/β-catenin signaling. Different components of the two pathways are involved in this crosstalk, forming a complex regulatory network. This review summarizes our current understanding of the molecular mechanisms underlying the cross-regulation between the two pathways and discusses their involvement in inflammation and inflammation-associated diseases such as cancer.

In this review, we summarize the current evidence for both positive and negative regulation of NF-κB-mediated inflammation by Wnt/β-catenin signaling and elaborate on the underlying molecular mechanisms. We also describe the reciprocal regulation of Wnt/β-catenin signaling by the NF-κB pathway and novel models for the cooperation of these two pathways in regulating gene transcription. The major components involved in the cross-regulation are discussed. We sought to describe the complexity of the crosstalk between Wnt/β-catenin and NF-κB signaling to link it with the biological importance for inflammation and cancer, and to discuss its potential impact on the development of new therapeutic options.

Anti- and Proinflammatory Roles of Wnt/β-Catenin Signaling​

Given both repressing and stimulating effects of Wnt/β-catenin signaling on NF-κB activity, it is not surprising that Wnt/β-catenin possesses both anti- and proinflammatory functions at the organismal level. The exact outcome might thus be context-dependent and/or a question of the balance between two contrary functions. So far, most evidence supports that Wnt/β-catenin signaling downregulates production of proinflammatory cytokines, including IL-1β, IL-6, IL-8, and TNF-α, in different cell types and stimulated with various stimuli, such as LPS, cytokines, viruses, and bacteria, regardless of the responsible mechanisms for Wnt/β-catenin-mediated repression of NF-κB activity (31–35, 37, 38).

An anti-inflammatory role of Wnt/β-catenin pathway in vivo has been demonstrated in mice (40, 41). In a mouse model of warm liver ischemia and reperfusion injury (IRI), disruption of β-catenin signaling increased hepatocellular damage and enhanced hepatic DC maturation/function and PTEN/TLR4 local inflammation (40). The protective effect of β-catenin was, at least partly, due to induction of PI3K/Akt signaling and a reduced TLR4-driven inflammatory response in DCs. In agreement with this study, another study also points out an anti-inflammatory role of β-catenin by demonstrating that depletion of β-catenin in DCs leads to enhanced inflammatory responses and disease onset in a mouse model of inflammatory bowel disease (41). In addition, GSK-3 inhibition potently suppressed inflammatory responses in mice challenged with LPS (65). However, a cross-regulation between NF-κB and β-catenin in these specific studies has yet to be proven.

Conversely, a proinflammatory role of Wnt/β-catenin pathway in vivo has been observed in hepatocellular carcinoma in Apc KO mice (51). Oncogenic β-catenin signaling induced an inflammatory program in hepatocytes that involved a direct transcriptional control by β-catenin and activation of the NF-κB pathway. A subset of chemokines was induced by β-catenin activation while none of the canonical proinflammatory cytokines was influenced, implying that oncogenic β-catenin signaling may promote tumor-associated inflammation indirectly through shaping the cellular compositions in the microenvironment. Another study also reported a positive effect of β-catenin in LPS-induced proinflammatory cytokine production in human bronchial epithelial cells (58).

In conclusion, both anti-inflammatory and proinflammatory functions of Wnt/β-catenin pathway were observed, depending on the conditions and regulated through different mechanisms. Wnt/β-catenin also differentially affects NF-κB-mediated subsets of target genes and biological functions (e.g., inflammation, cell proliferation, and apoptosis) in response to different stimuli. It will be crucial to disentangle the precise role of Wnt/β-catenin signaling in inflammation in a cell/tissue- and physiology/pathology-specific context.

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