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.