Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology最新文献

Repetitive traumatic brain injury (RTBI) refers to brain injuries resulting from an external mechanical force causing cumulative and frequently severe neurological consequences. This study aimed to explore the neuroprotective effect of alogliptin (ALO) on RTBI-provoked endoplasmic reticulum (ER) stress and investigate the potential underlying mechanisms. For RTBI induction, rats were exposed to a sharp-edged weight at the right interior frontal area of the right cortex, one drop per day for five successive days. ALO (20 mg/kg/day, p.o.) was administered for one week. Results depicted that ALO recovered motor abnormalities and enhanced motor coordination in the open field test, decreased immobility and increased climbing time in the forced swimming test, and corrected histological aberrations. Moreover, ALO counteracted RTBI-triggered ER stress via suppression of activating transcription factor 6 (ATF6), glucose-regulated protein 78 (GRP78), aggregation of β-amyloid and Tau proteins, as well as elevation of the cortical content of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrKB). ALO also exhibited an antioxidant and anti-inflammatory potential in addition to its effect on the gene expression of miRNAs (miRNA-322 and miRNA-125b). In conclusion, ALO exhibited a neuroprotective effect by mitigating ER stress induced in an RTBI rat model.

Sevoflurane (Sevo) anaesthesia in children is linked to an increased incidence of postoperative emergence agitation (EA) and potential neurotoxicity in developing brains. However, the specific risks of subanaesthetic foetal or neonatal exposure to Sevo remain unclear. This study evaluates the safety and efficacy of combining dexmedetomidine (Dex) with Sevo to manage EA in paediatric anaesthesia. A systematic review and meta-analysis of randomized controlled clinical trials involving children under 8 years old revealed that Dex significantly reduces EA incidence when administered via intravenous, perineural, and intranasal routes. Using in utero electroporation, we found that pregnant mice exposed to 2.5% Sevo at embryonic days 14.5 and 15.5 exhibited transient neuronal migration deficits, with 25% of neurons delayed in deeper cortical layers. However, these neurons migrated to the cortex by postnatal day 8. Neonatal mice exposed to 2.5% Sevo experienced a 10% reduction in dendritic spine density in adolescence, associated with impaired somatosensory function, as assessed by the Von Frey test. Remarkably, Dex pretreatment ameliorated these pathological and functional changes. Thus, foetal or neonatal Sevo exposure can delay neuronal migration and reduce dendritic spine density. Dex co-administration effectively mitigates these adverse outcomes, supporting its potential use in paediatric anaesthesia to protect developing brains.

Tauopathies are neurodegenerative diseases characterized by accumulation of hyperphosphorylated tau protein (P-tau). The gut microbiota (GM) is symbiotic with the host and altered in neurodegenerative diseases. Amitriptyline (AMI) is a functional inhibitor of acid sphingomyelinase (ASM) which is abnormally highly expressed in brains of Alzheimer patients. Little data is known about the role of colonic ASM in management of tauopathy. Therefore, the aim of this study was to investigate the role of AMI on reversing gut dysbiosis, ceramide levels, colonic inflammation and intestinal barrier disruption in tauopathy through the bidirectional gut-brain axis. P301S transgenic mice were administered AMI for 35 days. Colonic ASM, ceramides, inflammation and membrane integrity were assessed besides fecal microbiome analysis and serum lipopolysaccharides to assess intestinal membrane disruption. Levels of hippocampal P-tau, protein phosphatase 2 A and neurogenesis were assessed along with cognitive behavior. AMI treatment significantly reduced colonic ASM, ceramide levels, increased abundance of Harryflintia, Dubosiella, and Parasutterella and decreased abundance of Lactobacillus, Lachnoclostridium, Oscillibacter, Oscillospiracea UCG-003, Colidextribacter, Roseburia, Butyricicoccus, and Sphingomondales. In contrast, P301S mice displayed an altered GM profile with enriched Firmicutes and Clostridia, and low proportions of Bacteroidota- a phylum associated with intestinal barrier protection-, and Ruminococcaceae. Also, AMI treatment decreased inflammation and restored colonic membrane integrity with subsequent decrease in serum lipopolysaccharides, P-tau in hippocampus and improvement in cognitive behaviour and neurogenesis. The current results indicate that AMI has neuroprotective effects against tauopathy through modulation of ASM activity, associated ceramide levels, GM composition, colonic inflammation and membrane integrity through bidirectional gut-brain axis.

Maternal immune activation (MIA) during pregnancy has been implicated as a key environmental risk factor in autism spectrum disorder (ASD). Interferon-alpha (IFN-α), a type I interferon, may disrupt fetal neurodevelopment, yet its mechanistic impact remains insufficiently understood. This study explores the effects of maternal IFN-α exposure on neurobehavioral and neurobiological outcomes in a Wistar rat model. Pregnant rats received IFN-α on gestational day 10, and offspring were evaluated through behavioral assays, neurochemical analyses, and histopathological assessments. IFN-α exposure resulted in significant reductions in GABA, 5-HIAA, and GAD-67 levels, particularly in male offspring, indicating neurotransmitter dysregulation. Histologically, neuronal loss was observed in the hippocampal CA1 and CA3 regions and cerebellar Purkinje cells. Astrocyte activation, reflected by increased GFAP immunoreactivity, was prominent, suggesting a neuroinflammatory response. Additionally, reduced brain-derived neurotrophic factor (BDNF) and elevated tumor necrosis factor-alpha (TNF-α) levels support the presence of inflammation-induced synaptic dysfunction and impaired neuroplasticity. Behaviorally, male offspring exhibited reduced sociability and impaired social novelty recognition. Both sexes demonstrated deficits in motor coordination and exploratory activity. These findings align with core ASD phenotypes and underscore a heightened male vulnerability. Overall, the study provides compelling evidence that prenatal IFN-α exposure leads to persistent neuroimmune, neurochemical, and structural alterations resembling ASD. The results highlight the need for further research into immune-mediated neurodevelopmental disruptions and sex-specific vulnerabilities, offering potential pathways for preventive and therapeutic interventions targeting MIA-related risk mechanisms.

Although transient receptor potential melastatin 3 (TRPM3) channels are primarily known for their role in spinal nociception, emerging evidence suggests their involvement in psychiatric conditions and central reward processing. Menopause, characterized by estrogen decline, induces neuroimmune activation and increases pro-inflammatory factors such as ciliary neurotrophic factor (CNTF). While a direct regulatory effect of CNTF on TRPM3 is not well established, both are involved in inflammation-related signaling, suggesting potential crosstalk. TRPM3 responds to neuroinflammatory and neurotrophic signals and may contribute to postmenopausal cognitive decline. However, this link remains unexplored. Naringenin, a natural flavonoid with estrogen-like properties, has been reported to inhibit TRPM3 channels and may help to alleviate postmenopausal memory impairment. This study aimed to investigate the role of elevated CNTF levels in increasing TRPM3 expression in the dentate gyrus (DG), contributing to cognitive deficits, and to assess the potential of naringenin in reversing these effects. Bilateral ovariectomy (OVX) was performed on female Sprague-Dawley rats, followed by treatment with naringenin (2.5, 5 and 10 mg/kg, intraperitoneal) for 14 days. Cognitive functions were assessed using the novel object recognition and passive avoidance tests. CNTF levels in the plasma and the DG, along with TRPM3 expression in the DG, were measured using ELISA and immunohistochemistry, respectively. Dendritic arborization in DG neurons was analyzed using Golgi-Cox staining. OVX rats showed impaired cognition, elevated CNTF and TRPM3 expression, and reduced dendritic complexity. Naringenin treatment reversed these changes, suggesting its potential to improve postmenopausal cognitive decline by modulating CNTF levels and TRPM3 activity in the DG.

Generalized myasthenia gravis (gMG) is an antibody mediated autoimmune neuromuscular junction disorder characterized by muscle weakness and fatigue as well as acetylcholine receptor antibody (AChR-Ab) as the main presence. A proportion of patients fail to achieve minimal symptom expression (MSE), furthermore 10-20% of them develop into refractory under conventional immunotherapy. We conducted a retrospective study to explore the effectiveness and safety of telitacicept in gMG and thymoma-associated MG (TAMG) patients. The treatment response was assessed by the variation of QMG, MG-ADL and MG-QOL-15 scores. Time to MSE as well as usage of corticosteroid were also evaluated. In this retrospective study, we included 22 AChR-gMG patients (15 women, 7 men), including 7 refractory and 12 TAMG, who were treated with telitacicept by following-up at least 6 months. Compared to the baseline, a significant decrease in QMG, ADL and MG-QOL-15 scores was observed at every visit, especially for the QMG score with at least 3 points decline in all the patients in week 4. Twenty patients attained MSE and the time to MSE was 4 months during the observed period. At the last follow-up, the dose of prednisone of all the patients treated with telitacicept was ≤ 5 mg/d. The AChR-Ab titers and CD19⁺ B cells significantly decreased from baseline to week 24. Telitacicept is generally well tolerated, the most common (18%) adverse effect was mild and transient injected site swelling. Our study provides evidence to support that telitacicept is beneficial and well tolerated in the management of gMG especially in refractory MG and TAMG. Clinical outcomes showed increased efficacy of telitacicept when used earlier in the disease course, which leads to a sparing of prednisone.

Mood and behavior-related comorbidities are often reported with food allergies, an atopic condition that elevates histamine (HA) levels in tissues and circulation. However, whether allergy-induced HA directly affects the central nervous system is unclear. Previously, we demonstrated that the levels of HA and its receptor subtype, H3 receptor (H3R), were elevated in the brains of mice with subclinical cow's milk allergy (CMA) generated by sensitizing C57BL/6J mice to a bovine whey allergen, β-lactoglobulin (BLG, Bos d 5). Furthermore, these BLG-sensitized CMA mice showed depression-like behavior associated with mast cell activation, neuroinflammation, and cortical demyelination, leading us to postulate that peripheral immune responses raised brain HA and dysregulated the neuronal histaminergic system. Hypothesizing that the autoregulatory function of H3R signaling is pivotal in eliciting altered behavior and neuropathologies, we investigated whether thioperamide, a brain-permeable H3R-selective antagonist, would attenuate the changes observed in CMA mice. Male and female CMA mice were fed a whey-containing diet for 2 weeks without or with thioperamide. While sensorimotor functions were not impaired in CMA mice of either sex, some aspects of affective and cognitive behaviors were significantly altered in males. Male CMA mice also showed more IgE-immunopositive, degranulated mast cells in the dura mater than females, regardless of thioperamide treatment. Importantly, thioperamide reduced CMA-associated behavioral and neuropathological changes in male mice, although it also uniquely affected female mice. Our results suggest that thioperamide ameliorates CMA-associated behavioral changes and neuropathologies via H3R inhibition in a sex-dependent manner.

Tramadol (TM) abuse negatively affects the central nervous system, especially brain regions like the hippocampus involved in cognition. Recent studies have demonstrated neuroprotective effects of Vitamin C (Vit C) in various neurological diseases. No study has yet examined the effects of Vit C on tramadol-induced synaptic plasticity impairment. Therefore, we aimed to investigate the neuroprotective effects of Vit C on cognitive performance and synaptic plasticity in tramadol-exposed rats. Fifty-two juvenile male rats (30 days old) were divided into four groups: TM (30 mg/kg/day, intraperitoneally in the first week, 40 mg/kg/day in the second week and 50 mg/kg/day in third and fourth weeks), Vit.C (200 mg/kg/day, orally for 4 weeks), TM + Vit.C (as in the TM and Vit C groups, Vit C administered half an hour prior to TM), and Ctrl (0.25 mL saline/day for 4 weeks). Behavioral tests (open field, Morris water maze, novel object recognition) assessed locomotor activity and memory. In vivo recordings evaluated synaptic plasticity, and hippocampal oxidative stress markers [malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC)] were measured according to the manufacturers' protocols with ELISA. TM caused learning and memory deficits, reduced long-term potentiation (LTP) induction, and disrupted the oxidative stress balance in the hippocampus. In contrast, Vit C inhibited these changes. These findings suggest that Vit C can attenuate cognitive impairments associated with chronic TM consumption, likely through modulation of hippocampal oxidative stress and enhancement of LTP induction. Therefore, Vit C could be a promising candidate for further investigation as a potential therapeutic agent to mitigate cognitive dysfunction associated with TM use.

Multiple sclerosis (MS) is a long-lasting autoimmune condition characterized by myelin destruction and neurodegeneration. Research indicates that ferroptosis significantly influences MS pathogenesis, exacerbating neuronal tissue damage. Our study intended to explore the possible neuroprotective role of fisetin (FIS) in cuprizone (CPZ) model of MS and the associated molecular mechanisms. The 9-week experiment comprised a 5-week demyelination period in which C57BL/6 mice were provided with 0.2% w/w CPZ added to rodent chow, followed by a 4-week remyelination period in which mice were fed CPZ-free chow. FIS (80 mg/kg/day) was given by oral gavage to mice daily for 4 weeks starting in the 2nd week of demyelination. For remyelination, FIS was administered daily during the 4 weeks recovery. During demyelination, FIS significantly improved CPZ-induced behavioral and locomotor deficits, as demonstrated by tail suspension test and inverted screen grip strength test. LFB and H & E staining, MBP, GFAP and vimentin immunostaining revealed that FIS treatment significantly improved myelination, alleviated astrogliosis and neuronal injury in CPZ-fed mice throughout both phases. FIS attenuated ferroptosis and neuroinflammation during de- and remyelination as supported by reduced brain iron deposits, IL-1 β, MDA concentrations and restored GPX4. Moreover, FIS significantly downregulated NCOA4 and TfR1 gene expression and TfR1 protein level but upregulated FTH1 gene expression and ferritin protein level. Additionally, FIS upregulated Olig-1 during demyelination, but not remyelination. Fisetin has a potential neuroprotective effect in CPZ model of MS and can be studied as a promising adjuvant therapy to enhance remyelination and mitigate disability in MS patients possibly by modulating ferroptosis pathway.

Diabetes mellitus exacerbates cerebral ischemic damage by potentiating neuroinflammation. We hypothesized that activation of the bradykinin type 2 receptor, a mediator of inflammation and vascular dynamics, might be detrimental to ischemic injury development in diabetic animals. We monitored the acute phase of cerebral ischemia in type 1 diabetic mice, diabetic bradykinin type 2 receptor knock-out mice, and their non-diabetic controls using neurological assessment, magnetic resonance imaging, and a comprehensive immuno-histochemical and morphological analysis to quantify changes in microglial, neutrophil, and neuronal populations. Our findings reveal that bradykinin type 2 receptor deficiency ameliorates neurological deficit in non-diabetic mice, despite similar ischemic lesion volumes across all investigated groups. Furthermore, in non-diabetic animals, the bradykinin type 2 receptor plays a discernible role in edema resolution, neuroprotection, and regulation of microglial response to ischemia. However, diabetes, as a stroke comorbidity, alters the involvement of the bradykinin type 2 receptor in ischemic injury development. Bradykinin type 2 receptor-deficient diabetic animals demonstrate delayed microglial cell loss and reduced microglial reactivity following ischemia compared to diabetic animals with functional bradykinin type 2 receptors. The attenuated immune response is accompanied by a marked absence of infiltrating neutrophils within the ischemic territory and improved neuronal survival. This study demonstrates that diabetes profoundly modifies the role of bradykinin type 2 receptor in cerebral ischemic injury, influencing both acute neuroinflammation and cell survival. These findings support the potential of the bradykinin type 2 receptor as a therapeutic target for stroke in diabetic population, warranting further investigation.