Regulatory T lymphocytes in traumatic brain injury.

Traumatic brain injury (TBI) presents a significant global health challenge with no effective therapies developed to date. Regulatory T lymphocytes (Tregs) have recently emerged as a potential therapy due to their critical roles in maintaining immune homeostasis, reducing inflammation, and promoting brain repair. Following TBI, fluctuations in Treg populations and shifts in their functionality have been noted. However, the precise impact of Tregs on the pathophysiology of TBI remains unclear. In this review, we discuss recent advances in understanding the intricate roles of Tregs in TBI and other brain diseases. Increased knowledge about Tregs may facilitate their future application as an immunotherapy target for TBI treatment.

Regulatory T cell expansion promotes white matter repair after stroke.

Recent research highlights the function of regulatory T cells (Tregs) in white matter integrity in CNS diseases. Approaches that expand the number of Tregs have been utilized to improve stroke recovery. However, it remains unclear if Treg augmentation preserves white matter integrity early after stroke or promotes white matter repair. This study evaluates the effect of Treg augmentation on white matter injury and repair after stroke. Adult male C57/BL6 mice randomly received Treg or splenocyte (2 million, iv) transfer 2 h after transient (60 min) middle cerebral artery occlusion (tMCAO). Immunostaining showed improved white matter recovery after tMCAO in Treg-treated mice compared to mice received splenocytes. In another group of mice, IL-2/IL-2 antibody complexes (IL-2/IL-2Ab) or isotype IgG were administered (i.p) for 3 consecutive days starting 6 h after tMCAO, and repeated on day 10, 20 and 30. The IL-2/IL-2Ab treatment boosted the number of Tregs in blood and spleen and increased Treg infiltration into the ischemic brain. Longitudinal in vivo and ex vivo diffusion tensor imaging analysis revealed an increase in fractional anisotropy 28d and 35d, but not 14d, after stroke in IL-2/IL-2Ab-treated mice compared to isotype-treated mice, suggesting a delayed improvement in white matter integrity. IL-2/IL-2Ab also improved sensorimotor functions (rotarod test and adhesive removal test) 35d after stroke. There were correlations between white matter integrity and behavior performance. Immunostaining confirmed the beneficial effects of IL-2/IL-2Ab on white matter structures 35d after tMCAO. IL-2/IL-2Ab treatment starting as late as 5d after stroke still improved white matter integrity 21d after tMCAO, suggesting long-term salutary effects of Tregs on the late-stage tissue repair. We also found that IL-2/IL-2Ab treatment reduced the number of dead/dying OPCs and oligodendrocytes in the brain 3d after tMCAO. To confirm the direct effect of Tregs on remyelination, Tregs were cocultured with lysophosphatidyl choline (LPC)-treated organotypic cerebella. LPC exposure for 17 h induced demyelination in organotypic cultures, followed by gradual spontaneous remyelination upon removal of LPC. Co-culture with Tregs accelerated remyelination in organotypic cultures 7d after LPC. In conclusion, Boosting the number of Tregs protects oligodendrocyte lineage cells early after stroke and promotes long-term white matter repair and functional recovery. IL-2/IL-2Ab represents a feasible approach of Treg expansion for stroke treatment.

Abnormal compositions of gut microbiota and metabolites are associated with susceptibility versus resilience in rats to inescapable electric stress.

BACKGROUND: Increasing evidence suggests the role of gut microbiota in resilience versus vulnerability after stress. However, the role of gut microbiota and microbiome-derived metabolites in resilience versus susceptibility in rodents exposed to stress remains unclear. METHODS: Adult male rats were exposed to inescapable electric stress under the learned helplessness (LH) paradigm. The composition of gut microbiota and metabolites in the brain and blood from control (no stress) rats, LH resilient rats, and LH susceptible rats were examined. RESULTS: At the genus level, the relative abundances of Asaccharobacter, Eisenbergiella, and Klebsiella in LH susceptible rats were significantly higher than that of LH resilient rats. At the species level, the relative abundances of several microbiome were significantly altered between LH susceptible rats and LH resilient rats. Furthermore, there were several metabolites in the brain and blood altered between LH susceptible rats and LH resilient rats. A network analysis showed correlations between the abundance of several microbiome and metabolites in the brain (or blood). LIMITATIONS: Detailed roles of microbiome and metabolites are unclear. CONCLUSIONS: These findings suggest that abnormal compositions of the gut microbiota and metabolites might contribute to susceptibility versus resilience in rats subjected to inescapable electric foot shock.

Repeated use of 3,4-methylenedioxymethamphetamine is associated with the resilience in mice after chronic social defeat stress: A role of gut-microbiota-brain axis.

3,4-Methylenedioxymethamphetamine (MDMA), the most widely used illicit compound worldwide, is the most attractive therapeutic drug for post-traumatic stress disorder (PTSD). Recent observational studies of US adults demonstrated that lifetime MDMA use was associated with lower risk of depression. Here, we examined whether repeated administration of MDMA can affect resilience versus susceptibility in mice exposed to chronic social defeat stress (CSDS). CSDS produced splenomegaly, anhedonia-like phenotype, and higher plasma levels of interleukin-6 (IL-6) in the saline-treated mice. In contrast, CSDS did not cause these changes in the MDMA-treated mice. Analysis of gut microbiome found several microbes altered between saline + CSDS group and MDMA + CSDS group. Untargeted metabolomics analysis showed that plasma levels of N-epsilon-methyl-L-lysine in the saline + CSDS group were significantly higher than those in the control and MDMA + CSDS groups. Interestingly, there were positive correlations between plasma IL-6 levels and the abundance of several microbes (or plasma N-epsilon-methyl-L-lysine) in the three groups. Furthermore, there were also positive correlations between the abundance of several microbes and N-epsilon-methyl-L-lysine in the three groups. In conclusion, these data suggest that repeated administration of MDMA might contribute to stress resilience in mice subjected to CSDS through gut-microbiota-brain axis.

Key role of the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve in demyelination of the cuprizone-treated mouse brain.

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.

A key role of miR-132-5p in the prefrontal cortex for persistent prophylactic actions of (R)-ketamine in mice.

(R,S)-ketamine is known to elicit persistent prophylactic effects in rodent models of depression. However, the precise molecular mechanisms underlying its action remain elusive. Using RNA-sequencing analysis, we searched for novel molecular target(s) that contribute to the prophylactic effects of (R)-ketamine, a more potent enantiomer of (R,S)-ketamine in chronic restraint stress (CRS) model. Pretreatment with (R)-ketamine (10 mg/kg, 1 day before CRS) significantly ameliorated body weight loss, increased immobility time of forced swimming test, and decreased sucrose preference of sucrose preference test in CRS-exposed mice. RNA-sequencing analysis of prefrontal cortex (PFC) revealed that several miRNAs such as miR-132-5p might contribute to sustained prophylactic effects of (R)-ketamine. Methyl CpG binding protein 2 (MeCP2) is known to regulate brain-derived neurotrophic factor (BDNF) expression. Quantitative RT-PCR confirmed that (R)-ketamine significantly attenuated altered expression of miR-132-5p and its regulated genes (Bdnf, Mecp2, Tgfb1, Tgfbr2) in the PFC of CRS-exposed mice. Furthermore, (R)-ketamine significantly attenuated altered expression of BDNF, MeCP2, TGF-ß1 (transforming growth factor ß1), and synaptic proteins (PSD-95, and GluA1) in the PFC of CRS-exposed mice. Administration of agomiR-132-5p decreased the expression of Bdnf and Tgfb1 in the PFC, resulting in depression-like behaviors. In contrast, administration of antagomiR-132-5p blocked the increased expression of miR-132-5p and decreased expression of Bdnf in the PFC of CRS-exposed mice, resulting in antidepressant-like effects. In conclusion, our data show a novel role of miR-132-5p in the PFC underlying depression-like phenotypes in CRS model and the sustained prophylactic effects of (R)-ketamine.

A role of microRNA-149 in the prefrontal cortex for prophylactic actions of (R)-ketamine in inflammation model.

MicroRNAs (or miRNAs) are short, regulatory RNAs that act as post-transcriptional repressors of gene expression. Recently, we reported that the nuclear factor of activated T cells 4 (NFATc4) signaling might contribute to sustained prophylactic effects of new antidepressant (R)-ketamine in lipopolysaccharide (LPS)-treated inflammation model of depression. In this study, we examined the role of miRNAs (miR-149 and miR-7688-5p) which can regulate NFATc4 in the prefrontal cortex (PFC) of male mice after administration of LPS (1.0 mg/kg). There was a positive correlation between the expression of Nfatc4 and the expression of miR-149 in the PFC. There was also a negative correlation between gene expression of Nfatc4 and gene expression of miR-7688-5p in the PFC. Gut microbiota analysis showed that pretreatment with (R)-ketamine (10 mg/kg) could restore altered composition of gut microbiota in LPS-treated mice. A network analysis showed that gut microbiota may regulate gene expression of Nfatc4 and miR-149 (or miR-7688-5p) in the PFC. Finally, inhibition of miR-149 by antagomiR-149 blocked LPS-induced depression-like behavior by attenuating LPS-induced expression of NFATc4 in the PFC. These findings suggest that the regulation of NFATc4 signaling by miR-149 might play a role in persistent prophylactic effects of (R)-ketamine, and that gut microbiota may regulate the gene expression of miRNAs in the PFC through gut-microbiota-brain axis.

Effects of spleen nerve denervation on depression-like phenotype, systemic inflammation, and abnormal composition of gut microbiota in mice after administration of lipopolysaccharide: A role of brain-spleen axis.

BACKGROUND: Accumulating evidence suggests the role of brain-spleen axis as well as brain-gut-microbiota axis in inflammation-related depression. The spleen mediates anti-inflammatory effects of the vagus nerve which plays a role in depression. However, the role of spleen nerve in inflammation-related depression remains unclear. METHODS: The effects of the splenic nerve denervation (SND) in the depression-like phenotype, systemic inflammation, and abnormal composition of gut microbiota in adult mice after administration of lipopolysaccharide (LPS) were examined. RESULTS: LPS (0.5 mg/kg) caused depression-like phenotype, systemic inflammation, splenomegaly, increased expression of Iba1 (ionized calcium-binding adapter molecule 1) and decreased expression of postsynaptic density protein-95 (PSD-95) in the hippocampus in the sham-operated mice. In contrast, LPS did not produce depression-like phenotype, and abnormal expressions of Iba1 and PSD-95 in the hippocampus in the SND-operated mice. Furthermore, SND significantly blocked LPS-induced increased plasma levels of pro-inflammatory cytokine interleukin-6 although SND did not affect LPS-induced splenomegaly and increased plasma levels of tumor necrosis factor-α in mice. There were significant changes in several microbiota among the four groups. Interestingly, there were correlations between the relative abundance of several microbiota and Iba1 (or PSD-95) expression in the hippocampus. In addition, expression of Iba1 in the hippocampus was correlated with the relative abundance of several microbiota. LIMITATIONS: Detailed mechanisms are unclear. CONCLUSIONS: These results suggest that the splenic nerve plays a role in inflammation-related depression, microglial activation in the hippocampus, and that gut microbiota may regulate microglial function in the brain via gut-microbiota-brain axis.

Loureirin C and Xanthoceraside Attenuate Depression-Like Behaviors and Expression of Interleukin-17 in the Prefrontal Cortex Induced by Chronic Unpredictable Mild Stress in Mice.

Major depressive disorder (MDD) is the most prevalent and serious psychiatric disease involving inflammation. Loureirin C and Xanthoceraside are extracts of dragon's blood and Xanthoceras sorbifolia Bunge, respectively, which have neuroprotective and anti-inflammatory properties. In this study, we examined whether Loureirin C and Xanthoceraside attenuated depression-like behaviors and inflammation induced by chronic unpredicted mild stress (CUMS) in mice. Adult C57BL/6 J mice exposed to CUMS for 4 weeks showed depression-like behaviors characterized by hyperactivity in a novel environment, decreased interaction time in the social interaction test, prolongation of eating latency in the novelty suppressed feeding test, and increased immobility in the forced swimming test. CUMS increased the expression of interleukin-17 (IL-17) in the prefrontal cortex (PFC). One week after exposure to CUMS, the mice were treated with Loureirin C (0.64 mg/kg) or Xanthoceraside (1.28 mg/kg) once a day for 3 weeks during CUMS. Loureirin C and Xanthoceraside significantly attenuated CUMS-induced behavioral impairment. Furthermore, both Loureirin C and Xanthoceraside prevented IL-17 expression induced by CUMS in the PFC. This data suggests that Loureirin C and Xanthoceraside have antidepressant-like properties that may be associated with the inhibition of IL-17 expression.

Gut-microbiota-brain axis in the vulnerability to psychosis in adulthood after repeated cannabis exposure during adolescence.

Increasing epidemiological evidence shows that the use of cannabis during adolescence could increase the risk for psychosis in adulthood. However, the precise mechanisms underlying long-lasting cannabis-induced risk for psychosis remain unclear. Accumulating evidence suggests the role of gut microbiota in the pathogenesis of psychiatric disorders. Here, we examined whether gut microbiota plays a role in the risk for psychosis of adult after exposure of cannabinoid (CB) receptor agonist WIN55,212-2 during adolescence. Repeated administration of WIN55,212-2 (2 mg/kg/day) during adolescence (P35-P45) significantly increased the expression of Iba1 (ionized calcium-binding adapter molecule 1) in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) of adult mice after administration of lipopolysaccharide (LPS: 0.5 mg/kg). In contrast, there were no changes in blood levels of pro-inflammatory cytokines between the two groups. Although alpha-diversity and beta-diversity of gut microbiota were no differences between the two groups, there were several microbes altered between the two groups. Interestingly, there were significant correlations between the relative abundance of microbiota and Iba1 expression in the mPFC and NAc. Furthermore, there were also significant correlations between the relative abundance of microbiota and several metabolites in the blood. These findings suggest that gut microbiota may play a role in the microglial activation in the mPFC and NAc of adult mice after repeated WIN55,212-2 exposure during adolescence. Therefore, it is likely that gut-microbiota-microglia crosstalk might play a role in increased risk for psychosis in adults with cannabis use during adolescence.

Soluble Epoxide Hydrolase as a Therapeutic Target for Neuropsychiatric Disorders.

It has been found that soluble epoxide hydrolase (sEH; encoded by the EPHX2 gene) in the metabolism of polyunsaturated fatty acids (PUFAs) plays a key role in inflammation, which, in turn, plays a part in the pathogenesis of neuropsychiatric disorders. Meanwhile, epoxy fatty acids such as epoxyeicosatrienoic acids (EETs), epoxyeicosatetraenoic acids (EEQs), and epoxyeicosapentaenoic acids (EDPs) have been found to exert neuroprotective effects in animal models of neuropsychiatric disorders through potent anti-inflammatory actions. Soluble expoxide hydrolase, an enzyme present in all living organisms, metabolizes epoxy fatty acids into the corresponding dihydroxy fatty acids, which are less active than the precursors. In this regard, preclinical findings using sEH inhibitors or Ephx2 knock-out (KO) mice have indicated that the inhibition or deficiency of sEH can have beneficial effects in several models of neuropsychiatric disorders. Thus, this review discusses the current findings of the role of sEH in neuropsychiatric disorders, including depression, autism spectrum disorder (ASD), schizophrenia, Parkinson's disease (PD), and stroke, as well as the potential mechanisms underlying the therapeutic effects of sEH inhibitors.

Effects of Subdiaphragmatic Vagotomy in the MPTP-induced Neurotoxicity in the Striatum and Colon of Mice.

Objective: Gut-microbiota-brain axis plays a role in the pathogenesis of Parkinson's disease (PD). The subdiaphragmatic vagus nerve serves as a major modulatory pathway between the gut microbiota and the brain. However, the role of subdiaphragmatic vagus nerve in PD pathogenesis are unknown. Here, we investigated the effects of subdiaphragmatic vagotomy (SDV) on the neurotoxicity in the mouse striatum and colon after administration of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). Methods: Sham or SVD was performed. Subsequently, saline or MPTP (10 mg/kg × 3, 2-hour interval) was administered to mice. Western blot analysis of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum and phosphorylated α-synuclein (p-α-Syn) in the colon was performed. Results: Repeated administration of MPTP significantly caused reduction of TH and DAT in the striatum and increase of p-α-Syn in the colon of mice. However, SDV did not affect the reduction of TH and DAT in the striatum and increases in p-α-Syn in the colon after repeated MPTP administration. Conclusion: These data suggest that subdiaphragmatic vagus nerve doses not play a role in the MPTP-induced neurotoxicity in the brain and colon.

Nuclear factor of activated T cells 4 in the prefrontal cortex is required for prophylactic actions of (R)-ketamine.

(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.

(R)-ketamine ameliorates demyelination and facilitates remyelination in cuprizone-treated mice: A role of gut-microbiota-brain axis.

Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. We recently reported that the new antidepressant (R)-ketamine could ameliorate the disease progression in experimental autoimmune encephalomyelitis model of MS. Cuprizone (CPZ) has been used to produce demyelination which resembles demyelination in MS patients. This study was undertaken to investigate whether (R)-ketamine could affect demyelination in CPZ-treated mice and remyelination after CPZ withdrawal. Repeated treatment with (R)-ketamine (10 mg/kg/day, twice weekly, for 6 weeks) significantly ameliorated demyelination and activated microglia in the brain compared with saline-treated mice. Furthermore, pretreatment with ANA-12 (TrkB antagonist) significantly blocked the beneficial effects of (R)-ketamine on the demyelination and activated microglia in the brain of CPZ-treated mice. The 16S rRNA analysis showed that (R)-ketamine significantly improved abnormal composition of gut-microbiota and decreased levels of lactic acid of CPZ-treated mice. In addition, there were significant correlations between demyelination (or microglial activation) in the brain and the relative abundance of several microbiome, suggesting a link between gut microbiota and brain. Interestingly, (R)-ketamine could facilitate remyelination in the brain after CPZ withdrawal. In conclusion, the study suggests that (R)-ketamine could ameliorate demyelination in the brain of CPZ-treated mice through TrkB activation, and that gut-microbiota-microglia crosstalk may play a role in the demyelination of CPZ-treated mice. Therefore, it is likely that (R)-ketamine could be a new therapeutic drug for MS.

(R)-ketamine ameliorates the progression of experimental autoimmune encephalomyelitis in mice.

Multiple sclerosis (MS) is an immune-mediated neurological disease that attacks the central nervous system, including spinal cord and brain. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used model for MS. Depression is the most prevalent comorbidity in MS patients. We previously demonstrated that (R)-ketamine would be a novel antidepressant without side effects of ketamine. This study was undertaken to investigate whether (R)-ketamine could attenuate disease progression in EAE mouse model. (R)-ketamine (10 mg/kg/day for 15 days) significantly attenuated the reduction of body weight in EAE model mice compared to saline-treated mice. Furthermore, (R)-ketamine ameliorated the clinical EAE scores compared to saline-treated mice. Moreover, (R)-ketamine significantly attenuated the marked increases in the pathological scores, microglial activation, and blood-brain barrier integrity in the spinal cord compared to saline-treated mice. In conclusion, the current study suggests that (R)-ketamine could ameliorate EAE clinical scores and pathological changes in the spinal cord of EAE mice. Therefore, it is likely that (R)-ketamine would be a new potential prophylactic drug for MS.

Regulation of neurotoxicity in the striatum and colon of MPTP-induced Parkinson's disease mice by gut microbiome.

Increasing evidence suggests the role of gut-microbiota-brain axis in the pathogenesis of Parkinson's disease (PD). The objective of this study was to examine whether repeated administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) can influence the neurotoxicity in the striatum and colon, and the composition of gut microbiota and short-chain fatty acids (SCFAs) in feces of adult mice. MPTP caused the reduction of dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the striatum, and increases in phosphorylated α-synuclein (p-α-Syn) in the striatum and colon. There was a negative correlation between the expression of TH in the striatum and the expression of p-α-Syn in the colon, suggesting a role of gut-brain communication. MPTP caused abnormalities in the α- and ß-diversity of gut microbiota in the mice. Furthermore, the relative abundance of the genus Faecalicatena in the MPTP-treated group was significantly lower than that of control group. Interestingly, there was a positive correlation between the genus Faecalicatena and the expression of TH in the striatum. Moreover, MPTP did not alter the levels of SCFAs in feces samples. However, there was a positive correlation between the relative abundance of the genus Faecalicatena and propionic acid. The data suggest that MPTP-induced increases in colonic p-α-Syn expression might be associated with dopaminergic neurotoxicity in the striatum via gut-microbiota-brain axis.

(R)-Ketamine ameliorates lethal inflammatory responses and multi-organ injury in mice induced by cecum ligation and puncture.

AIMS: Sepsis is a life-threatening organ dysfunction syndrome arising from infection-induced uncontrolled systemic inflammatory responses. Patients surviving severe sepsis also exhibit increased mortality due to enhanced vulnerability to infections. In this study, we examined whether (R)-ketamine could prevent against lethal sepsis-induced systemic inflammation and inflammatory organ injury. MAIN METHODS: Septic model was induced by cecal ligation and puncture (CLP) surgery on adult mice. (R)-ketamine (10 or 15 mg/kg) was administrated intraperitoneally (i.p.) 24 h before and/or immediately after CLP. KEY FINDINGS: Combined prophylactic and therapeutic use of (R)-ketamine (10 mg/kg), as well as either prophylactic or therapeutic use of (R)-ketamine at a single dose of 15 mg/kg did not reduce 14-day mortality after CLP. However, combined prophylactic and therapeutic use of (R)-ketamine (15 mg/kg) significantly increased 14-day survival rate, attenuated sepsis-induced marked drop in the rectal temperature and increase in the plasma levels of inflammatory cytokines [i.e., interleukin (IL)-6, IL-17A, tumor necrosis factor (TNF)-α, IL-1ß, and IL-10] 12 h after CLP. Furthermore, (R)-ketamine alleviated sepsis-induced increase in the organ injury markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), myocardial kinase (CK-MB), and creatinine 24 h after CLP. Moreover, the increased lung wet/dry weight ratio, pulmonary morphological injury and the pulmonary levels of inflammatory cytokines were also attenuated by (R)-ketamine. SIGNIFICANCE: Combined prophylactic and therapeutic use of (R)-ketamine could attenuate systemic inflammation and inflammatory multi-organ injury in mice after CLP-induced lethal sepsis. Therefore, (R)-ketamine would be a potential prophylactic and therapeutic drug for patients prone to sepsis.

Autism-like Behaviors in Male Juvenile Offspring after Maternal Glyphosate Exposure.

OBJECTIVE: Exposure to the herbicide glyphosate during pregnancy and lactation may increase the risk for autism spectrum disorder (ASD) in offspring. Recently, we reported that maternal exposure of formulated glyphosate caused ASD-like behaviors in juvenile offspring. Here, we investigated whether maternal exposure of pure glyphosate could cause ASD-like behaviors in juvenile offspring. METHODS: Water or 0.098% glyphosate was administered as drinking water from E5 to P21 (weaning). Behavioral tests such as grooming test and three-chamber social interaction test in male offspring were performed from P28 to P35. RESULTS: Male offspring showed ASD-like behavioral abnormalities (i.e., increasing grooming behavior and social interaction deficit) after maternal exposure of glyphosate. CONCLUSION: The findings suggest that the exposure of glyphosate during pregnancy and lactation may cause ASD-like behavioral abnormalities in male juvenile offspring. It is likely that glyphosate itself, but not the other ingredients, may contribute to ASD-like behavioral abnormalities in juvenile offspring.

(R)-Ketamine attenuates LPS-induced endotoxin-derived delirium through inhibition of neuroinflammation.

RATIONALE: (R)-Ketamine produced beneficial effects in a variety of models of inflammatory diseases, including low dose of bacterial lipopolysaccharide (LPS) (0.5-1.0 mg/kg)-induced endotoxemia. LPS-treated mice have been used as animal model of delirium. OBJECTIVES: We investigated the effects of (R)-ketamine in neuroinflammation and cognitive impairment in rodents after administration of high dose of LPS. METHODS: LPS (5 mg/kg) or saline was administered intraperitoneally (i.p.) to mice. (R)-Ketamine (10 mg/kg) was administrated i.p. 24 h before and/or 10 min after LPS injection. RESULTS: LPS (5.0 mg/kg) caused a remarkable splenomegaly and increased plasma levels of pro-inflammatory cytokines [i.e., interleukin (IL-6), IL-17A, and interferon (IFN)-γ]. There were positive correlations between spleen weight and plasma cytokines levels. Furthermore, LPS led to increased levels of pro-inflammatory cytokines in the prefrontal cortex (PFC) and hippocampus. Moreover, LPS impaired the natural and learned behaviors, as demonstrated by a decrease in the number of mice's entries and duration in the novel arm in the Y maze test and an increase in the latency of mice to eat the food in the buried food test. Interestingly, the treatment with (R)-ketamine (twice 24 h before and 10 min after LPS injection) significantly attenuated LPS-induced splenomegaly, central and systemic inflammation, and cognitive impairment. CONCLUSION: Our results highlighted the importance of combined prophylactic and therapeutic use of (R)-ketamine in the attenuation of LPS-induced systemic inflammation, neuroinflammation, and cognitive impairment in mice. It is likely that (R)-ketamine could be a prophylactic drug for delirium.