Creatine, Similar To Ketamine, Counteracts Depressive-Like Behavior Induced By Corticosterone Via PI

[paymanz]

Creatine, Similar to Ketamine, Counteracts Depressive-Like Behavior Induced by Corticosterone via PI3K/Akt/mTOR Pathway. - PubMed - NCBI

Ketamine has emerged as a novel strategy to treat refractory depression, producing rapid remission, but elicits some side effects that limit its use. In an attempt to investigate a safer compound that may afford an antidepressant effect similar to ketamine, this study examined the effects of the ergogenic compound creatine in a model of depression, and the involvement of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in its effect. In order to induce a depressive-like behavior, mice were administered with corticosterone (20 mg/kg, per os (p.o.)) for 21 days. This treatment increased immobility time in the tail suspension test (TST), an effect abolished by a single administration of creatine (10 mg/kg, p.o.) or ketamine (1 mg/kg, i.p.), but not by fluoxetine (10 mg/kg, p.o., conventional antidepressant). Treatment of mice with wortmannin (PI3K inhibitor, 0.1 μg/site, intracerebroventricular (i.c.v.)) or rapamycin (mTOR inhibitor, 0.2 nmol/site, i.c.v.) abolished the anti-immobility effect of creatine and ketamine. None of the treatments affected locomotor activity of mice. The immunocontents of p-mTOR, p-p70S6 kinase (p70S6K), and postsynaptic density-95 protein (PSD95) were increased by creatine and ketamine in corticosterone or vehicle-treated mice. Moreover, corticosterone-treated mice presented a decreased hippocampal brain-derived neurotrophic factor (BDNF) level, an effect abolished by creatine or ketamine. Altogether, the results indicate that creatine shares with ketamine the ability to acutely reverse the corticosterone-induced depressive-like behavior by a mechanism dependent on PI3K/AKT/mTOR pathway, and modulation of the synaptic protein PSD95 as well as BDNF in the hippocampus, indicating the relevance of targeting these proteins for the management of depressive disorders. Moreover, we suggest that creatine should be further investigated as a possible fast-acting antidepressant.

 

[Terma]

I saw this in the SImilar Threads while lurking and went through the painful login problem just to bump this.

This is a really cool study. In my guessing, Akt/mTor pathway must be really important in depression.

So here you have glucocorticoids essentially causing depression, and the mTor promoters relieving it.

This is one of the same pathways through which Tianeptine works, as well as opioids acutely, and Tia is one of the most fast-acting 'nootropics' available.

That said it's a very low-level pathway so it doesn't tell the whole story.

 

[paymanz]

I saw this in the SImilar Threads while lurking and went through the painful login problem just to bump this.

This is a really cool study. In my guessing, Akt/mTor pathway must be really important in depression.

So here you have glucocorticoids essentially causing depression, and the mTor promoters relieving it.

This is one of the same pathways through which Tianeptine works, as well as opioids acutely, and Tia is one of the most fast-acting 'nootropics' available.

That said it's a very low-level pathway so it doesn't tell the whole story.

Rho kinase inhibition is interesting too
The ROCK inhibitor Fasudil prevents chronic restraint stress-induced depressive-like behaviors and dendritic spine loss in rat hippocampus — University Andrés Bello

Statins May Exert Beneficial Effects Through A Pathway Other Than It's Cholesterol Lowering Action

 

[Terma]

ROCK is downstream from mTorC1, meanwhile BDNF is thought to modulate both mTorC1 and mTorC2.

I'd postulate a possible cause is an imbalance between mTorC1 and mTorC2 activation, the proportion needed (to correct the issue) may be situationally-, cell type- and even cell phase-specific.

(Edit: That will probably seem confusing or outright wrong depending on what you read; but ROCK <-> mTorC1 influence is bidirectional; many mTor pathway elements affect each other circularly through feedback inhibition and other)

 

[Terma]

In other words I have a nagging suspicion the answer is time-dependent, or basically, significantly lies in fixing cellular circadian rhythms.

I would have to spend days re-linking the studies I read and finding new ones, but here's a known starting point:

Ketamine Influences CLOCK:BMAL1 Function Leading to Altered Circadian Gene Expression

Major mood disorders have been linked to abnormalities in circadian rhythms, leading to disturbances in sleep, mood, temperature, and hormonal levels. We provide evidence that ketamine, a drug with rapid antidepressant effects, influences the function of the circadian molecular machinery. Ketamine modulates CLOCK:BMAL1-mediated transcriptional activation when these regulators are ectopically expressed in NG108-15 neuronal cells. Inhibition occurs in a dose-dependent manner and is attenuated after treatment with the GSK3β antagonist SB21673. We analyzed the effect of ketamine on circadian gene expression and observed a dose-dependent reduction in the amplitude of circadian transcription of the Bmal1, Per2, and Cry1 genes. Finally, chromatin-immunoprecipitation analyses revealed that ketamine altered the recruitment of the CLOCK:BMAL1 complex on circadian promoters in a time-dependent manner. Our results reveal a yet unsuspected molecular mode of action of ketamine and thereby may suggest possible pharmacological antidepressant strategies.

(shoulda posted all that in one post, can't keep this up)

 

[LeeLemonoil]

Nothing about mTor in here, but Apigenin also seems to be therapeutic at cortico-induced affective disorders.
@Terma

Apigenin reverses depression-like behavior induced by chronic corticosterone treatment in mice. - PubMed - NCBI
Apigenin reverses depression-like behavior induced by chronic corticosterone treatment in mice.

Abstract
Previous researches found that apigenin exerted antidepressant-like effects in rodents. However, it is unclear whether the neurotrophic system is involved in the antidepressant-like effects of apigenin. Our present study aimed to explore the neurotrophic related mechanism of apigenin in depressive-like mice induced by chronic corticosterone treatment. Mice were repeatedly injected with corticosterone (40 mg/kg) subcutaneously (s.c) once daily for consecutive 21 days. Apigenin (20 and 40 mg/kg) and fluoxetine (20 mg/kg) were administered 30 min prior to the corticosterone injection. The behavioral tests indicated that apigenin reversed the reduction of sucrose preference and the elevation of immobility time in mice induced by chronic corticosterone treatment. In addition, the increase in serum corticosterone levels and the decrease in hippocampal brain-derived neurotrophic factor (BDNF) levels in corticosterone-treated mice were also ameliorated by apigenin administration. Taken together, our findings intensively confirmed the antidepressant-like effects of apigenin and indicated that the antidepressant-like mechanism of apigenin was mediated, at least partly by up-regulation of BDNF levels in the hippocampus.