橋本 謙二

Beta-hydroxybutyrate (BHB), an endogenous NLRP3 inflammasome inhibitor, has been shown to be associated with the pathophysiology of depression in rodents. However its active mechanism has not been revealed. Herein, we probed both the pathways and brain regions involved in BHB's antidepressant-like effects in a learned helplessness (LH) rat model of depression. A single bilateral infusion of BHB into the cerebral ventricles induced the antidepressant-like effects on the LH rats. The antidepressant-like effects of BHB were blocked by the TrkB inhibitor ANA-12 and the AMPA receptor antagonist NBQX, indicating that the antidepressant-like effects of BHB involve BDNF-TrkB signaling and AMPA receptor activation. Further, infusions of BHB into the prelimbic and infralimbic portions of medial prefrontal cortex, the dentate gyrus of hippocampus, and the basolateral region of amygdala produced the antidepressant-like effects on LH rats. However, infusions of BHB into the central region of amygdala, the CA3 region of hippocampus, and the shell and core regions of nucleus accumbens had no effect. Finally, a single bilateral infusion of BHB into the cerebral ventricles of naive rats strengthened learning ability on repeated active avoidance test where saline-infused animals failed to increase avoidance responses.

Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. Dietary intake of cuprizone (CPZ) produces demyelination resembling that of patients with MS. Given the role of the vagus nerve in gut–microbiota–brain axis in development of MS, we performed this study to investigate whether subdiaphragmatic vagotomy (SDV) affects demyelination in CPZ-treated mice. SDV significantly ameliorated demyelination and microglial activation in the brain compared with sham-operated CPZ-treated mice. Furthermore, 16S ribosomal RNA analysis revealed that SDV significantly improved the abnormal gut microbiota composition of CPZ-treated mice. An untargeted metabolomic analysis demonstrated that SDV significantly improved abnormal blood levels of metabolites in CPZ-treated mice compared with sham-operated CPZ-treated mice. Notably, there were correlations between demyelination or microglial activation in the brain and the relative abundance of several microbiome populations, suggesting a link between gut microbiota and the brain. There were also correlations between demyelination or microglial activation in the brain and blood levels of metabolites. Together, these data suggest that CPZ produces demyelination in the brain through the gut–microbiota–brain axis via the subdiaphragmatic vagus nerve.

Finding from animal models of depression indicated that Toll-like receptor 4 (TLR4) is associated with the pathophysiology of depression. Herein, the TLR4 antagonists TAK-242 and baicalin induced antidepressant-like effects in a rat learned helplessness model of depression. The antidepressant-like effects of both TLR4 antagonists were blocked by the TrkB inhibitor ANA-12. Also, the antidepressant-like effects of TAK-242 were blocked by the treatment with AMPA receptor antagonist NBQX. The antidepressant-like effects of the TLR4 antagonist TAK-242 involves BDNF-TrkB signaling and AMPA receptor activation.

(R, S)-ketamine has prophylactic antidepressant-like effects in rodents; however, the precise molecular mechanisms underlying its action remain unknown. Using RNA-sequencing analysis, we searched novel molecular target(s) that contribute to the prophylactic effects of (R)-ketamine, a more potent enantiomer of (R, S)-ketamine. Pretreatment with (R)-ketamine (10 mg/kg, 6 days before) significantly ameliorated body weight loss, splenomegaly, and increased immobility time of forced swimming test in lipopolysaccharide (LPS: 1.0 mg/kg)-treated mice. RNA-sequencing analysis of prefrontal cortex (PFC) and subsequent IPA (Ingenuity Pathway Analysis) revealed that the nuclear factor of activated T cells 4 (NFATc4) signaling might contribute to sustained prophylactic effects of (R)-ketamine. Quantitative RT-PCR confirmed that (R)-ketamine significantly attenuated the increased gene expression of NFATc4 signaling (Nfatc4, Cd4, Cd79b, H2-ab1, H2-aa) in the PFC of LPS-treated mice. Furthermore, pretreatment with NFAT inhibitors (i.e., NFAT inhibitor and cyclosporin A) showed prophylactic effects in the LPS-treated mice. Similar to (R)-ketamine, gene knockdown of Nfatc4 gene by bilateral injection of adeno-associated virus (AAV) into the mPFC could elicit prophylactic effects in the LPS-treated mice. In conclusion, our data implicate a novel NFATc4 signaling pathway in the PFC underlying the prophylactic effects of (R)-ketamine for inflammation-related depression.

BACKGROUND: The excessive blockade of dopamine D2 receptors (DRD2s) with long-term antipsychotic treatment is known to induce a dopamine supersensitivity state (DSS). The mechanism of DSS is speculated to be a compensatory up-regulation of DRD2s, but an excess blockade of DRD2s can also cause glutamatergic neuronal damage. Herein, we investigated whether antipsychotic-induced neuronal damage plays a role in the development of DSS. METHODS: Haloperidol (HAL; 0.75 mg/kg/day for 14 days) or vehicle was administered to rats via an osmotic mini-pump. Haloperidol-treated rats were divided into groups of DSS rats and non-DSS rats based on their voluntary locomotion data. We then determined the tissue levels of glutamate transporter-1 (GLT-1)/glutamine synthetase (GS) and heat shock protein-70 (HSP-70) in the rats' brain regions. RESULTS: The levels of HSP-70 in the striatum and CA-3 region of the DSS rats were significantly higher than those of the control and non-DSS rats, whereas the dentate gyrus HSP-70 levels in both the DSS and non-DSS rats were increased versus the controls. The levels of GLT-1/GS in the CA-3 and nucleus accumbens were increased in the DSS rats. CONCLUSIONS: These results suggest that the DSS rats experienced striatal neuronal damage and indicate that a HAL-induced upregulation of HSP-70 and the GLT-1/GS system in the CA3 may be involved in the development of DSS. It remains unknown why the non-DSS rats did not suffer neuronal damage. In view of the need for therapeutic strategies for treatment-resistant schizophrenia, dopamine supersensitivity psychosis, and tardive dyskinesia, further investigations of our findings are warranted.

<title>Abstract</title><sec> <title>Background</title> To control the spread of the new SARS-CoV-2 infection's disease (COVID-19), appropriate precautionary behaviors by the public should be promoted. There are international differences in public cognitive and behavioral pattern, attitudes toward information sources, and anxiety about COVID-19. Information about these differences could increase understanding of the patterns of epidemic-related anxiety and behavior, and would help optimize future policies for preventing the next wave of the epidemic. </sec><sec> <title>Methods</title> To examine between-country differences in perception, attitude, and precautionary behaviors toward COVID-19, we conducted a cross-sectional study using an online questionnaire survey. Participants were adults who had been registered in Cross Marketing Group Inc. and living in the UK, Spain, or Japan. A total of 8,000 people stratified by age were recruited on a first-come, first-serve basis. Knowledge of and anxiety about COVID-19, the frequency of access and perceived credibility of several information sources, and the frequency of each precautionary behavior were examined on March 27–28, 2020, in Japan and April 17–21, 2020, in the UK and Spain. </sec><sec> <title>Results</title> Knowledge, anxiety, and the frequency of precautionary behaviors were higher in the UK and Spain than in Japan. Participants with infected acquaintances were more concerned about COVID-19. However, participants in the UK rarely wore a medical mask. Participants in the UK and Spain were more eager to obtain information about COVID-19 than those in Japan. Participants in Spain tended not to trust official information and to believe specialists’ comments instead. </sec><sec> <title>Conclusion</title> The rapidity of the spread of COVID-19, cultural background, and recent political situations seemed to contribute to the international differences here. </sec>

Background: Brain-derived neurotrophic factor (BDNF) antisense RNA (BDNF-AS) was identified as naturally conserved non-coding antisense RNA that suppresses the transcription of BDNF. Methods: We measured the expression of BDNF mRNA and BDNF-AS mRNA in iPSC and NSC from bipolar disorder (BD) patients and healthy control subjects, and postmortem brain samples such as the corpus callosum, the Brodmann area (BA8), and BA46 from BD patients and age- and sex-matched controls. Results: The expression of BDNF mRNA in iPSC from BD patients (n = 6) was significantly lower than that of control subjects (n = 4) although the expression of BDNF mRNA in NSC from BD patients was significantly higher than that of control subjects. In contrast, there were no changes in the expression of BDNF-AS mRNA in both iPSC and NSC between two groups. The expression of BDNF mRNA in the BA46 from BD patients (n = 35) was significantly lower than that of controls (n = 34) although the expression of BDNF mRNA in the corpus callosum and BA8 was not different between two groups (n = 15). In contrast, there were no changes in expression of BDNF-AS mRNA in the three brain regions between two groups. Interestingly, there were significant positive correlations between BDNF mRNA expression and BDNF-AS mRNA expression in the postmortem brain samples. Limitations: Sample sizes are relatively low. Conclusions: Our data suggest that abnormalities in the expression of BDNF, but not BDNF-AS, play a role in the pathogenesis of BD.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) antisense RNA (BDNF-AS) was identified as naturally conserved non-coding antisense RNA that suppresses the transcription of BDNF. METHODS: We measured the expression of BDNF mRNA and BDNF-AS mRNA in iPSC and NSC from bipolar disorder (BD) patients and healthy control subjects, and postmortem brain samples such as the corpus callosum, the Brodmann area (BA8), and BA46 from BD patients and age- and sex-matched controls. RESULTS: The expression of BDNF mRNA in iPSC from BD patients (n = 6) was significantly lower than that of control subjects (n = 4) although the expression of BDNF mRNA in NSC from BD patients was significantly higher than that of control subjects. In contrast, there were no changes in the expression of BDNF-AS mRNA in both iPSC and NSC between two groups. The expression of BDNF mRNA in the BA46 from BD patients (n = 35) was significantly lower than that of controls (n = 34) although the expression of BDNF mRNA in the corpus callosum and BA8 was not different between two groups (n = 15). In contrast, there were no changes in expression of BDNF-AS mRNA in the three brain regions between two groups. Interestingly, there were significant positive correlations between BDNF mRNA expression and BDNF-AS mRNA expression in the postmortem brain samples. LIMITATIONS: Sample sizes are relatively low. CONCLUSIONS: Our data suggest that abnormalities in the expression of BDNF, but not BDNF-AS, play a role in the pathogenesis of BD.

The transcription nuclear factor-erythroid factor 2-related factor 2 (Nrf2) plays a key role in inflammation that is involved in depression. We previously reported that Nrf2 knock-out (KO) mice exhibit depression-like phenotypes through systemic inflammation. (R)-ketamine, an enantiomer of ketamine, has rapid-acting and long-lasting antidepressant-like effects in rodents. We investigated whether (R)-ketamine can produce antidepressant-like effects in Nrf2 KO mice. Effects of (R)-ketamine on the depression-like phenotypes in Nrf2 KO mice were examined. Furthermore, the role of TrkB in the antidepressant-like actions of (R)-ketamine was also examined. In the tail-suspension test (TST) and forced swimming test (FST), (R)-ketamine (10 mg/kg) significantly attenuated the increased immobility times of TST and FST in the Nrf2 KO mice. In the sucrose preference test (SPT), (R)-ketamine significantly ameliorated the reduced preference of SPT in Nrf2 KO mice. Decreased expression of synaptic proteins (i.e., GluA1 and PSD-95) in the medial prefrontal cortex (mPFC) of Nrf2 KO mice was significantly ameliorated after a single injection of (R)-ketamine. Furthermore, the pre-treatment with the TrkB antagonist ANA-12 (0.5 mg/kg) significantly blocked the rapid and long-lasting antidepressant-like effects of (R)-ketamine in Nrf2 KO mice. Furthermore, ANA-12 significantly antagonized the beneficial effects of (R)-ketamine on decreased expression of synaptic proteins in the mPFC of Nrf2 KO mice. These findings suggest that (R)-ketamine can produce rapid and long-lasting antidepressant-like actions in Nrf2 KO mice via TrkB signaling.

The authors note that the author name Debin Wang should instead appear as Debin Wan. The corrected author line appears below. The online version has been corrected.

Glial cell line-derived neurotrophic factor (GDNF) may play an important role in attention. We investigated the association between serum GDNF levels and clinical status in unmedicated adults with attention deficit/hyperactivity disorder (ADHD) (n = 16) and healthy controls (n = 33); the levels were comparable between the ADHD and control groups (107.2 ± 31.7 vs. 110.5 ± 40.0 pg/mL, respectively; p = 0.77). In the ADHD group, higher GDNF serum levels were associated with severe subjective inattention (r = 0.528, p = 0.035). These preliminary results suggest that the serum GDNF level may not be a suitable biomarker for adult ADHD, although it may be associated with the pathophysiology of persistent inattention in adult ADHD.

While the long-term administration of antipsychotics is known to cause dopamine supersensitivity psychosis (DSP), recent studies revealed that DSP helps form the foundation of treatment resistance. Electroconvulsive shock (ES) is one of the more effective treatments for treatment-resistant schizophrenia. The objective of this study was to examine whether repeated ES can release rats from dopamine supersensitivity states such as striatal dopamine D2 receptor (DRD2) up-regulation and voluntary hyperlocomotion following chronic administration of haloperidol (HAL). HAL (0.75 mg/kg/day) was administered for 14 days via mini-pumps implanted in rats, and DRD2 density and voluntary locomotion were measured one day after drug cessation to confirm the development of dopamine supersensitivity. The rats with or without dopamine supersensitivity received repeated ES or sham treatments, and then DRD2 density was assessed and a voluntary locomotion test was performed. Chronic treatment with HAL led to the up-regulation of striatal DRD2 and hyperlocomotion in the rats one day after drug cessation. We thus confirmed that these rats experienced a dopamine supersensitivity state. Moreover, after repeated ES, locomotor activity and DRD2 density in the DSP model rats fell to the control level, while an ES sham operation had no effect on the dopamine supersensitivity state. The present study suggests that repeated ES could release DSP model rats from dopamine supersensitivity states. ES may be helpful for patients with DSP.

Background: The brain-gut-microbiota axis plays a role in the pathogenesis of stress-related disorders such as depression. In this study, we examined the effects of fecal microbiota transplantation (FMT) in mice with antibiotic-treated microbiota depletion. Methods: The fecal microbiota was obtained from mice subjected to chronic social defeat stress (CSDS) and control (no CSDS) mice. FMT from these two groups was performed to antibiotic-treated mice. 16S rRNA analysis was performed to examine the composition of gut microbiota. Furthermore, the effects of subdiaphragmatic vagotomy in depression-like phenotypes after ingestion of microbes were examined. Results: The ingestion of fecal microbiota from CSDS-susceptible mice resulted in an anhedonia-like phenotype, higher plasma levels of interleukin-6 (IL-6), and decreased expression of synaptic proteins in the prefrontal cortex (PFC) in antibiotic-treated mice but not in water-treated mice. 16S rRNA analysis suggested that two microbes (Lactobacillus intestinalis and Lactobacillus reuteri) may be responsible for the anhedonia-like phenotype in antibiotic-treated mice after FMT. Ingestion of these two microbes for 14 days led to depression- and anhedonia-like phenotypes, higher plasma IL-6 levels, and decreased expression of synaptic proteins in the PFC of antibiotic-treated mice. Interestingly, subdiaphragmatic vagotomy significantly blocked the development of behavioral abnormalities, elevation of plasma IL-6 levels, and downregulation of synaptic proteins in the PFC after ingestion of these two microbes. Conclusions: These findings suggest that microbiota depletion using an antibiotic cocktail is essential for the development of FMT-induced behavioral changes and that the vagus nerve plays a key role in behavioral abnormalities in antibiotic-treated mice after the ingestion of L. intestinalis and L. reuteri. Therefore, it is likely that the brain-gut-microbiota axis participates in the pathogenesis of depression via the vagus nerve.

BACKGROUND: The brain-gut-microbiota axis plays a role in the pathogenesis of stress-related disorders such as depression. In this study, we examined the effects of fecal microbiota transplantation (FMT) in mice with antibiotic-treated microbiota depletion. METHODS: The fecal microbiota was obtained from mice subjected to chronic social defeat stress (CSDS) and control (no CSDS) mice. FMT from these two groups was performed to antibiotic-treated mice. 16S rRNA analysis was performed to examine the composition of gut microbiota. Furthermore, the effects of subdiaphragmatic vagotomy in depression-like phenotypes after ingestion of microbes were examined. RESULTS: The ingestion of fecal microbiota from CSDS-susceptible mice resulted in an anhedonia-like phenotype, higher plasma levels of interleukin-6 (IL-6), and decreased expression of synaptic proteins in the prefrontal cortex (PFC) in antibiotic-treated mice but not in water-treated mice. 16S rRNA analysis suggested that two microbes (Lactobacillus intestinalis and Lactobacillus reuteri) may be responsible for the anhedonia-like phenotype in antibiotic-treated mice after FMT. Ingestion of these two microbes for 14 days led to depression- and anhedonia-like phenotypes, higher plasma IL-6 levels, and decreased expression of synaptic proteins in the PFC of antibiotic-treated mice. Interestingly, subdiaphragmatic vagotomy significantly blocked the development of behavioral abnormalities, elevation of plasma IL-6 levels, and downregulation of synaptic proteins in the PFC after ingestion of these two microbes. CONCLUSIONS: These findings suggest that microbiota depletion using an antibiotic cocktail is essential for the development of FMT-induced behavioral changes and that the vagus nerve plays a key role in behavioral abnormalities in antibiotic-treated mice after the ingestion of L. intestinalis and L. reuteri. Therefore, it is likely that the brain-gut-microbiota axis participates in the pathogenesis of depression via the vagus nerve.

Background The brain-gut-microbiota axis plays a role in the pathogenesis of stress-related disorders such as depression. In this study, we examined the effects of fecal microbiota transplantation (FMT) in mice with antibiotic-treated microbiota depletion. Methods The fecal microbiota was obtained from mice subjected to chronic social defeat stress (CSDS) and control (no CSDS) mice. FMT from these two groups was performed to antibiotic-treated mice. 16S rRNA analysis was performed to examine the composition of gut microbiota. Furthermore, the effects of subdiaphragmatic vagotomy in depression-like phenotypes after ingestion of microbes were examined. Results The ingestion of fecal microbiota from CSDS-susceptible mice resulted in an anhedonia-like phenotype, higher plasma levels of interleukin-6 (IL-6), and decreased expression of synaptic proteins in the prefrontal cortex (PFC) in antibiotic-treated mice but not in water-treated mice. 16S rRNA analysis suggested that two microbes (Lactobacillus intestinalisandLactobacillus reuteri) may be responsible for the anhedonia-like phenotype in antibiotic-treated mice after FMT. Ingestion of these two microbes for 14 days led to depression- and anhedonia-like phenotypes, higher plasma IL-6 levels, and decreased expression of synaptic proteins in the PFC of antibiotic-treated mice. Interestingly, subdiaphragmatic vagotomy significantly blocked the development of behavioral abnormalities, elevation of plasma IL-6 levels, and downregulation of synaptic proteins in the PFC after ingestion of these two microbes. Conclusions These findings suggest that microbiota depletion using an antibiotic cocktail is essential for the development of FMT-induced behavioral changes and that the vagus nerve plays a key role in behavioral abnormalities in antibiotic-treated mice after the ingestion ofL. intestinalisandL. reuteri. Therefore, it is likely that the brain-gut-microbiota axis participates in the pathogenesis of depression via the vagus nerve.

Monoamine neuronal system abnormality is hypothesized to be the neurochemical pathology in depression, as it is supported by the efficacy of conventional antidepressants. The learned helplessness paradigm generates depression-like (LH) and non-depression-like (non-LH) behavioral models. Examination of the neurochemical states accompanying such distinct behavioral phenotypes can facilitate investigations of the mechanisms underlying resilience and the search for new strategies for depression prevention and therapy. Here, we measured the levels of monoamines, including noradrenaline (NA), serotonin (5-HT), and dopamine (DA), and their metabolites in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), hippocampus, nucleus accumbens (NAc), amygdala, and striatum in LH, non-LH, and non-manipulated (naïve) rats. Compared with LH rats, non-LH rats showed lower 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and NA turnovers in the amygdala and higher 5-HT levels in the NAc. Compared with naïve rats, non-LH rats showed increased DA and homovanillic acid (HVA) levels in the amygdala and increased 5-hydroxyindoleacetic acid (5-HIAA) levels in the hippocampus and NAc, whereas LH rats exhibited increased HVA levels and DA turnovers in the hippocampus, decreased 5-HIAA levels in the mPFC, increased DA turnovers in the OFC, and decreased DA turnovers in the amygdala. Comparison between LH and non-LH suggest that suppressed amygdaloid NA activity and elevated 5-HT activity in the NAc are related to stress resilience. Changes that occurred in LH or non-LH rats when compared with those in naïve rats suggest that suppressed DA activity in the hippocampus and OFC; elevated DA activity in the amygdala; and facilitated 5-HT activity in the hippocampus, mPFC, and NAc are phenomena related to the expression of a non-depression-like phenotype.

Allopregnanolone (ALLO, 3α5α-tetrahydroprogesterone) was found to be effective for depressed patients. Animal models of depression indicate that ALLO is associated with the pathophysiology of depression. Traditional antidepressant drugs produce antidepressant effects via the monoamine system, with consequent up-regulation of brain-derived neurotrophic factor (BDNF). This study was designed to examine whether the antidepressant effects of ALLO involve BDNF-TrkB signaling or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation on the learned helplessness paradigm. The antidepressant-like effect of ALLO infusion into the cerebral ventricle was blocked by coinfusion of TrkB inhibitor ANA-12, but not by co-administration of AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfoamoylbenzo(f)quinoxaline (NBQX). Thus, the antidepressant-like effect of ALLO involves BDNF signaling independent from AMPA receptor activation.

BACKGROUND: The colony stimulating factor 1 receptor (CSF1R) regulates microglia/macrophage proliferation, differentiation and survival; however, the precise role of this protein in psychiatric disorders is unknown. CSF1R is also known to interact with the transcription factor PU.1 (SPI1). Here we studied whether the expressions of CSF1R and SPI1 are altered in the postmortem samples (parietal cortex, cerebellum, spleen) from patients with major psychiatric disorders. METHODS: Protein expression of CSF1R and SPI1 in the parietal cortex, cerebellum and spleen from control, major depressive disorder (MDD), schizophrenia (SZ), and bipolar disorder (BD) groups was measured. RESULTS: Levels of CSF1R in the spleen, but not cerebellum and parietal cortex, from MDD and SZ groups were significantly lower than the control group. There was a positive correlation between CSF1R levels in the spleen and CSF1R levels in the parietal cortex in the all subjects from four groups. Furthermore, levels of SPI1 in the cerebellum and spleen from MDD and SZ groups were significantly higher than the control group. Levels of SPI1 in the parietal cortex were not different among the four groups. Interestingly, there was a negative correlation between CSF1R and SPI1 levels in the spleen of the all subjects from four groups. There was also a negative correlation between CSF1R and SPI1 levels in the spleen of MDD group. LIMITATIONS: The small number in each group may limit our interpretation. CONCLUSIONS: Abnormalities in CSF1R and SPI1 in the brain-spleen axis might, in part, play a role in the pathophysiology of MDD.

Ketamine, an anesthetic developed in the early 1960s, is also a popular abused drug among young people at dance parties and raves and among spiritual seekers, because it produces schizophrenia-like symptoms and dissociation (i.e., out-of-body experience). Regarding mood disorders, ketamine exerts robust antidepressant actions in treatment-resistant patients with depression. Ketamine is a racemic mixture comprising equal parts of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine). The United States (US) Food and Drug Administration approved the J&J (S)-ketamine nasal spray for treatment-resistant depression on March 5, 2019; the spray was then approved in Europe (December 19, 2019). Although (R)-ketamine has lower affinity for the N-methyl-d-aspartate receptor (NMDAR) vs. (S)-ketamine, (R)-ketamine has greater potency and longer-lasting antidepressant-like actions in animal models of depression. Importantly, (R)-ketamine has less detrimental side effects than does (R,S)-ketamine or (S)-ketamine in rodents, monkeys, and humans. A role for the brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) receptor in the antidepressant effects of ketamine and its two enantiomers has been suggested. A recent RNA-sequencing analysis suggested that the transforming growth factor β1 (TGF-β1) plays a role in the antidepressant effects of (R)-ketamine. A recent pilot study demonstrated that (R)-ketamine had rapid-acting and sustained antidepressant effects in treatment-resistant patients with depression. In this article, the author reviews the mechanisms of the antidepressant actions of the enantiomers of ketamine and its metabolites, (S)-norketamine and (2R,6R)-hydroxynorketamine (HNK) and discusses the role of the brain-gut-microbiota axis and brain-spleen axis in stress-related psychiatric disorders, such as depression.

BACKGROUND: The brain-gut-microbiota axis plays a role in the pathogenesis of stress-related psychiatric disorders; however, its role in the resilience versus susceptibility after stress remains unclear. Dietary nutrient betaine is suggested to affect the gut microbiome. Here, we examined whether betaine supplementation can affect anhedonia-like phenotype in mice subjected to chronic social defeat stress (CSDS). METHODS: CSDS was performed during betaine supplementation. Sucrose preference test and 16S rRNA analysis of fecal samples were performed. RESULTS: CSDS did not produce an anhedonia-like phenotype in the betaine-treated mice, but did induce an anhedonia-like phenotype in water-treated mice. Furthermore, CSDS treatment did not alter the plasma levels of interleukin-6 (IL-6) of betaine-treated mice whereas CSDS caused higher plasma levels of IL-6 in water-treated mice. Betaine supplementation ameliorated the abnormal diversity and composition of the microbiota in the host gut after CSDS. At the genus level, CSDS caused marked increases in the several bacteria of water-treated mice, but not betaine-treated mice. CSDS increased levels of short-chain fatty acids (i.e., succinic acid and acetic acid) in feces from water-treated mice, but not betaine-treated mice. Interestingly, there are positive correlations between short-chain fatty acids (i.e., succinic acid, acetic acid, butyric acid) and several bacteria among the groups. LIMITATIONS: Specific microbiome were not determined. CONCLUSIONS: These findings suggest that betaine supplementation contributed to resilience to anhedonia in mice subjected to CSDS through anti-inflammation action. Therefore, it is likely that betaine could be a prophylactic nutrient to prevent stress-related psychiatric disorders.

Viral infections have detrimental impacts on neurological functions, and even to cause severe neurological damage. Very recently, coronaviruses (CoV), especially severe acute respiratory syndrome CoV 2 (SARS-CoV-2), exhibit neurotropic properties and may also cause neurological diseases. It is reported that CoV can be found in the brain or cerebrospinal fluid. The pathobiology of these neuroinvasive viruses is still incompletely known, and it is therefore important to explore the impact of CoV infections on the nervous system. Here, we review the research into neurological complications in CoV infections and the possible mechanisms of damage to the nervous system.

Many psychiatric patients have been infected with COVID-19, and patients with COVID-19 may develop psychiatric symptoms after treatment with antiviral drugs. Given the tolerability and minimal P450 interactions, antidepressants (i.e., citalopram, escitalopram etc.), antipsychotics (i.e., olanzapine) and valproate can be considered to be safe in combination with antiviral drugs.

As of April 15, 2020, the ongoing coronavirus disease 2019 (COVID-2019) pandemic has swept through 213 countries and infected more than 1,870,000 individuals, posing an unprecedented threat to international health and the economy. There is currently no specific treatment available for patients with COVID-19 infection. The lessons learned from past management of respiratory viral infections have provided insights into treating COVID-19. Numerous potential therapies, including supportive intervention, immunomodulatory agents, antiviral therapy, and convalescent plasma transfusion, have been tentatively applied in clinical settings. A number of these therapies have provided substantially curative benefits in treating patients with COVID-19 infection. Furthermore, intensive research and clinical trials are underway to assess the efficacy of existing drugs and identify potential therapeutic targets to develop new drugs for treating COVID-19. Herein, we summarize the current potential therapeutic approaches for diseases related to COVID-19 infection and introduce their mechanisms of action, safety, and effectiveness.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder. Epidemiological studies suggest that the exposure of the herbicide glyphosate may influence the development of PD in humans. In this study, we examined whether the exposure of glyphosate can affect the reduction of dopamine transporter (DAT) in the striatum and tyrosine hydroxylase (TH) in the substantial nigra (SNr) of mouse brain after repeated administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Repeated injections of MPTP (10 mg/kg × 3, 2-h interval) significantly decreased the density of DAT-immunoreactivity in the striatum and the number of TH-immunoreactivity in the SNr. Glyphosate exposure for 14 days significantly potentiated MPTP-induced dopaminergic neurotoxicity in the striatum and SNr of mouse brain. This study suggests that glyphosate exposure might exacerbate MPTP-induced dopaminergic neurotoxicity in the striatum and SNr of adult mice. It is likely that exposure of glyphosate may be an environmental risk factor for PD since glyphosate has been used widely in the world.

Phosphodiesterase (PDE) 10A is an attractive therapeutic target for schizophrenia. Here, we investigated the antipsychotic-like effects of a novel PDE10A inhibitor, 1-({2-(7-fluoro-3-methylquinoxalin-2-yl)-5-[(3R)-3-fluoropyrrolidin-1-yl]pyrazolo[1,5-α]pyrimidin-7-yl}amino)-2-methylpropan-2-ol hydrochloride (MT-3014) in rats. MT-3014 showed a potent and selective inhibitory effect against PDE10A (IC50 = 0.357 nmol/L). Oral administration of MT-3014 (1.0-10 mg/kg) significantly increased the levels of cAMP, cGMP and cAMP response element-binding protein (CREB) phosphorylation in the rat striatum. MT-3014 decreased MK-801 (0.075 mg/kg)-induced hyperactivity (ED50 = 0.30 mg/kg) in a dose-dependent manner, although it decreased spontaneous locomotion in control rats (ED50 = 0.48 mg/kg); its effects were equivalent to those of risperidone. MT-3014 (0.3-3.0 mg/kg and 0.2 mg/kg) attenuated MK-801-induced prepulse inhibition deficits and cognitive deficits in rats, respectively, whereas risperidone attenuated MK-801-induced prepulse inhibition at only a high dose and failed to improve MK-801-induced cognitive deficits. Similar to risperidone (ID50 = 0.63 mg/kg), MT-3014 suppressed the conditioned avoidance response (ID50 = 0.32 mg/kg). Interestingly, MT-3014 did not elicit catalepsy and plasma prolactin increases at high doses. Furthermore, it also did not affect body weight. A positron emission tomography study using [11C]IMA107 showed a plasma concentration-dependent increase in brain PDE10A occupancy after oral administration of MT-3014 within the pharmacological dose range in rats. Brain PDE10A occupancy corresponding to the ID50 value in the conditioned avoidance response was approximately 60%, predicting the target occupancy in patients with schizophrenia. These results suggest that MT-3014 may be a novel antipsychotic drug, which is expected to have additional effects on cognitive impairment, without the prominent side effects associated with current atypical antipsychotics.

The vagus nerve plays a role in the cross talk between the brain and gut microbiota, which could be involved in depression. The subdiaphragmatic vagus nerve serves as a major modulatory pathway between the brain and gut microbiota. Here, we investigated the effects of subdiaphragmatic vagotomy (SDV) on the depression-like phenotype and the abnormal composition of gut microbiota in mice after lipopolysaccharide (LPS) administration. LPS caused a depression-like phenotype, inflammation, increase in spleen weight, and downregulation of synaptic proteins in the medial prefrontal cortex (mPFC) in the sham-operated mice. In contrast, LPS did not produce a depression-like phenotype and downregulated synaptic proteins in the mPFC after SDV. The spleen weight and plasma levels of pro-inflammatory cytokines in the SDV + LPS group were lower than those of the sham + LPS group. Interestingly, there were positive correlations between the plasma levels of pro-inflammatory cytokines and spleen weight, suggesting a relationship between inflammatory events and spleen weight. Furthermore, LPS led to significant alterations in gut microbiota diversity in sham-operated mice, but not SDV-operated mice. In an unweighted UniFrac PCoA, the dots representing the sham + LPS group were located far away from the dots representing the other three groups. Our results suggest that LPS produces a depression-like phenotype, increases spleen weight, triggers inflammation, downregulates synaptic proteins in the mPFC, and leads to abnormal composition of gut microbiota via the subdiaphragmatic vagus nerve. It is likely that the vagus nerve plays a crucial role in the brain-gut-microbiota axis.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) improves depressive symptoms and motor function in stroke patients. While metabolic derangement of the kynurenine pathway has been reported in stroke patients, the effect of rTMS on this pathway remains unknown. This study was performed to investigate the effect of rTMS on serum levels of kynurenine and tryptophan in stroke patients. METHODS: Sixty-two stroke patients received rTMS in addition to intensive rehabilitation and 33 stroke patients received intensive rehabilitation alone for 14 days. The rTMS involved low-frequency stimulation (at 1 Hz) of the primary motor cortex on the unaffected side of the cerebrum. The depressive state of the patients was evaluated with the Beck Depression Inventory (BDI) before and after treatment. Motor function of the patients was evaluated with Fugl-Meyer Assessment (FMA). Serum levels of kynurenine and tryptophan levels were also measured before and after treatment. RESULTS: The serum tryptophan level decreased in the group receiving rTMS to the right brain and increased in the group receiving rTMS to the left brain. The serum kynurenine/tryptophan ratio was elevated in the group receiving rTMS to the right brain. The BDI indicated improvement of depressive symptoms in the rehabilitation alone group and the group receiving rTMS to the right brain plus rehabilitation. The FMA improved in all groups. CONCLUSIONS: The effect of low-frequency rTMS on the kynurenine pathway may differ depending on whether it is applied to the right or left cerebral hemisphere.

Sleep is known to play an important role in immune function. However, the effects of sleep quality during hospitalization for COVID-19 remain unclear. This retrospective, single-center cohort study was conducted to investigate the effects of sleep quality on recovery from lymphopenia and clinical outcomes in hospitalized patients with laboratory-confirmed COVID-19 admitted to the West District of Wuhan Union Hospital between January 25 and March 15, 2020. The Richards-Campbell sleep questionnaire (RCSQ) and Pittsburgh Sleep Quality Index (PSQI) were used to assess sleep quality. The epidemiological, demographic, clinical, laboratory, treatment, and outcome data were collected from electronic medical records and compared between the good-sleep group and poor-sleep group. In all, 135 patients (60 in good-sleep group and 75 in poor-sleep group) were included in this study. There were no significant between-group differences regarding demographic and baseline characteristics, as well as laboratory parameters upon admission and in-hospital treatment. Compared with patients in the good-sleep group, patients in the poor-sleep group had lower absolute lymphocyte count (ALC) (day 14: median, 1.10 vs 1.32, P = 0.0055; day 21: median, 1.18 vs 1.48, P = 0.0034) and its reduced recovery rate (day 14: median, 56.91 vs 69.40, P = 0.0255; day 21: median, 61.40 vs 111.47, P = 0.0003), as well as increased neutrophil-to-lymphocyte ratio (NLR; day 14: median, 3.17 vs 2.44, P = 0.0284; day 21: median, 2.73 vs 2.23, P = 0.0092) and its associated deterioration rate (day 14: median, -39.65 vs -61.09, P = 0.0155; day 21: median, -51.40% vs -75.43, P = 0.0003). Nine [12.0%] patients in the poor-sleep group required ICU care (P = 0.0151); meanwhile, none of the patients in good-sleep group required ICU care. Patients in the poor-sleep group had increased duration of hospital stay (33.0 [23.0-47.0] days vs 25.0 [20.5-36.5] days, P = 0.0116) compared to those in the good-sleep group. An increased incidence of hospital-acquired infection (seven [9.3%] vs one [1.7%]) was observed in the poor-sleep group compared to the good-sleep group; however, this difference was not significant (P = 0.1316). In conclusion, poor sleep quality during hospitalization in COVID-19 patients with lymphopenia is associated with a slow recovery from lymphopenia and an increased need for ICU care.

BACKGROUND: Soluble epoxide hydrolase (sEH) in the metabolism of polyunsaturated fatty acids might play a role in the pathogenesis of major psychiatric disorders. Here we studied whether expression of sEH protein is altered in the postmortem samples (parietal cortex, and liver) from patients with major psychiatric disorders. METHODS: Protein expression of sEH in the parietal cortex and liver from control, major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) groups was measured. RESULTS: Levels of sEH in the parietal cortex and liver from MDD, BD, and SZ groups were significantly higher than the control group. Interestingly, there was a positive correlation between sEH protein in the parietal cortex and sEH protein the liver in all groups. LIMITATIONS: The small number in each group may limit our interpretation. CONCLUSIONS: This study shows that the increased expression of sEH in the brain and liver might play a role in the pathogenesis of major psychiatric disorders, suggesting a role of brain - liver axis in major psychiatric disorders.

AIM: Matrix metalloproteinase-9 (MMP-9) has been shown to modulate synaptic plasticity and may contribute to the pathophysiology of schizophrenia. This study investigated the peripheral levels of MMP-9 and its association with cognitive functions in patients with schizophrenia to see the possible involvement of MMP-9 in pathophysiology of schizophrenia, especially in cognitive decline. METHODS: We measured the plasma levels of MMP-9 in 257 healthy controls and 249 patients with schizophrenia, including antipsychotic drug-free patients. We also explored the possible association between plasma MMP-9 levels and cognitive performance in healthy controls and patients with schizophrenia using the Wechsler Adult Intelligence Scale, Third Edition (WAIS- III), the Wechsler Memory Scale-Revised (WMS-R), and the Rey Auditory Verbal Learning Test (AVLT). RESULTS: We found that the plasma levels of MMP-9 were significantly higher in patients with schizophrenia, including antipsychotic drug-free patients, than in healthy controls. We found a significant negative association between plasma MMP-9 levels and cognitive performance in controls and patients with schizophrenia. CONCLUSION: Together, these convergent data suggest a possible biological mechanism for schizophrenia, whereby increased MMP-9 levels are associated with cognitive impairment.

AIM: Epidemiological data suggest that maternal immune activation (MIA) plays a role in the etiology of neuropsychiatric disorders including autism spectrum disorder (ASD) and schizophrenia. However, there is no prophylactic nutrition that can prevent the onset of neurodevelopmental disorders in offspring after MIA. The aim of this study was undertaken to examine whether dietary intake of glucoraphanin (GF: the precursor of a natural anti-inflammatory compound sulforaphane) can prevent the onset of behavioral abnormalities in offspring after MIA. METHODS: One percent of GF food pellet or normal food pellet was given into female mice during pregnancy and lactation (from E5 to P21). Saline (5 mL/kg/d) or poly(I:C) (5 mg/kg/d) was injected into pregnant mice from E12 to E17. Behavioral tests and immunohistochemistry of parvalbumin (PV) were performed in male offspring. RESULTS: Dietary intake of GF during pregnancy and lactation prevented cognitive deficits and social interaction deficits in the juvenile offspring after MIA. Furthermore, dietary intake of GF during pregnancy and lactation prevented cognitive deficits in the adult offspring after MIA. Moreover, dietary intake of GF prevented the reduction of PV immunoreactivity in the medial prefrontal cortex of adult offspring after MIA. CONCLUSION: These data suggest that dietary intake of GF during pregnancy and lactation could prevent behavioral abnormalities in offspring after MIA.

Epidemiological studies suggest that exposure to herbicides during pregnancy might increase risk for autism spectrum disorder (ASD) in offspring. However, the precise mechanisms underlying the risk of ASD by herbicides such as glyphosate remain unclear. Soluble epoxide hydrolase (sEH) in the metabolism of polyunsaturated fatty acids is shown to play a key role in the development of ASD in offspring after maternal immune activation. Here, we found ASD-like behavioral abnormalities in juvenile offspring after maternal exposure to high levels of formulated glyphosate. Furthermore, we found higher levels of sEH in the prefrontal cortex (PFC), hippocampus, and striatum of juvenile offspring, and oxylipin analysis showed decreased levels of epoxy-fatty acids such as 8 (9)-EpETrE in the blood, PFC, hippocampus, and striatum of juvenile offspring after maternal glyphosate exposure, supporting increased activity of sEH in the offspring. Moreover, we found abnormal composition of gut microbiota and short-chain fatty acids in fecal samples of juvenile offspring after maternal glyphosate exposure. Interestingly, oral administration of TPPU (an sEH inhibitor) to pregnant mothers from E5 to P21 prevented ASD-like behaviors such as social interaction deficits and increased grooming time in the juvenile offspring after maternal glyphosate exposure. These findings suggest that maternal exposure to high levels of glyphosate causes ASD-like behavioral abnormalities and abnormal composition of gut microbiota in juvenile offspring, and that increased activity of sEH might play a role in ASD-like behaviors in offspring after maternal glyphosate exposure. Therefore, sEH may represent a target for ASD in offspring after maternal stress from occupational exposure to contaminants.

Cytochrome P450 (CYP) metabolism of arachidonic acid (ARA) produces epoxy fatty acids (EpFAs) such as epoxyeicosatrienoic acids (EETs) that are known to exert protective effects in inflammatory disorders. Endogenous EpFAs are further metabolized into corresponding diols by the soluble epoxide hydrolase (sEH). Through inhibition of sEH, many studies have demonstrated the cardioprotective and renoprotective effects of EpFAs; however, the role of sEH inhibition in modulating the pathogenesis of neuroinflammatory disorders is less well described. In this review, we discuss the current knowledge surrounding the effects of sEH inhibition and EpFA action in neuroinflammatory disorders such as Parkinson's Disease (PD), stroke, depression, epilepsy, and Alzheimer's Disease (AD), as well as the potential mechanisms that underlie the therapeutic effects of sEH inhibition.

Clinical and preclinical studies have shown that the N-methyl-d-aspartate receptor antagonist ketamine exerts rapid and long-lasting antidepressant effects. Although ketamine metabolites might also have potential antidepressant properties, controversial results have been reported for (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) in particular, and there is little information regarding the effects of other ketamine metabolites. Here we aimed to compare the effects of (R)-norketamine ((R)-NK), (S)-NK, (2R,6R)-HNK, and (2S,6S)-HNK in a mouse model of depression induced by chronic corticosterone (CORT) injection. None of the ketamine metabolites at doses up to 20 mg/kg showed antidepressant-like activity in naïve male C57BL6/J mice. Chronic CORT treatment increased immobility in the forced swim test and caused anhedonic-like behaviors in the female encounter test. A single administration of (S)-NK and (2S,6S)-HNK dose-dependently reduced the enhanced immobility at 30 min after injection in chronic CORT-treated mice, while (R)-NK or (2R,6R)-HNK did not. Additionally, (S)-NK and (2S,6S)-HNK, but not (R)-NK or (2R,6R)-HNK, improved chronic CORT-induced anhedonia at 24 h after the injection. These results suggest that (S)-ketamine metabolites (S)-NK and (2S,6S)-HNK have potent acute and sustained antidepressant effects in rodents.