SARS-CoV-2 virus, the etiologic agent of COVID-19, has affected almost every aspect of human life, precipitating stress-related pathology in vulnerable individuals. As the prevalence rate of posttraumatic stress disorder in pandemic survivors exceeds that of the general and special populations, the virus may predispose to this disorder by directly interfering with the stress-processing pathways. The SARS-CoV-2 interactome has identified several antigens that may disrupt the blood-brain-barrier by inducing premature senescence in many cell types, including the cerebral endothelial cells. This enables the stress molecules, including angiotensin II, endothelin-1 and plasminogen activator inhibitor 1, to aberrantly activate the amygdala, hippocampus, and medial prefrontal cortex, increasing the vulnerability to stress related disorders. This is supported by observing the beneficial effects of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in both posttraumatic stress disorder and SARS-CoV-2 critical illness. In this narrative review, we take a closer look at the virus-host dialog and its impact on the renin-angiotensin system, mitochondrial fitness, and brain-derived neurotrophic factor. We discuss the role of furin cleaving site, the fibrinolytic system, and Sigma-1 receptor in the pathogenesis of psychological trauma. In other words, learning from the virus, clarify the molecular underpinnings of stress related disorders, and design better therapies for these conditions. In this context, we emphasize new potential treatments, including furin and bromodomains inhibitors.
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In our previous work on delirium, we hypothesized that dysfunctional AQP-4, led to impaired information processing, connecting these proteins to neuroplasticity and memory formation (Sfera et al., 2015; Ritchie et al., 2020). This is now supported by data, demonstrating that AQP-4 receptors are essential for brain activation during mental work and deactivation during downtime or sleep, revealing an inverse relationship between memory formation and ISF circulation (Sfera and Osorio, 2014; DiNuzzo and Nedergaard, 2017). Indeed, astrocytic end feet, express the most AQP-4 channels in the entire CNS, playing a key role in brain activation and deactivation (Mader and Brimberg, 2019).
Astrocytes have previously been implicated in PTSD as they regulate synaptic transmission, plasticity, and the formation of aversive memories (Nagelhus and Ottersen, 2013; Saur et al., 2016). To participate in neuroplasticity as well as in the glymphatic circulation, astrocytes require activation by BDNF (Brigadski and Leßmann, 2020). In this regard, PTSD-associated hypermnesia and dissociative amnesia may be traced to astrocytic deactivation (Kol et al., 2020). For example, preclinical studies have associated fear with dysfunctional glymphatic circulation, further connecting the astrocyte to stressful experiences (Li et al., 2020). As astrocytic activation restores the glymphatic circulation, lowering anxiety and fear in animal models, stimulation of these cells may emerge as a therapeutic strategy for SRDs (Martin-Fernandez et al., 2017; Verkhratsky and Nedergaard, 2018; Figure 3). Other preclinical studies have reported that ANG II inhibits GABAergic transmission in the CNS, triggering anxiety and fear, further connecting dysfunctional RAS to SRDs (Li and Pan, 2005; Wang et al., 2018; Zhou et al., 2019). This is significant as it may explain the high prevalence of PTSD in COVID-19 survivors.
Astrocytes have been reported to drive LTP as they shuttle lactate to active neurons, increasing plasticity and memory formation (Hagiwara and Kubo, 2007). Indeed, preclinical studies have associated amnesia with impaired astrocytic lactate transporters, while studies in humans linked psychological stress to the upregulated plasma lactate (Suzuki et al., 2011; Descalzi et al., 2019). Moreover, patients with neuromyelitis optica, a rare autoimmune disease marked by autoantibodies against AQP-4, demonstrated elevated lactate concentrations, suggesting an inverse relationship between glycolysis and the expression of water channels in astrocytic end-feet (Kubera et al., 2012). Along these lines, novel studies have shown that lactate circulates through AQP-4 and that glycolysis is inversely corelated with the expression of water channels (Jarius et al., 2014). Indeed, lactate is upregulated during brain activation, likely to facilitate water entry into astrocytes, while during idle time or slow wave sleep, AQP-4 channels are downregulated to facilitate the glymphatic clearance (Jarius et al., 2014).
Several viruses, including HIV and SARS-CoV-2, were associated with AQP-4 autoantibodies, suggesting that disabling the water channels to upregulate lactate may be a strategy adopted by select pathogens (Lundgaard et al., 2017; Rahimy et al., 2017; Mariajoseph-Antony et al., 2020; Tice et al., 2020; Erickson et al., 2021). Indeed, AQP-4 autoantibodies were found in a subset of COVID-19 patients with neurological symptoms, linking defective water channels to COVID-19 critical illness (Corrêa et al., 2021). In contrast, normal aging was associated with upregulated AQP-4 and loss of glycolysis, further emphasizing the inverse relationship between water channels and brain lactate (Owasil et al., 2020; Corrêa et al., 2021).
Taken together, dysfunctional AQP-4 interferes with RAS and the brain metabolism. As viruses thrive in lactate-rich environments, they may have developed the capability to disable AQP-4 channels, promoting glycolysis and excessive lactate that increases SRD vulnerability.
As the SARS-CoV-2 virus thrives on lactate, it preferentially targets ECs, that under normal circumstances, derive most of their energy from glycolysis. In addition, as the virus induces EC senescence, it may upregulates lactate further, generating a friendly microenvironment for its replication. Excessive brain lactate, as discussed above, likely triggers PTSD symptoms by activating ASIC1a and downregulating AQP-4 (Smoller et al., 2014; Quagliato et al., 2018; Li et al., 2020).
Propranolol, an established glycolysis inhibitor, has been utilized in PTSD for decades as it facilitates the extinction of fear learning, linking this cognitive defect to excessive lactate (Vaiva et al., 2003; Brohée et al., 2018; Ganji and Reddy, 2021). In addition, propranolol protects ECs by restoring mitochondrial integrity, increasing PTSD resilience (Giustino et al., 2016). Propranolol also blocks the Warburg effect, disrupting the energy supply of both malignant and virus-infected cells, emphasizing the anticancer and antiviral properties of this drug (Iwai et al., 2002; Lucido et al., 2018; Barbieri et al., 2020; Vasanthakumar, 2020).
Aside from its role as a metabolite, lactate is also a signaling molecule that interacts with G-protein-coupled receptor 81 (GPR81), increasing angiogenesis and opposing ECs senescence (Morland et al., 2015, 2017). Interestingly, preclinical studies reported that GPR81 agonists trigger anxiety via cAMP, suggesting that blocking these receptors could be therapeutic in SRDs (Morland et al., 2015; Shan et al., 2020). Interestingly, a cAMP transcription factor, cAMP response element-binding (CREB) protein, was implicated in PTSD, and can be inhibited by dopamine blockers (Tsang and Lal, 1977; Martini et al., 2013; Keil et al., 2016).
Another mitochondria-protective agent with therapeutic potential in PTSD is dichloroacetate (DCA), a lactate inhibitor with established anticancer and antiviral properties (Kho et al., 2019). Despite these benefits, DCA use in PTSD is likely limited by its serious adverse effects such as peripheral neuropathy and delirium (Table 2).
Mitochondrial transplant, used with some success in pediatric patients with Pearson’s syndrome, may also benefit PTSD patients by replacing damaged organelles (Emani and McCully, 2018). However, as of this time, it is unclear whether transplanted mitochondria can survive in the extracellular environment or selectively enter in the defective cells, indicating that this intervention is not ready for clinical practice at this time. However, another procedure based on introducing functional mitochondria directly into dysfunctional cells may be more promising for PTSD (Gomzikova et al., 2021).
Women with PTSD demonstrated low CSF levels of allopregnanolone and pregnanolone, further linking this disorder to mitochondrial dysfunction (Rasmusson et al., 2006; Almeida et al., 2021). Interestingly, allopregnanolone, also known as brexanolone, was approved by the Food and Drug Administration (FDA) for the treatment of postpartum depression (Pineles et al., 2018; Morrison et al., 2019). Earlier studies found that allopregnanolone improved the BBB permeability, indicating potential benefits for senescent endothelia and PTSD (brexanolone is currently in clinical trials for this disorder) (NCT04468360). Moreover, allopregnanolone was found therapeutic in PTSD and severe COVID-19, as it might reverse some aspects of endothelial senescence (Lüscher and Möhler, 2019). In addition, progesterone was reported beneficial for both COVID-19 and PTSD, possibly by increasing NO in cerebral ECs (Balan et al., 2019; Ney et al., 2019; Seligowski et al., 2020). Indeed, as mentioned above, NO pathology contributes to PTSD and is currently in clinical trials for COVID-19 (Ghandehari et al., 2021) (NCT04601077) (Table 2).
PTSD as an Endothelial Disease: Insights From COVID-19
SARS-CoV-2 virus, the etiologic agent of COVID-19, has affected almost every aspect of human life, precipitating stress-related pathology in vulnerable individuals. As the prevalence rate of posttraumatic stress disorder in pandemic survivors exceeds ...
www.ncbi.nlm.nih.gov
Of Stress and Water
Cerebral ECs form the BBB with astrocytic end-feet, structures rich in aquaporin-4 (AQP-4) channels that also engender the glymphatic system, a waste disposal apparatus, located between astrocytic processes and ECs (Daneman and Prat, 2015; Krikov et al., 2008). Interstitial fluid (ISF) circulation through this space facilitates the clearance of molecular debris and contributes to the brain-wide diffusion of peptides, neurotransmitters, BDNF and viral particles (Jessen et al., 2015; Plog and Nedergaard, 2018; Figure 3). A growing body of evidence connected that AQP-4 to BDNF and neuroplasticity in the hippocampus, amygdala and mPFC (Szu and Binder, 2016; Huber et al., 2018). On the other hand, dysfunctional AQP-4 channels were associated with depression, insomnia, dysfunctional synaptic plasticity, and impaired fear extinction (Scharfman and Binder, 2013; Berntsen and Rubin, 2014). For example, AQP-4 knockout mice displayed both corticosterone-induced depression and defective memory, symptoms reversed by mifepristone and fluoxetine, linking the brain water circulation to SRDs (Kong et al., 2014; Di Benedetto et al., 2016). Moreover, astrocytic end-feet were demonstrated to contain abundant angiotensinogen, a molecule regulated by AQP-4, connecting this protein to RAS (Wei et al., 2019). Interestingly, ARBs and ACEi were demonstrated to upregulate peritoneal AQP-4, suggesting that these agents may have a similar effect in astrocytic end-feet (Matsushita et al., 2010). In addition, as COVID-19 was reported to target hippocampal astrocytes, the virus likely alters AQP-4 (via ANG II), disrupting synaptic plasticity and fear extinction (Imai et al., 2001; Tavčar et al., 2021).In our previous work on delirium, we hypothesized that dysfunctional AQP-4, led to impaired information processing, connecting these proteins to neuroplasticity and memory formation (Sfera et al., 2015; Ritchie et al., 2020). This is now supported by data, demonstrating that AQP-4 receptors are essential for brain activation during mental work and deactivation during downtime or sleep, revealing an inverse relationship between memory formation and ISF circulation (Sfera and Osorio, 2014; DiNuzzo and Nedergaard, 2017). Indeed, astrocytic end feet, express the most AQP-4 channels in the entire CNS, playing a key role in brain activation and deactivation (Mader and Brimberg, 2019).
Astrocytes have previously been implicated in PTSD as they regulate synaptic transmission, plasticity, and the formation of aversive memories (Nagelhus and Ottersen, 2013; Saur et al., 2016). To participate in neuroplasticity as well as in the glymphatic circulation, astrocytes require activation by BDNF (Brigadski and Leßmann, 2020). In this regard, PTSD-associated hypermnesia and dissociative amnesia may be traced to astrocytic deactivation (Kol et al., 2020). For example, preclinical studies have associated fear with dysfunctional glymphatic circulation, further connecting the astrocyte to stressful experiences (Li et al., 2020). As astrocytic activation restores the glymphatic circulation, lowering anxiety and fear in animal models, stimulation of these cells may emerge as a therapeutic strategy for SRDs (Martin-Fernandez et al., 2017; Verkhratsky and Nedergaard, 2018; Figure 3). Other preclinical studies have reported that ANG II inhibits GABAergic transmission in the CNS, triggering anxiety and fear, further connecting dysfunctional RAS to SRDs (Li and Pan, 2005; Wang et al., 2018; Zhou et al., 2019). This is significant as it may explain the high prevalence of PTSD in COVID-19 survivors.
Astrocytes have been reported to drive LTP as they shuttle lactate to active neurons, increasing plasticity and memory formation (Hagiwara and Kubo, 2007). Indeed, preclinical studies have associated amnesia with impaired astrocytic lactate transporters, while studies in humans linked psychological stress to the upregulated plasma lactate (Suzuki et al., 2011; Descalzi et al., 2019). Moreover, patients with neuromyelitis optica, a rare autoimmune disease marked by autoantibodies against AQP-4, demonstrated elevated lactate concentrations, suggesting an inverse relationship between glycolysis and the expression of water channels in astrocytic end-feet (Kubera et al., 2012). Along these lines, novel studies have shown that lactate circulates through AQP-4 and that glycolysis is inversely corelated with the expression of water channels (Jarius et al., 2014). Indeed, lactate is upregulated during brain activation, likely to facilitate water entry into astrocytes, while during idle time or slow wave sleep, AQP-4 channels are downregulated to facilitate the glymphatic clearance (Jarius et al., 2014).
Several viruses, including HIV and SARS-CoV-2, were associated with AQP-4 autoantibodies, suggesting that disabling the water channels to upregulate lactate may be a strategy adopted by select pathogens (Lundgaard et al., 2017; Rahimy et al., 2017; Mariajoseph-Antony et al., 2020; Tice et al., 2020; Erickson et al., 2021). Indeed, AQP-4 autoantibodies were found in a subset of COVID-19 patients with neurological symptoms, linking defective water channels to COVID-19 critical illness (Corrêa et al., 2021). In contrast, normal aging was associated with upregulated AQP-4 and loss of glycolysis, further emphasizing the inverse relationship between water channels and brain lactate (Owasil et al., 2020; Corrêa et al., 2021).
Taken together, dysfunctional AQP-4 interferes with RAS and the brain metabolism. As viruses thrive in lactate-rich environments, they may have developed the capability to disable AQP-4 channels, promoting glycolysis and excessive lactate that increases SRD vulnerability.
Mitochondria and Lactate
Most cells throughout the body obtain ATP from mitochondria-associated OXPHOS but under hypoxic conditions switch to glycolysis, deriving energy from lactate (Naoi et al., 2006; Owasil et al., 2020). The SARS-CoV-2 virus may target mitochondria to acquire iron and block the import of MAVS, while at the same time it rewires the cellular metabolism to aerobic glycolysis in a Warburg-like effect encountered in malignant cells (Wilson, 2017; Figure 4). Damaged organelles release mitochondrial DNA (mDNA), including copy number (mtDNAcn) and cell-free mitochondrial DNA (cf-mtDNA), emphasizing potential biomarkers for both PTSD and COVID-19 critical illness (Bersani et al., 2016; Chauhan et al., 2019; Scozzi et al., 2021; Trumpff et al., 2021).As the SARS-CoV-2 virus thrives on lactate, it preferentially targets ECs, that under normal circumstances, derive most of their energy from glycolysis. In addition, as the virus induces EC senescence, it may upregulates lactate further, generating a friendly microenvironment for its replication. Excessive brain lactate, as discussed above, likely triggers PTSD symptoms by activating ASIC1a and downregulating AQP-4 (Smoller et al., 2014; Quagliato et al., 2018; Li et al., 2020).
Propranolol, an established glycolysis inhibitor, has been utilized in PTSD for decades as it facilitates the extinction of fear learning, linking this cognitive defect to excessive lactate (Vaiva et al., 2003; Brohée et al., 2018; Ganji and Reddy, 2021). In addition, propranolol protects ECs by restoring mitochondrial integrity, increasing PTSD resilience (Giustino et al., 2016). Propranolol also blocks the Warburg effect, disrupting the energy supply of both malignant and virus-infected cells, emphasizing the anticancer and antiviral properties of this drug (Iwai et al., 2002; Lucido et al., 2018; Barbieri et al., 2020; Vasanthakumar, 2020).
Aside from its role as a metabolite, lactate is also a signaling molecule that interacts with G-protein-coupled receptor 81 (GPR81), increasing angiogenesis and opposing ECs senescence (Morland et al., 2015, 2017). Interestingly, preclinical studies reported that GPR81 agonists trigger anxiety via cAMP, suggesting that blocking these receptors could be therapeutic in SRDs (Morland et al., 2015; Shan et al., 2020). Interestingly, a cAMP transcription factor, cAMP response element-binding (CREB) protein, was implicated in PTSD, and can be inhibited by dopamine blockers (Tsang and Lal, 1977; Martini et al., 2013; Keil et al., 2016).
Another mitochondria-protective agent with therapeutic potential in PTSD is dichloroacetate (DCA), a lactate inhibitor with established anticancer and antiviral properties (Kho et al., 2019). Despite these benefits, DCA use in PTSD is likely limited by its serious adverse effects such as peripheral neuropathy and delirium (Table 2).
Mitochondrial transplant, used with some success in pediatric patients with Pearson’s syndrome, may also benefit PTSD patients by replacing damaged organelles (Emani and McCully, 2018). However, as of this time, it is unclear whether transplanted mitochondria can survive in the extracellular environment or selectively enter in the defective cells, indicating that this intervention is not ready for clinical practice at this time. However, another procedure based on introducing functional mitochondria directly into dysfunctional cells may be more promising for PTSD (Gomzikova et al., 2021).
Mitochondria and Neurosteroids
Neurosteroids, synthesized in the CNS, adrenals, and gonads, are agonists at GABA-A receptors, that play a major role in regulating multiple brain signaling pathways (Lightowlers et al., 2020). Mitochondria initiate steroidogenesis by importing cholesterol to synthesize pregnenolone, a precursor molecule, that exits the organelle and is converted to progesterone, pregnanolone, and allopregnanolone in the cytoplasm (Zorumski et al., 2013).Women with PTSD demonstrated low CSF levels of allopregnanolone and pregnanolone, further linking this disorder to mitochondrial dysfunction (Rasmusson et al., 2006; Almeida et al., 2021). Interestingly, allopregnanolone, also known as brexanolone, was approved by the Food and Drug Administration (FDA) for the treatment of postpartum depression (Pineles et al., 2018; Morrison et al., 2019). Earlier studies found that allopregnanolone improved the BBB permeability, indicating potential benefits for senescent endothelia and PTSD (brexanolone is currently in clinical trials for this disorder) (NCT04468360). Moreover, allopregnanolone was found therapeutic in PTSD and severe COVID-19, as it might reverse some aspects of endothelial senescence (Lüscher and Möhler, 2019). In addition, progesterone was reported beneficial for both COVID-19 and PTSD, possibly by increasing NO in cerebral ECs (Balan et al., 2019; Ney et al., 2019; Seligowski et al., 2020). Indeed, as mentioned above, NO pathology contributes to PTSD and is currently in clinical trials for COVID-19 (Ghandehari et al., 2021) (NCT04601077) (Table 2).
