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

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.

Neuropathic pain is a chronic pain condition characterized by complex pathogenesis and poor prognosis. EB (Eupalinolide B), a highly bioactive sesquiterpene lactone derived from Eupatorium lindleyanum DC, has been demonstrated to possess multiple pharmacological activities, including antihistamine, antibacterial, and antioxidant effects. USP7 (ubiquitin-specific protease 7) is a crucial deubiquitinating enzyme in eukaryotes, while the Keap1, Nrf2, and HO-1 signaling pathways play pivotal roles in the development of neuropathic pain. Our study established a spared nerve injury model in mice and employed multiple molecular biology experiments to investigate the regulatory role of EB in the USP7/Keap1/Nrf2 pathway and its mechanisms in neuropathic pain. Results showed significantly elevated USP7 and Keap1 protein expression in the spinal cord of SNI mice, while Nrf2 and HO-1 levels were markedly reduced. EB treatment downregulated USP7 expression, promoted Keap1 ubiquitination and degradation, thereby elevating Nrf2/HO-1 protein levels. This inhibited microglial proliferation and M1 polarization, reduced the production of proinflammatory factors (TNF-α, IL-1β, IL-6), and significantly ameliorated mechanical and thermal hyperalgesia in SNI mice. Long-term intraperitoneal injection of EB did not cause any significant side effects in the heart, liver, or kidneys of SNI mice. In summary, EB exerts anti-inflammatory and analgesic effects by modulating the USP7/Keap1/Nrf2 signaling pathway, offering a potential novel therapeutic strategy for neuropathic pain.

Ubiquitination is a key enzymatic process where ubiquitin molecules covalently attach to substrate proteins, regulating their degradation, trafficking, and signaling. This process ensures cellular homeostasis by controlling protein quality and abundance, and it plays a vital role in immunity, DNA repair, and the cell cycle. Further, ubiquitination involves a sophisticated network of enzymes, domains, and receptors, providing pathway flexibility. However, dysregulation of ubiquitination due to aberrant enzyme function is implicated in various disorders, including cancer, diabetes, stroke, and neurodegenerative diseases (NDDs). Additionally, the ubiquitin-proteasome system (UPS) not only mediates protein degradation but also influences inflammation and subcellular localization. This review explores the pivotal role of ubiquitination and deubiquitination enzymes in the onset and progression of NDDs. It highlights their involvement in protein aggregation, mitochondrial impairment, neuroinflammation, and altered synaptic function. Special focus is placed on mutations in E3 ligases (e.g., E3 ubiquitin ligase encoded by PARK2 (Parkin), C-terminus of Hsp70-interacting protein (CHIP)) and deubiquitinases (e.g., USP14, ubiquitin C-terminal hydrolases (UCHL1)), which disrupt proteostasis and lead to the accumulation of neurotoxic proteins, such as Aβ, tau, α-synuclein, and mHtt. Moreover, post-translational modifications (PTMs), including phosphorylation, acetylation, and oxidative stress, further modulate UPS activity and disease progression. Lastly, the review also evaluates emerging therapeutic strategies aimed at restoring proteostasis, including proteasome-targeting small molecules (e.g., bortezomib, IU1-47), natural compounds (e.g., curcumin, resveratrol), RNA-based therapies (e.g., miR-101, circHIPK3), and dietary approaches (e.g., Mediterranean and ketogenic diets), offering a foundation for future neurodegenerative disease treatment.

Chemotherapy-induced neuropathic pain (CINP) affects up to 80% of cancer patients treated with cytostatic drugs like paclitaxel (PTX), leading to significant chronic sensorimotor dysfunction. Current pharmacological treatments often cause CNS side effects such as sedation and addiction. Increasing evidence indicates that native µ- and δ-opioid receptors (ORs) can associate to form heteromers in discrete brain regions. However, the role of µ-δ heteromer in CINP remains unclear. Therefore, we investigated the analgesic activity of CYM51010, a µ-δ heteromer agonist in CINP and how µ-δ heteromer activation regulates neuropathic pain. Systemic CYM51010 administration significantly alleviated evoked and ongoing pain in CINP mice, without inducing drug-seeking behavior, unlike morphine, which was consistent with earlier findings observed in SNL rats. Molecular analysis revealed that CYM51010 significantly decreased the increased TRPV1 and p38α expression in the dorsal root ganglion as well as spinal tissues of CINP mice. CYM51010 also reduced the expression of NF-κB, microglial markers (ICAM-1 & IBA1), and pro-inflammatory cytokines (TNF-α, IL-1β). Findings from the current study indicate that µ-δ heteromer activation represents a promising therapeutic target for chemotherapy-induced neuropathic pain (CINP), potentially enabling effective pain relief with reduced central side effects.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. It typically manifests as a triad of progressive psychiatric, cognitive, and motor symptoms. The resulting mutant HTT (mHTT) protein disrupts cellular homeostasis and promotes neuroinflammation. The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome is a key mediator of neuroinflammatory responses, activating caspase-1 and promoting the release of interleukin (IL)-1β and IL-18. In this study, we investigated the neuroprotective potential of glucosamine (GlcN) in HD. Our results demonstrate that GlcN effectively attenuates lipopolysaccharide (LPS)/ATP-induced NLRP3 inflammasome activation in BV2 microglia, leading to a significant reduction in IL-1β and IL-18 secretion. Mechanistically, GlcN suppresses microglial activation by inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway, thereby reducing nuclear factor-κB (NF-κB) activation. In the R6/2 transgenic mouse model of HD, oral administration of GlcN significantly enhanced neuronal survival, reduced mHTT aggregation, suppressed NLRP3 inflammasome activation, and attenuated astrocytic and microglial activation. Furthermore, GlcN improved motor performance and extended the lifespan of R6/2 mice. These findings suggest that GlcN confers neuroprotection in HD by attenuating neuroinflammation through inhibition of the NLRP3 inflammasome. Our study shows that GlcN is an effective treatment candidate for HD by targeting neuroinflammatory pathways, particularly through inhibition of the NLRP3 inflammasome, thereby presenting a promising strategy to slow disease progression.

Emerging evidence links zinc dyshomeostasis to the pathogenesis of Parkinson's disease (PD), highlighting the need to explore zinc-based interventions. Zinc has five stable isotopes, with ⁶⁴Zn and ⁶⁶Zn being the most abundant. Notably, healthy brain tissue is enriched in the lighter isotope ⁶⁴Zn, while heavier isotopes are hypothesized to accumulate with age. This study examined the therapeutic potential of intravenously administered isotopically enriched ⁶⁴Zn aspartate (⁶⁴Zn-asp) in a rat model of PD induced by a single stereotactic intranigral injection of lipopolysaccharide (LPS, 10 μg), which simulates acute neuroinflammation followed by progressive neurodegeneration. Treatment effects were evaluated using behavioral assessments, immunological profiling, biochemical and molecular analyses, and histopathology. Rats treated with ⁶⁴Zn-asp showed a pronounced anti-inflammatory shift in microglial/macrophage metabolic profiles and reduced reactive astrogliosis. These changes were accompanied by improved motor performance and decreased anxiety-like behavior. Immunohistochemistry confirmed preservation of dopaminergic neurons. Overall, these findings suggest that ⁶⁴Zn-asp attenuates neuroinflammation and supports neuronal survival, indicating its potential as a candidate for disease-modifying strategies in PD.

Cerebral ischemia-reperfusion (I/R) injury is a critical condition leading to severe neurological deficits. Inflammation, driven by microglial polarization, plays a significant role in the progression of I/R injury. Gallic acid (GA), a natural polyphenol, has been recognized for its anti-inflammatory and neuroprotective properties. Male mice subjected to middle cerebral artery occlusion (MCAO) were treated with GA. Neurological deficits, infarct size, and brain edema were assessed to evaluate the neuroprotective effects of GA. In vitro, oxygen-glucose deprivation/reoxygenation (OGD/R) models were used to simulate I/R injury in microglial cells. The polarization of microglia was analyzed by flow cytometry, qPCR, and Western blot, focusing on M1 and M2 markers. Autophagy and inflammasome activation were investigated using Western blot, immunofluorescence, and flow cytometry, with the effects of GA modulated by autophagy and inflammasome inhibitors. GA treatment significantly improved neurological outcomes in MCAO mice by reducing infarct size, brain edema, and promoting the M2 polarization of microglia while inhibiting M1 polarization. GA enhanced autophagy and suppressed NLRP3 inflammasome activation via the mTOR pathway, reducing pro-inflammatory cytokine expression. Inhibition of autophagy reversed the protective effects of GA, leading to increased M1 polarization and exacerbated neuroinflammation. Additionally, activation of the NLRP3 inflammasome counteracted GA's effects, emphasizing the role of this pathway in microglial modulation. GA exerts neuroprotective effects in cerebral I/R injury by modulating microglial polarization through the NLRP3/mTOR axis. Its ability to promote autophagy and suppress inflammasome activation positions GA as a potential therapeutic agent for reducing neuroinflammation and improving outcomes in I/R injury.