Parvalbumin interneurons in human ventromedial prefrontal cortex: a comprehensive post-mortem study of myelination and perineuronal nets in neurotypical individuals and depressed suicides with and without a history of child abuse.

Cortical parvalbumin interneurons (PV+) are major regulators of excitatory/inhibitory information processing, and their maturation is associated with the opening of developmental critical periods (CP). Recent studies reveal that cortical PV+ axons are myelinated, and that myelination along with perineuronal net (PNN) maturation around PV+ cells is associated with the closures of CP. Although PV+ interneurons are susceptible to early-life stress, their relationship between their myelination and PNN coverage remains unexplored. This study compared the fine features of PV+ interneurons in well-characterized human post-mortem ventromedial prefrontal cortex samples (n = 31) from depressed suicides with or without a history of child abuse (CA) and matched controls. In healthy controls, 81% of all sampled PV+ interneurons displayed a myelinated axon, while a subset (66%) of these cells also displayed a PNN, proposing a relationship between both attributes. Intriguingly, a 3-fold increase in the proportion of unmyelinated PV+ interneurons with a PNN was observed in CA victims, along with greater PV-immunofluorescence intensity in myelinated PV+ cells with a PNN. This study, which is the first to provide normative data on myelination and PNNs around PV+ interneurons in human neocortex, sheds further light on the cellular and molecular consequences of early-life adversity on cortical PV+ interneurons.

Targeting SRSF3 restores immune mRNA translation in microglia/macrophages following cerebral ischemia.

We recently described a novel ribosome-based regulatory mechanism/checkpoint that controls innate immune gene translation and microglial activation in non-sterile inflammation orchestrated by RNA binding protein SRSF3. Here we describe a role of SRSF3 in the regulation of microglia/macrophage activation phenotypes after experimental stroke. Using a model-system for analysis of the dynamic translational state of microglial ribosomes we show that 24 h after stroke highly upregulated immune mRNAs are not translated resulting in a marked dissociation of mRNA and protein networks in activated microglia/macrophages. Next, microglial activation after stroke was characterized by a robust increase in pSRSF3/SRSF3 expression levels. Targeted knockdown of SRSF3 using intranasal delivery of siRNA 24 h after stroke caused a marked knockdown of endogenous protein. Further analyses revealed that treatment with SRSF3-siRNA alleviated translational arrest of selected genes and induced a transient but significant increase in innate immune signaling and IBA1+ immunoreactivity peaking 5 days after initial injury. Importantly, delayed SRSF3-mediated increase in immune signaling markedly reduced the size of ischemic lesion measured 7 days after stroke. Together, our findings suggest that targeting SRSF3 and immune mRNA translation may open new avenues for molecular/therapeutic reprogramming of innate immune response after ischemic injury.

5-HT3 Receptor Antagonists in Neurologic and Neuropsychiatric Disorders: The Iceberg Still Lies beneath the Surface.

5-HT3 receptor antagonists, first introduced to the market in the mid-1980s, are proven efficient agents to counteract chemotherapy-induced emesis. Nonetheless, recent investigations have shed light on unappreciated dimensions of this class of compounds in conditions with an immunoinflammatory component as well as in neurologic and psychiatric disorders. The promising findings from multiple studies have unveiled several beneficial effects of these compounds in multiple sclerosis, stroke, Alzheimer disease, and Parkinson disease. Reports continue to uncover important roles for 5-HT3 receptors in the physiopathology of neuropsychiatric disorders, including depression, anxiety, drug abuse, and schizophrenia. This review addresses the potential of 5-HT3 receptor antagonists in neurology- and neuropsychiatry-related disorders. The broad therapeutic window and high compliance observed with these agents position them as suitable prototypes for the development of novel pharmacotherapeutics with higher efficacy and fewer adverse effects.

Microglia-derived galectin-3 in neuroinflammation; a bittersweet ligand?

Galectins are soluble ß-galactoside-binding proteins found in all multicellular organisms. Galectins may act as danger-associated molecular patterns in innate immunity and/or as pattern-recognition receptors that bind to pathogen-associated molecular patterns. Among different galectin family members, galectin-3 has been the focus of studies in neurodegenerative diseases in recent years. This lectin modulates brain innate immune responses, microglia activation patterns in physiological and pathophysiological settings in a context-dependent manner. Galectin-3 is considered as a pivotal tuner of macrophage and microglial activity. Indeed galectin-3 acts as a double edged sword in neuroinflammatory context and this multimodal lectin has diverse roles in physiological and pathophysiological conditions. Better understanding of galectin-3 physiology (its extracellular and intracellular actions) and structure (its C terminus vs. N terminus) is instrumental to design molecules that selectively modulate galectin-3 function toward neuroprotective phenotypes. Several experimental studies using different approaches and methods have demonstrated both protective and deleterious effects of galectin-3 in neuroinflammatory diseases. According to the crucial role of galectin-3 in modulation of innate immune response in brain, it is an attractive target in drug discovery of neurodegenerative diseases. The current insight attempts to provide an updated and balanced discussion on the role of galectin-3 as a complex endogenous immune modulator. This helps to have a better insight into the development of galectin-3 modulators with translational value in different neurological disorders including stroke and neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease and Parkinson's disease.

Intra-prefrontal cyclosporine potentiates ketamine-induced fear extinction in rats.

Several brain regions, including the medial prefrontal cortex (mPFC), are important in the process of fear extinction learning. Ketamine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, which is shown to play a role in extinction modulation. Ketamine and calcineurin (CN), an intracellular protein phosphatase, have several common targets in the cells. Therefore, in the present study, our aim is to investigate the possible role of calcineurin in the mPFC on the enhancing effects of ketamine in fear extinction. First, different doses of a CN inhibitor, cyclosporine-A (CsA), were micro-injected into the infralimbic (IL) region of the mPFC prior to extinction training in a classical conditioning model in rats. Next, sub-effective doses of CsA (Intra-mPFC) and ketamine (i.p.) were co-administered in another cohort of rats to find their possible interactions. Enzymatic activity of calcineurin was measured in the IL-mPFC following drug administration. We used the elevated plus-maze (EPM) and open field (OF) test for further behavioral assessments. The results showed that CsA can enhance the extinction of conditioned fear and inhibit the enzyme CN at a dose of 20 nM. The combination of sub-effective doses of CsA (5 nM) and ketamine (10 mg/kg) could again enhance the extinction of fear and reduce CN activity in the region. Our results propose that inhibition of CN in the IL-mPFC is involved in the extinction of fear and ketamine enhancement of extinction is probably mediated by reducing CN activity in this part of the brain.

Oxytocinergic system mediates the proconvulsant effects of sildenafil: The role of calcineurin.

Sildenafil is a phosphodiesterase type 5 inhibitor used to treat male erectile dysfunction and pulmonary hypertension. A potential side effect of sildenafil is a noticeable decrease in seizure threshold. Oxytocin (OXT) secretion and the subsequent cAMP-responsive element-binding (CREB) phosphorylation are involved in proconvulsant effects of sildenafil in experimental models. The aim of the present study was to investigate the potential role of OXT receptors and their downstream calcineurin (CN)/inducible nitric oxide synthase (iNOS) pathways in proconvulsant effects of sildenafil. The pentylenetetrazole (PTZ)-induced seizure was used as a standard convulsion model in this study. Cortical CN activity, hippocampal nitrite levels, and proinflammatory cytokine content were measured. Our results indicated that following PTZ administration, sildenafil significantly increased CN activity at 40 mg/kg, respectively, in the control group. The combination of sildenafil and OXT receptor antagonist, atosiban (10 µg/kg, i.c.v) 30 min before sildenafil administration significantly reduced the CN activity. Also, the subeffective dose of CN inhibitor cyclosporine (5 mg/kg) 30 min before the administration of effective dose of sildenafil (40 mg/kg) reversed proconvulsant actions of sildenafil. This effect was iNOS-dependent because pretreatment of a low dose of aminoguanidine (20 mg/kg) 15 min before the administration of a low dose of cyclosporine (1 mg/kg) reversed the proconvulsant action of sildenafil (40 mg/kg). Finally, sildenafil induced the elevation of tumor necrosis factor alpha (TNF-α) and the nitrite level was blocked by the administration of cyclosporine in PTZ-treated mice. Collectively, our data provide insights into the role of OXT receptor/CN/iNOS pathway in the proconvulsant aspect of sildenafil.

Involvement of central opioid receptors in protective effects of methadone on experimental colitis in rats.

PURPOSE: There are several lines of evidence on the protective roles of opioids in gastrointestinal inflammatory conditions. This study aims to distinguish the central and peripheral roles of methadone, a non-selective opioid receptor agonist, in an acute model of ulcerative colitis in male rats. METHODS: Ulcerative colitis was induced by intrarectal administration of acetic acid 4%. Methadone was injected subcutaneously (s.c.), 5 and 10 mg/kg, and intracerebroventricular (i.c.v.), 50 and 300 ng/rat. Opioid antagonists were employed. Methylnaltrexone (MNTX; 5 mg/kg, i.p.), a peripherally acting opioid receptor antagonist, and naltrexone (NTX; 5 mg/kg, i.p. and 10 ng/rat, i.c.v.), a peripherally and centrally acting opioid receptor antagonist were injected before methadone (10 mg/kg, s.c. and or 300 ng/rat, i.c.v.) administration. NTX (5 mg/kg, i.p. and 10 ng/rat, i.c.v.) were administered 30 min prior to administration of methadone (10 mg/kg, s.c. and 300 ng/rat, i.c.v.), respectively. MNTX (5 mg/kg, i.p.) was injected 30 min prior to methadone (10 mg/kg, s.c.). Seventy-two hours following colitis induction, macroscopic and microscopic mucosal lesions, and the colonic levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1ß (IL-1ß) were determined. RESULTS: Methadone (300 ng/rat, i.c.v.) and Methadone (5 and 10 mg/kg, s.c.) improved the macroscopic and microscopic scores through opioid receptors. Also, a significant reduction in TNF-α and IL-1ß was observed. Peripherally and centrally injected NTX significantly reversed methadone 10 mg/kg s.c. anti-inflammatory effects while MNTX could not completely reverse this effect. Moreover, centrally administered methadone (300 ng/rat) showed the anti-inflammatory effect which was reversed by central administration of NTX (10 ng/rat). CONCLUSIONS: The opioid receptors mainly the central opioid receptors may mediate the protective actions of methadone on the experimental model of inflammatory bowel disease in rat.

IL-10 Controls Early Microglial Phenotypes and Disease Onset in ALS Caused by Misfolded Superoxide Dismutase 1.

While reactive microgliosis is a hallmark of advanced stages of amyotrophic lateral sclerosis (ALS), the role of microglial cells in events initiating and/or precipitating disease onset is largely unknown. Here we provide novel in vivo evidence of a distinct adaptive shift in functional microglial phenotypes in preclinical stages of superoxide dismutase 1 (SOD1)-mutant-mediated disease. Using a mouse model for live imaging of microglial activation crossed with SOD1(G93A) and SOD1(G37R) mouse models, we discovered that the preonset phase of SOD1-mediated disease is characterized by development of distinct anti-inflammatory profile and attenuated innate immune/TLR2 responses to lipopolysaccharide (LPS) challenge. This microglial phenotype was associated with a 16-fold overexpression of anti-inflammatory cytokine IL-10 in baseline conditions followed by a 4.5-fold increase following LPS challenge. While infusion of IL-10R blocking antibody, initiated at day 60, caused a significant increase in markers of microglial activation and precipitated clinical onset of disease, a targeted overexpression of IL-10 in microglial cells, delivered via viral vectors expressed under CD11b promoter, significantly delayed disease onset and increased survival of SOD1(G93A) mice. We propose that the high IL-10 levels in resident microglia in early ALS represent a homeostatic and compensatory "adaptive immune escape" mechanism acting as a nonneuronal determinant of clinical onset of disease. Significance statement: We report here for the first time that changing the immune profile of brain microglia may significantly affect clinical onset and duration of disease in ALS models. We discovered that in presymptomatic disease microglial cells overexpress anti-inflammatory cytokine IL-10. Given that IL-10 is major homeostatic cytokine and its production becomes deregulated with aging, this may suggest that the capacity of microglia to adequately produce IL-10 may be compromised in ALS. We show that blocking IL-10 increased inflammation and precipitated clinical disease onset, whereas overexpression of IL-10 in microglia using a gene therapy approach significantly delayed disease onset and increased survival of ALS mice. Based on our results, we propose that targeted overexpression of IL-10 in microglia may have therapeutic potential in ALS.

Involvement of PPARγ in the protective action of tropisetron in an experimental model of ulcerative colitis.

Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal (GI) tract. Tropisetron, a selective 5-HT3 receptor antagonist, is highly used to counteract chemotherapy-induced emesis. Previous studies revealed the anti-inflammatory properties of this drug. The aim of this study was to evaluate the role of peroxisome proliferator-activated receptor gamma (PPARγ) receptor in the protective effect of tropisetron in an animal model of ulcerative colitis. Experimental colitis was induced by a single intra-colonic instillation of 4% (V/V) acetic acid in male rats. Tropisetron (3 mg/kg) and GW9662 (PPARγ antagonist) (5 mg/kg) were given twice daily for 2 days after colitis induction. Forty-eight hours after induction of colitis, colon was removed and macroscopic and microscopic features were given. Moreover, colonic concentrations of malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) levels, myeloperoxidase (MPO), and PPARγ activity were assessed. Both macroscopic and histopathological features of colonic injury were markedly ameliorated by tropisetron. Likewise, levels of NO, MDA, TNF-α, and IL-1ß diminished significantly (p < .05). GW9662 reversed the effect of tropisetron on these markers partially or completely. In addition, tropisetron increased the PPARγ and decreased the MPO activity (p < .05). Tropisetron exerts notable anti-inflammatory effects in acetic acid-induced colitis in rats, which is probably mediated through PPARγ receptors.

Therapeutic potential of cannabinoids in counteracting chemotherapy-induced adverse effects: an exploratory review.

Cannabinoids (the active constituents of Cannabis sativa) and their derivatives have got intense attention during recent years because of their extensive pharmacological properties. Cannabinoids first developed as successful agents for alleviating chemotherapy associated nausea and vomiting. Recent investigations revealed that cannabinoids have a wide range of therapeutic effects such as appetite stimulation, inhibition of nausea and emesis, suppression of chemotherapy or radiotherapy-associated bone loss, chemotherapy-induced nephrotoxicity and cardiotoxicity, pain relief, mood amelioration, and last but not the least relief from insomnia. In this exploratory review, we scrutinize the potential of cannabinoids to counteract chemotherapy-induced side effects. Moreover, some novel and yet important pharmacological aspects of cannabinoids such as antitumoral effects will be discussed.

The role of serotonin in memory: interactions with neurotransmitters and downstream signaling.

Serotonin, or 5-hydroxytryptamine (5-HT), is found to be involved in many physiological or pathophysiological processes including cognitive function. Seven distinct receptors (5-HT1-7), each with several subpopulations, have been identified for serotonin, which are different in terms of localization and downstream signaling. Because of the development of selective agonists and antagonists for these receptors as well as transgenic animal models of cognitive disorders, our understanding of the role of serotonergic transmission in learning and memory has improved in recent years. A large body of evidence indicates the interplay between serotonergic transmission and other neurotransmitters including acetylcholine, dopamine, γ-aminobutyric acid (GABA) and glutamate, in the neurobiological control of learning and memory. In addition, there has been an alteration in the density of serotonergic receptors in aging and Alzheimer's disease, and serotonin modulators are found to alter the process of amyloidogenesis and exert cognitive-enhancing properties. Here, we discuss the serotonin-induced modulation of various systems involved in mnesic function including cholinergic, dopaminergic, GABAergic, glutamatergic transmissions as well as amyloidogenesis and intracellular pathways.

The role of different serotonin receptor subtypes in seizure susceptibility.

5-Hydroxytryptamine (5-HT) has the most diverse set of receptors in comparison with any other neurotransmitter or hormone in the body. To date, seven families of 5-HT receptors have been characterized. A great number of studies have been published regarding the role of 5-HT and its receptors in seizures. However, with a few exceptions, the net effect of activating or inhibiting each 5-HT receptor subtype on the development or severity of seizures remains controversial. Additionally, the results of studies, which have used knockout animals to investigate the role of 5-HT receptors in seizures, have sometimes been contradictory to those which have used pharmacological tools. The present study aims to review the available data regarding the influence of each receptor subtype on seizure development and, when possible, reconcile between the apparently different results obtained in these studies.

Nitric oxide mediates the anticonvulsant effects of thalidomide on pentylenetetrazole-induced clonic seizures in mice.

Thalidomide is an old glutamic acid derivative which was initially used as a sedative medication but withdrawn from the market due to the high incidence of teratogenicity. Recently, it has reemerged because of its potential for counteracting number of diseases, including neurodegenerative disorders. Other than the antiemetic and hypnotic aspects, thalidomide exerts some anticonvulsant properties in experimental settings. However, the underlying mechanisms of thalidomide actions are not fully realized yet. Some investigations revealed that thalidomide could elicit immunomodulatory or neuromodulatory properties by affecting different targets, including cytokines (such as TNF α), neurotransmitters, and nitric oxide (NO). In this regard, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether the anticonvulsant effect of thalidomide is affected through modulation of the l-arginine-nitric oxide pathway or not. Injection of a single effective dose of thalidomide (10 mg/kg, i.p. or higher) significantly increased the seizure threshold (P<0.05). On the one hand, pretreatment with low and per se noneffective dose of l-arginine [NO precursor] (10, 30 and 60 mg/kg) prevented the anticonvulsant effect of thalidomide. On the other hand, NOS inhibitors [l-NAME and 7-NI] augmented the anticonvulsant effect of a subeffective dose of thalidomide (1 and 5 mg/kg, i.p.) at relatively low doses. Meanwhile, several doses of aminoguanidine [an inducible NOS inhibitor] (20, 50 and 100 mg/kg) failed to alter the anticonvulsant effect of thalidomide significantly. In summary, our findings demonstrated that the l-arginine-nitric oxide pathway can be involved in the anticonvulsant properties of thalidomide, and the role of constitutive nNOS is prominent in the reported neuroprotective feature.

Antinociceptive and antidiarrheal effects of pioglitazone in a rat model of diarrhoea-predominant irritable bowel syndrome: role of nitric oxide.

Irritable bowel syndrome (IBS) is a prevalent disease characterized by abdominal pain and abnormal bowel habits. Pioglitazone is a peroxisome proliferator-activated receptor (PPAR) γ agonist and, although it is mostly used as an antidiabetic agent, it has been reported to have analgesic effects. Nitric oxide (NO), a gaseous molecule that mediates many of the effects of pioglitazone, has been implicated in the pathophysiology of IBS. The aim of the present study was to investigate the effects of pioglitazone on symptoms in a rat model of diarrhoea-predominant IBS (D-IBS).and to determine the role of NO in these effects. Diarrhoea-predominant IBS was induced by intracolonic instillation of acetic acid. Pioglitazone (2 mg/kg, i.p.) was administered on Days 7, 9 and 11 after acetic acid instillation. To investigate the mechanism involved in pioglitazone action, rats were also administered either the PPARγ antagonist GW9662 (3 mg/kg, i.p.), the NO synthase (NOS) inhibitor N(G) -nitro-l-arginine methyl ester (l-NAME; 10 mg/kg, i.p.) or the NO precursor l-arginine (250 mg/kg, i.p.) along with pioglitazone. Visceral hypersensitivity, nociceptive thresholds, defecation frequency, stool form, serum and colon NO production and inducible (i) NOS activity were assessed 1 h after the final injection of pioglitazone or dimethylsulphoxide (used as the vehicle). Pioglitazone reduced visceral hypersensitivity and defecation frequency, increased nociceptive thresholds, NO production and iNOS activity and shifted stool form towards hard stools in D-IBS rats. These effects of pioglitazone were significantly reversed by l-NAME, but not GW9662. l-Arginine augmented the effects of pioglitazone. In conclusion, pioglitazone alleviates symptoms in a rat model of D-IBS through an NO-dependent mechanism.

Protective effect of hydroalcoholic olive leaf extract on experimental model of colitis in rat: involvement of nitrergic and opioidergic systems.

The aim of the present study is to investigate the possible protective effect of dry olive leaf extract (OLE) against acetic acid-induced ulcerative colitis in rats, as well as the probable modulatory effect of nitrergic and opioidergic systems on this protective impact. Olive leaf extract was administered (250, 500 and 750 mg/kg) orally for two successive days, starting from the colitis induction. To assess the involvement of nitrergic and opioidergic systems in the possible protective effect of OLE, L-NG-Nitroarginine Methyl Ester (10 mg/kg) and naltrexone (5 mg/kg) intraperitoneal (i.p.) were applied 30 min before administration of the extract for two successive days, respectively. Colonic status was investigated 48 h following induction through macroscopic, histological and biochemical analyses. Olive leaf extract dose-dependently attenuated acetic acid-provoked chronic intestinal inflammation. The extract significantly reduces the severity of the ulcerative lesions and ameliorated macroscopic and microscopic scores. These observations were accompanied by a significant reduction in the elevated amounts of TNF-α and interlukin-2 markers. Moreover, both systems blockage reversed protective effects of OLE in the rat inflammatory bowel disease model. These finding demonstrated, for the first time, a possible role for nitrergic and opioidergic systems in the aforementioned protective effect, and the extract probably exerted its impact increasing nitric oxide and opioid tones.

Psychiatric Comorbidities of Inflammatory Bowel Disease: It Is a Matter of Microglia's Gut Feeling.

Inflammatory bowel disease (IBD), a common term for Crohn's disease and ulcerative colitis, is a chronic, relapse-remitting condition of the gastrointestinal tract that is increasing worldwide. Psychiatric comorbidities, including depression and anxiety, are more prevalent in IBD patients than in healthy individuals. Evidence suggests that varying levels of neuroinflammation might underlie these states in IBD patients. Within this context, microglia are the crucial non-neural cells in the brain responsible for innate immune responses following inflammatory insults. Alterations in microglia's functions, such as secretory profile, phagocytic activity, and synaptic pruning, might play significant roles in mediating psychiatric manifestations of IBD. In this review, we discuss the role played by microglia in IBD-associated comorbidities.

Chondroitin sulfate glycan sulfation patterns influence histochemical labeling of perineuronal nets: a comparative study of interregional distribution in human and mouse brain.

Perineuronal nets (PNNs) are a condensed subtype of extracellular matrix that form a net-like coverings around certain neurons in the brain. PNNs are primarily composed of chondroitin sulfate (CS) proteoglycans from the lectican family that consist of CS-glycosaminoglycan (CS-GAG) side chains attached to a core protein. CS disaccharides can exist in various isoforms with different sulfation patterns. Literature suggests that CS disaccharide sulfation patterns can influence the function of PNNs as well as their labeling. This study was conducted to characterize such interregional CS disaccharide sulfation pattern differences in adult human (N = 81) and mouse (N = 19) brains. Liquid chromatography tandem mass spectrometry was used to quantify five different CS disaccharide sulfation patterns, which were then compared to immunolabeling of PNNs using Wisteria Floribunda Lectin (WFL) to identify CS-GAGs and anti-aggrecan to identify CS proteoglycans. In healthy brains, significant regional and species-specific differences in CS disaccharide sulfation and single versus double-labeling pattern were identified. A secondary analysis to investigate how early-life stress (ELS) impacts these PNN features discovered that although ELS increases WFL+ PNN density, the CS-GAG sulfation code and single versus double PNN-labeling distributions remained unaffected in both species. These results underscore PNN complexity in traditional research, emphasizing the need to consider their heterogeneity in future experiments.

Tropisetron attenuates amyloid-beta-induced inflammatory and apoptotic responses in rats.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder featured by deposition of beta-amyloid (Aß) plaques in the hippocampus and associated cortices and progressive cognitive decline. Tropisetron, a selective 5-HT3 receptor antagonist, is conventionally used to counteract chemotherapy-induced emesis. Recent investigations describe antiphlogistic properties for tropisetron. It has been shown that tropisetron protects against rat embolic stroke. We investigated protective properties of tropisetron in a beta-amyloid (Aß) rat model of AD and possible involvement of 5-HT3 receptors. MATERIAL AND METHODS: Aß (1-42) was injected into the hippocampus of male rats. Animals were treated intracerebroventricularly with tropisetron, mCPBG (selective 5-HT3 receptor agonist) or mCPBG plus tropisetron on days 1, 3, 5 and 7. Seven days following Aß administration, inflammatory markers (TNF-α, COX-2, iNOS and NF-κB), apoptotic markers (caspase 3 cytochrome c release) and calcineurin phosphatase activity were assessed in hippocampus. RESULTS: Seven days following Aß inoculation, control animals displayed dramatic increase in TNF-α, COX-2, iNOS, NF-κB, active caspase 3, cytochrome c release and calcineurin phosphatase activity in the hippocampus. Tropisetron significantly diminished the elevated levels of these markers and reversed the cognitive deficit. Interestingly, tropisetron was also found to be a potent inhibitor of calcineurin phosphatase activity. The selective 5-HT3 receptor agonist mCPBG, when co-administered with tropisetron, completely reversed the procognitive and anti-apoptotic properties of tropisetron while it could only partially counteract the anti-inflammatory effects. mCPBG alone significantly aggravated Aß-induced injury. CONCLUSION: Our findings indicate that tropisetron protects against Aß-induced neurotoxicity in vivo through both 5-HT3 receptor-dependent and independent pathways.

Estradiol reduces depressive-like behavior through inhibiting nitric oxide/cyclic GMP pathway in ovariectomized mice.

Estradiol decline has been associated with depressive-like behavior in female mice and NO has been suggested to play a major role in the pathogenesis of major depression. This study was conducted to investigate the antidepressant-like effects of acute estradiol administration in female ovariectomized (OVX) mice and the possible role of nitric oxide (NO)/cyclic GMP (cGMP) pathway. To this end, bilateral ovariectomy was performed in female mice and different doses of estradiol were injected alone or in combination with non-specific NO synthase (NOS) inhibitor (L-NAME), selective neural NOS (nNOS) inhibitor (7-NI), an NO precursor (L-arginine) or selective phosphodiesterase type 5 inhibitor (sildenafil). The duration of immobility was recorded in the forced swimming test (FST) to assess the depressive behavior. Moreover, hippocampal levels of NO were determined in select groups. 10 days following the procedure, OVX mice showed significantly prolonged immobility time in comparison with the sham group. Estradiol (3, 10, and 30 µg/kg, s.c.), when injected 1 h prior to FST, exerted antidepressant-like effects in OVX mice. Both L-NAME (30 mg/kg, i.p.), and 7-NI (50 mg/kg, i.p.) significantly reduced the immobility times of OVX mice. Administration of a sub-effective dose of L-NAME (10mg/kg), 15 min after a sub-effective dose of estradiol (1 µg/kg, s.c.) had a robust antidepressant-like effect in OVX mice. Also a sub-effective dose of 7-NI (25 mg/kg), 30 min after a sub-effective dose of estradiol (1 µg/kg, s.c.) showed antidepressant-like effect in OVX mice. Both the NO precursor L-arginine (750 mg/kg, i.p.) and the cGMP-specific phosphodiesterase type 5 inhibitor sildenafil (5 mg/kg, i.p.), 30 min before estradiol treatment, prevented the antidepressant-like effect of a potent dose of estradiol (10 µg/kg, s.c.) in OVX mice. The present findings suggest that suppression of the NO synthase/NO/cGMP pathway may be involved in the antidepressant-like effects of estradiol in OVX mice.

Cell type specific transcriptomic differences in depression show similar patterns between males and females but implicate distinct cell types and genes.

Major depressive disorder (MDD) is a common, heterogenous, and potentially serious psychiatric illness. Diverse brain cell types have been implicated in MDD etiology. Significant sexual differences exist in MDD clinical presentation and outcome, and recent evidence suggests different molecular bases for male and female MDD. We evaluated over 160,000 nuclei from 71 female and male donors, leveraging new and pre-existing single-nucleus RNA-sequencing data from the dorsolateral prefrontal cortex. Cell type specific transcriptome-wide threshold-free MDD-associated gene expression patterns were similar between the sexes, but significant differentially expressed genes (DEGs) diverged. Among 7 broad cell types and 41 clusters evaluated, microglia and parvalbumin interneurons contributed the most DEGs in females, while deep layer excitatory neurons, astrocytes, and oligodendrocyte precursors were the major contributors in males. Further, the Mic1 cluster with 38% of female DEGs and the ExN10_L46 cluster with 53% of male DEGs, stood out in the meta-analysis of both sexes.