J Neuroimmune Pharmacol [JOURNAL]
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200 papers
Temporin-1CEa and its Analog LK2(6)A(L) Confer Neuroprotective Effects in Parkinson's Disease Model by Attenuating Neuroinflammation Via the NF-κB and MAPK Signaling Pathways.
Zhang W, Qu M, Wang C … +1 more , Shang D
J Neuroimmune Pharmacol · 2025 Oct · PMID 41051619 · Full text
The formation of Parkinson's disease is affected by various factors, among which neuroinflammation mediated by microglial activation plays a crucial role in the advancement of neurodegenerative diseases. Antimicrobial pe...
The formation of Parkinson's disease is affected by various factors, among which neuroinflammation mediated by microglial activation plays a crucial role in the advancement of neurodegenerative diseases. Antimicrobial peptides temporin-1CEa and its analog LK2(6)A(L) exhibit excellent anti-inflammatory activity. To understand the anti-neuroinflammatory mechanisms of antimicrobial peptides in an immortalized mouse microglial cell line (BV2 cells), and assess neuroprotective effects in a PC12 cell line (rat adrenal pheochromocytoma cell) and Caenorhabditis elegans. Lipopolysaccharide (LPS, 500 ng/mL) was used to induce neuroinflammation in microglial BV2 cells. The effects of antimicrobial peptides on inflammatory cytokines and anti-inflammatory pathways activated by microglia were evaluated using cell counting kit-8 (CCK-8), enzyme-linked immunosorbent assay (ELISA), real-time quantitative PCR(RT-qPCR), and western blotting (WB). An apoptosis model was established by treating PC12 cells with the supernatant of LPS-stimulated BV2 cells, and the influence of antimicrobial peptides on apoptosis was analyzed via flow cytometry (FCM), Western blotting, and caspase-3 and caspase-9 activity assays. In the transgenic nematode BZ555, an LPS (200 μg/mL)-induced model of cephalic dopaminergic neurons (CEPs) injury was developed to explore the protective effects of antimicrobial peptides on dopaminergic neuron damage, food-sensing behavior, body bending, neurotoxicity, and lifespan. Furthermore, NL5901 was employed to evaluate the capacity of antimicrobial peptides to clear the accumulation of alpha-synuclein (α-synuclein) and their impact on body bending, neurotoxicity, and lifespan. Temporin-1CEa and LK2(6)A(L) inhibited the release of pro-inflammatory mediators by downregulating the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. At 3.125 μM, both temporin-1CEa and LK2(6)A(L) inhibited the apoptosis of PC12 cells induced by activated BV2 cells. In vivo experiments in nematodes demonstrated that temporin-1CEa and LK2(6)A(L) alleviated the damage to dopaminergic neurons induced by LPS and mitigated the capability to mitigate the accumulation of α-synuclein. In this study, antimicrobial peptides were shown to control inflammatory factors by downregulating the NF-κB and MAPK signaling pathways, thereby providing valuable insights for the agents in the neuroinflammation model of Parkinson's disease. Additionally, an unexpected finding revealed that these peptides could effectively reduce the accumulation of α-synuclein, which is a critical pathogenic factor, as its aggregated forms significantly contribute to Parkinson's disease progression. Notably, temporin-1CEa and LK2(6)A(L) exerted neuroprotective effects on dopaminergic neurons by inhibiting neuroinflammation and clearing the accumulation of α-synuclein.
Correction to: Inhibition of oxidative stress, neuroinflammatory cytokines, and protein expressions contributes to the antipsychotic effects of geraniol in mice with ketamine-induced schizophrenia.
Uruaka CI, Ben-Azu B, Omeiza NA … +6 more , Chidebe EO, Ajayi AM, Lemii CB, Nonju TI, Georgewill UO, Georgewill OA
J Neuroimmune Pharmacol · 2025 Sep · PMID 40974474 · Publisher ↗
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Rutin Attenuates Virus Entry and Replication and Exerts Neuroprotection in Experimental Models of Japanese Encephalitis.
Abate SK, Soni R, Jena P … +2 more , Banerjee A, Garabadu D
J Neuroimmune Pharmacol · 2025 Sep · PMID 40938453 · Publisher ↗
Japanese encephalitis virus (JEV), which belongs to the virus family of Flaviviridae, is a threat to more than three billion people globally. There are no antiviral agents against JEV despite the availability of vaccines...
Japanese encephalitis virus (JEV), which belongs to the virus family of Flaviviridae, is a threat to more than three billion people globally. There are no antiviral agents against JEV despite the availability of vaccines. This study considered the need for an effective drug against JEV by evaluating the antiviral and neuroprotective potentials of Chicoric Acid (CA) and Rutin in the in vitro and in vivo models of JE. In the in vitro study, CA and Rutin exhibited variable antiviral potency with IC values ranging from 11.03 to 24.04 µM and 16.45 to 26.84 µM in different treatment approaches. These agents demonstrated significant antiviral effects via viricidal activity and inhibiting the virus's entry into the host cells. In addition, treatment of JEV-infected SH-SY5Y cells with these compounds significantly reduced the intracellular viral load, the proportion of apoptotic cells, and the ROS level in a dose-dependent manner. In the in vivo studies, Rutin (50 mg/kg) significantly increased the survival rate and attenuated the encephalitis symptoms in the JEV-infected mice compared to other doses. Rutin (25 and 50 mg/kg) significantly reduced infectious viral particles, viral RNA, and viral NS3 protein expression in the mice's brains. Additionally, Rutin significantly mitigated JEV-induced neuroinflammation by decreasing microglial activation, inflammasome formation, proinflammatory cytokine, and ROS levels. In conclusion, Rutin exhibits non-specific viricidal activity, reduced viral load, and inflammatory cytokines; thus, it could be a potential therapeutic option in managing JE, subject to future investigations.
Emerging Role of Oligodendrocytes Malfunction in the Progression of Alzheimer's Disease.
Tylek K, Basta-Kaim A
J Neuroimmune Pharmacol · 2025 Sep · PMID 40887534 · Full text
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by hallmark pathologies such as amyloid-beta (Aβ) plaque accumulation, tau hyperphosphorylation, and progressive neuronal dysfunction. While...
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by hallmark pathologies such as amyloid-beta (Aβ) plaque accumulation, tau hyperphosphorylation, and progressive neuronal dysfunction. While much attention has focused on neurons and microglia, recent studies underscore the significant yet understudied roles of oligodendrocytes (OL) and oligodendrocyte precursor cells (OPC) in AD pathology. OL, responsible for myelin production and maintenance, are impaired early in AD, contributing to demyelination, synaptic dysfunction, and cognitive decline. Emerging evidence reveals that Aβ and tau pathology disrupt OPC differentiation and induce senescence, exacerbating neuroinflammation and reducing remyelination potential. Demyelination precedes overt AD symptoms, positioning it as a potential early biomarker. Furthermore, animal models reveal that OPC density and function deteriorate with age, particularly in the presence of Aβ plaques, highlighting their vulnerability in the AD environment. Transcriptomic studies also link cholesterol biosynthesis and lipid metabolism dysregulation in OPC to AD progression, emphasizing the intricate relationship between OL, metabolic processes, and amyloid toxicity. Additionally, the identification of disease-associated oligodendrocytes (DAO), characterized by altered gene expression and proximity to Aβ plaques, highlights their involvement in neuroinflammation and APP processing. This review synthesizes recent insights into OL and OPC dysfunction in AD, focusing on their roles in neuroinflammation, Aβ clearance, and myelin integrity. It discusses the potential of targeting OL and OPC pathways, such as enhancing remyelination and mitigating senescence, as novel therapeutic strategies. By addressing gaps in our understanding of OL dynamics, this work sheds light on their critical contributions to AD pathology and sets the stage for future research and intervention.
Telitacicept Inhibits the Maturation and Differentiation of B Lymphocytes in NMOSD.
Ding J, Xue C, Zhao X … +11 more , Pei X, Yu H, Li Q, Chen Y, Wang X, Yu W, Hao Y, Sun Y, Chen Z, Xie C, Guan Y
J Neuroimmune Pharmacol · 2025 Aug · PMID 40858888 · Publisher ↗
Telitacicept, a novel recombinant fusion protein comprising the ligand-binding domain of the TACI receptor and the Fc component of human IgG, has rarely been studied for the treatment of neuromyelitis optica spectrum dis...
Telitacicept, a novel recombinant fusion protein comprising the ligand-binding domain of the TACI receptor and the Fc component of human IgG, has rarely been studied for the treatment of neuromyelitis optica spectrum disorders (NMOSD). This study aimed to explore the effects of telitacicept in NMOSD mice. An NMOSD mouse model was constructed. Fifty microliters of 0.8 mg/mL telitacicept was injected intravenously on Days 4, 8, 12 and 16 postimmunization (p.i.). Behavioral scoring, magnetic resonance imaging and histopathological evaluation were conducted on Day 19. B lymphocytes and their subgroups were analyzed by flow cytometry. Concentration of serum IgM was measured using an ELISA kit. Concentrations of B lymphocyte stimulator (BLyS) and IL-6 were measured via LEGENDplex. Differentially expressed genes of B lymphocytes were screened via mRNA sequencing and verified by qPCR. Behavioral score of telitacicept-treated NMOSD mice significantly decreased (p < 0.0001). Inflammation, demyelination, loss of AQP4 and GFAP in the spinal cord were markedly alleviated (p < 0.05). B lymphocytes and their subsets were reduced to varying degrees (p < 0.05). Telitacicept treatment significantly reduced serum IgM levels (p < 0.01), as well as BLyS and IL-6 concentrations (p < 0.05). Telitacicept induced differential gene expression in B lymphocytes, inhibiting the expression of transcription factors related to B lymphocyte maturation, such as IRF8, BLIMP1, and Pou2af1, as well as cell surface receptors such as CD19 and CD21. Telitacicept has a therapeutic effect on NMOSD mice by regulating the differentiation of B lymphocyte subsets and inhibiting the production of pathogenic antibodies.
Oscillatory Dynamics Serving Verbal Working Memory Differ in People with HIV and Are Linked To Disease Duration.
McDonald KM, Springer SD, Schantell M … +9 more , Glesinger R, Horne LK, Okelberry HJ, John JA, Coutant AT, Willett MP, Johnson HJ, Spooner RK, Wilson TW
J Neuroimmune Pharmacol · 2025 Aug · PMID 40828449 · Full text
BACKGROUND: Medical advances have greatly improved the quality of life and extended the longevity of people with HIV (PWH). However, many PWH still develop neurocognitive deficits even in the presence of effective viral...
BACKGROUND: Medical advances have greatly improved the quality of life and extended the longevity of people with HIV (PWH). However, many PWH still develop neurocognitive deficits even in the presence of effective viral suppression, with impairments in verbal working memory (VWM) being among the most common. While previous neuroimaging studies have demonstrated altered neural responses during VWM, the underlying temporal dynamics and their relation to clinical indices of HIV remain poorly understood. HYPOTHESIS: PWH will have altered neural oscillatory dynamics in brain regions supporting VWM compared to controls, above and beyond the effect of age, and these oscillatory differences will scale with clinical indices of HIV. METHODS: 166 participants (77 virally-suppressed PWH, 89 demographically-matched controls) completed a VWM task during magnetoencephalography, which was separated into encoding and maintenance phases. Whole-brain, mixed-model ANCOVAs were performed to assess the effects of HIV status on neural dynamics controlling for age. RESULTS: PWH performed significantly worse on the task compared to controls. During encoding, there was a significant interaction of group-by-time window, such that PWH had significantly weaker alpha/beta oscillations in the left inferior frontal, superior temporal, and anterior cingulate relative to controls. Further, weaker activity in the anterior cingulate scaled with increased disease duration. PWH also displayed weaker alpha/beta oscillations during maintenance in frontal, temporal, parietal, anterior cingulate, and cerebellar cortices. CONCLUSIONS: PWH exhibited weaker task-related oscillatory activity during VWM, which was associated with disease duration in the anterior cingulate. Overall, these findings suggest that HIV modulates the neural dynamics underlying VWM, with progressive effects in some areas.
Sigma-1 Receptor Activation by Fluvoxamine Ameliorates ER Stress, Synaptic Dysfunction and Behavioral Deficits in a Ketamine Model of Schizophrenia.
Ahmed MK, Abdou K, Ibrahim WW … +2 more , Mohamed AF, El-Boghdady NA
J Neuroimmune Pharmacol · 2025 Jul · PMID 40711497 · Full text
Endoplasmic reticulum (ER) stress and misfolded proteins accumulation are recognized as central factors in the development of psychiatric disorders. This study evaluated the potential therapeutic effect of fluvoxamine, a...
Endoplasmic reticulum (ER) stress and misfolded proteins accumulation are recognized as central factors in the development of psychiatric disorders. This study evaluated the potential therapeutic effect of fluvoxamine, a potent sigma-1 receptor agonist in alleviating protein misfolding and the subsequent ER stress in ketamine-induced model of schizophrenia. NE100 hydrochloride, a sigma-1 receptor blocker, was used to investigate the role of this receptor in fluvoxamine-mediated effects. Rat model of schizophrenia was induced by intraperitoneal administration of ketamine (30 mg/kg/day) for 5 consecutive days. Then, rats were treated with fluvoxamine (30 mg/kg/day, p.o), with or without NE100 (1 mg/kg/day, i.p), for 14 days. Fluvoxamine improved the learning abilities, cognitive flexibility, and sociability functions of ketamine-subjected rats as evidenced in Morris water maze and three-chamber social interaction tests. It mitigated ketamine-induced inhibition of nNOS/PSD-95/NMDAR signaling pathway, thus augmented the function of parvalbumin-GABAergic neurons as indicated by increasing the prefrontal cortical levels of parvalbumin and GAD67. Fluvoxamine also attenuated the prefrontal cortical production of unfolded protein response markers, namely, IRE-1, PERK, and ATF-6, highlighting its ability to alleviate ER stress. Further, it exerted anti-apoptotic and anti-inflammatory effects as shown by lowering Iba-1, tumor necrosis factor-α (TNF-α), Bax, and caspase-12 levels contrary to elevating Bcl-2. Additionally, it attenuated the histopathological alterations in prefrontal cortical neurons. Noteworthy, the co-administration of NE100 reduced the advantageous effects of fluvoxamine, indicating the involvement of sigma-1 receptor in mediating the observed antipsychotic effects. Thus, sigma-1-mediated signaling pathways could be therapeutic targets for preventing or slowing schizophrenia progression.
Pyrroloquinoline Quinone Preconditioning Alleviates Ischemic Cerebral Injury Through Antioxidant and Anti-Inflammatory Mechanisms.
Xiao L, Wang M, Li J … +6 more , Wang H, Pu N, Bo X, Chen F, Zhou Y, Cheng Q
J Neuroimmune Pharmacol · 2025 Jul · PMID 40696055 · Publisher ↗
The underlying pathological mechanism of ischemic stroke is complex, with oxidative stress and inflammation being two key factors that are intertwined and mutually influential. They also serve as important potential targ...
The underlying pathological mechanism of ischemic stroke is complex, with oxidative stress and inflammation being two key factors that are intertwined and mutually influential. They also serve as important potential targets for the intervention of cerebral ischemia. Pyrroloquinoline quinone (PQQ) is known for its neuroprotective properties and the ability to modulate immune system function. Previous studies have demonstrated that PQQ mitigates brain infarction in rodent models of cerebral ischemia; however, the neuroprotective mechanisms underlying PQQ's effects against ischemic brain injury are not yet fully understood. This study used an MCAO rat model, an OGD model with SH-SY5Y cells, and an LPS-activated BV2 microglia model to investigate the neuroprotective functions of PQQ on brain ischemia. Using various experimental methods, including cell viability assays, oxidative stress damage assessments, inflammatory factor expression analysis, behavioral tests in animal models, and histological evaluations, we discovered that PQQ activates the nuclear translocation of Nrf2 in neurons, thereby enhancing downstream antioxidant responses. Additionally, PQQ inhibits NF-kB activation in microglia and suppresses their M1-type polarization, leading to decreased pro-inflammatory mediators' expression levels and reduced neural inflammatory damage. These results provide further insights into the neuroprotective mechanisms involved in PQQ's effects against cerebral ischemia and may offer evidence for its translational application in treating brain ischemia.
Macroalgae Polysaccharides Enhance Brain Health by Mitigating Scopolamine-induced Oxidative Stress and Inflammation Via Nrf-2/TLR4/NF-kB Pathways.
Shah Z, Iqbal A, Badshah SL … +7 more , Mir MA, Sohni S, Ullah H, Shah SA, Bashir N, Ayaz M, Daglia M
J Neuroimmune Pharmacol · 2025 Jul · PMID 40694170 · Publisher ↗
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder commonly associated with memory loss and difficulties in performing daily activities, particularly in the aging brain. PURPOSE OF THE STUDY: This study...
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder commonly associated with memory loss and difficulties in performing daily activities, particularly in the aging brain. PURPOSE OF THE STUDY: This study aimed to evaluate the neuroprotective effects of macroalgae-derived polysaccharides from seaweed against scopolamine-induced amnesia, oxidative stress, and amyloid plaque (Aβ) production in rodents, following standard experimental protocols. METHODS: Three novel polysaccharides were extracted from Chara vulgaris, Cladophora glomerata, and Spirogyra crassa, namely: methylated pectin-type polysaccharides (PS1), methylated pectin-type polysaccharides (homo galacturonan and rhamno galacturonan, PS2), Ulvan-type polysaccharide, and xyloglucan polysaccharides (PS3). These polysaccharides were characterized using a variety of analytical techniques, including SEM, FTIR, XRD, H-NMR, and C-NMR. The polysaccharides were administered at a dose of 30 mg/kg to male albino mice exposed to scopolamine (1 mg/kg) for three weeks. To assess their neuroprotective effects, Morris Water Maze (MWM) and Y-maze tests, antioxidant enzyme assays (Catalase, GSH, LPO), and western blotting were performed. RESULTS: The results showed that all three polysaccharides significantly (p ≤ 0.001) mitigated redox imbalance and reduced (p ≤ 0.001) microglial activation, thereby decreasing scopolamine-induced neuroinflammation and amyloid beta (Aβ) accumulation. Additionally, these polysaccharides improved neuronal synapses and cognitive function by modulating the NRf-2/TLR4/NF-kB signaling pathway. DATA ANALYSIS: The data analysis and graph generation were performed using GraphPad Prism software, version 5.0, with a significance level set at a p-value of < 0.05. CONCLUSION: The findings highlighted the potential of these three novel natural polysaccharides as promising candidates for the treatment of scopolamine-induced oxidative stress-mediated neurodegenerative disorders, such as Alzheimer's disease.
Erythropoietin (EPO) Alleviates Chronic Stress-Induced Depression by Modulating SIRT1-Mediated Mitochondrial Function.
Luo Y, Ali T, Hu Y … +5 more , Gong Q, Zheng C, Li L, Li S, Hao L
J Neuroimmune Pharmacol · 2025 Jul · PMID 40690054 · Publisher ↗
Mitochondrial dysfunction is a hallmark of many psychiatric disorders, and SIRT1 signaling plays a critical role in regulating mitochondrial dynamics, function, and autophagy. This study investigated the interplays betwe...
Mitochondrial dysfunction is a hallmark of many psychiatric disorders, and SIRT1 signaling plays a critical role in regulating mitochondrial dynamics, function, and autophagy. This study investigated the interplays between erythropoietin (EPO), mitochondrial protection, and SIRT1 signaling in depression. Chronic restraint stress (CRS)- induced depression mouse model and CORT-treated HT22 cells were employed, which were subsequently treated with EPO. CRS mice exhibited depressive-like behaviors, which were alleviated by EPO treatment, as evidenced by decreased immobility and increased sucrose preference. EPO also enhanced mitochondrial function by stimulating mitophagy and improving mitochondrial homeostasis, as indicated by elevated ATP levels, reduced nitric oxide, and restored expression of mitochondrial-related genes in both the hippocampus of CRS mice and CORT-treated HT22 cells. Additionally, EPO restored suppressed SIRT1 expression, promoted dendritic spine density and synaptic gene expression in the hippocampus, increased p-STAT5 phosphorylation, and increased NAMPT expression and NAD + levels. Notably, pharmacological inhibition of SIRT1 via EX-527 counteracted EPO effects, exacerbating depressive symptoms and mitochondrial homeostasis. Furthermore, EX-527 treatment decreased ATP levels and mitochondrial DNA copy numbers in CRS + EPO-treated mice and reduced ATG5 expression. However, EX-527 did not significantly impact BNIP3, Parkin, PINK1, LC3B-II, Ace-FOXO1, or FOXO1 expression. EX-527 exposure significantly increased Ac-LC3B precipitation in the hippocampus of CRS + EPO-treated mice and the COXIV/LAMP1 ratio in the HT22 cells. In summary, these results suggested that EPO antidepressant effects were mediated through SIRT1 regulation, which influenced LC3B deacetylation, improving CRS-induced mitochondrial dysfunction and autophagy impairment.
Magnolol Ameliorates Depression Through Modulating the TREM2-DOK3-ERK Pathway.
Guo Z, Yang H, Sun G … +3 more , Peng Q, Zhao W, Liu L
J Neuroimmune Pharmacol · 2025 Jul · PMID 40682684 · Publisher ↗
Depression is a mental disorder with a high incidence and high clinical cure rate but a low treatment acceptance rate and a high recurrence rate. Depression is often accompanied by neuroinflammation. Magnolol (MA), a pha...
Depression is a mental disorder with a high incidence and high clinical cure rate but a low treatment acceptance rate and a high recurrence rate. Depression is often accompanied by neuroinflammation. Magnolol (MA), a pharmacologically active compound in Magnolia officinalis, has an antidepressant effect. The aim of this study was to investigate the molecular mechanism of the antidepressant effect of MA in mice and BV2 microglia. MA increased sugar water preference in the sucrose preference test (SPT) and inhibited immobility time in the forced swim test (FST) but did not affect distance travelled in the open field test (OFT). MA reduced the levels of proinflammatory cytokines (IL-6, TNF-α and IL-1β) and increased the expression levels of BDNF and IL-10 to promote neuronal survival. MA inhibited not only the amoeba-like morphology of hippocampal microglia but also iNOS expression in BV2 microglia. MA increased the expression of TREM2 and the p-DOK3/DOK3 ratio but decreased the p-ERK/ERK ratio. The knockdown of TREM2 led to a decrease in the p-DOK3/DOK3 ratio and an increase in the p-ERK/ERK ratio while also inducing microglial activation, promoting the production of inflammatory factors, and abrogating the protective effects of MA. Our study suggested that MA attenuated CUMS-induced depression-like behaviour and microglial activation by reducing ERK phosphorylation through increased TREM2 expression and DOK3 phosphorylation, which may provide new approaches for the treatment of depression.
Activation of Hippocampal ACE2 Prevents the Dysbiosis-induced Depression-like Behavior in Mice by Enhanced Neurogenesis and Neuroprotection via Mas Receptor.
Takahashi K, Nakagawasai O, Kurokawa K … +4 more , Miyagawa K, Mochida-Saito A, Takeda H, Tsuji M
J Neuroimmune Pharmacol · 2025 Jul · PMID 40679669 · Publisher ↗
The association between gut microbiota imbalance and depression is well known; however, its underlying mechanisms remain unclear. Angiotensin (Ang)-converting enzyme 2 (ACE2) transforms Ang II into Ang (1-7), which exert...
The association between gut microbiota imbalance and depression is well known; however, its underlying mechanisms remain unclear. Angiotensin (Ang)-converting enzyme 2 (ACE2) transforms Ang II into Ang (1-7), which exerts antidepressant effects via the Mas receptor (MasR). However, the role of ACE2 in dysbiosis-related depression in the brain remains unclear. In this study, we assessed changes in brain ACE2 expression and whether diminazene aceturate (DIZE), an ACE2 activator, alleviates depression-like behavior in an antibiotic-induced (ABX) dysbiosis mouse model. The tail suspension test revealed depression-like behavior in ABX mice. Western blotting and immunohistochemistry revealed decreased expression levels of ACE2, Ang (1-7), p-CAMKII, p-CREB, BDNF, synaptophysin, p-PPARγ, CD206, TREM2, and IL-10 and reduced neurogenesis in the dentate gyrus of the hippocampus. Iba1, CD86, iNOS, IL-1β, TNF-α, and cleaved caspase-3 levels were increased, indicating microglial activation in the hippocampus. MasR staining was observed in neurons and microglia in the hippocampus of ABX mice. Furthermore, p-CAMKII and p-CREB staining was observed in neurons, while p-PPARγ staining was observed in microglia in the hippocampus of ABX mice treated with DIZE. DIZE administration prevented ABX-induced changes, whereas the effects of DIZE were abolished by co-administration with A779, a MasR inhibitor. These findings suggest that hippocampal ACE2 expression plays a crucial role in dysbiosis-related depression associated with gut microbiota imbalance, potentially offering a target for therapeutic interventions.
Inhibition of oxidative stress, neuroinflammatory cytokines, and protein expressions contributes to the antipsychotic effects of geraniol in mice with ketamine-induced schizophrenia.
Uruaka CI, Ben-Azu B, Omeiza NA … +6 more , Chidebe EO, Ajayi AM, Lemii CB, Nonju TI, Georgewill UO, Georgewill OA
J Neuroimmune Pharmacol · 2025 Jul · PMID 40608148 · Publisher ↗
Imbalances in redox and neuroinflammation are believed to play a role in the complex causes of schizophrenia, a widespread mental disorder characterized by abnormal behaviour. In this regard, we investigated the effects...
Imbalances in redox and neuroinflammation are believed to play a role in the complex causes of schizophrenia, a widespread mental disorder characterized by abnormal behaviour. In this regard, we investigated the effects of geraniol, a natural compound with various medicinal uses, on ketamine-induced schizophrenia-like behaviour, oxidative stress and neuroinflammation in mice. We conducted three sets of experiments with adult male Swiss mice (n = 7): drug alone, preventive and reversal groups. The treatments included saline (10 mL/kg/p.o./day), geraniol (25, 50 and 100 mg/kg/p.o./day) and risperidone (0.5 mg/kg/p.o./day) for 14 days, along with ketamine (20 mg/kg/i.p./day) injections between days 8-14 in the preventive group, or ketamine administration for full 14 days before therapeutic intervention from days 8-14 in the reversal group. We measured behavioural hyperactivity, cognition and sociability. Additionally, brain oxidative/nitrergic imbalance, inflammatory cytokines (TNF-α, IL-6) and proteins (COX-2, iNOS, NF-κB) were determined in the striatum, prefrontal cortex, and hippocampus. KET administration was associated with schizophrenia-like symptoms as characterized by increased hyperlocomotion, impaired spatial memory and social withdrawal, particularly in the reversal group. This was exacerbated by redox imbalance and neuroinflammation in specific brain regions. However, geraniol (25, 50 and 100 mg/kg) treatment significantly prevented and reversed the brain's insults by restoring ketamine-induced decreases in glutathione, superoxide-dismutase and catalase activities, reduced malondialdehyde and nitrite contents along with TNF-α and IL-6 concentrations. Geraniol also suppressed NF-κB, COX-2 and iNOS expressions in the striatum, prefrontal-cortex and hippocampus. Geraniol shows neuroprotective and neurorestorative effects against schizophrenia-like symptoms by inhibiting oxidative stress, neuroinflammatory cytokines, and protein expression in mouse brains.
Enhancing Neuroprotection Through Exercise: The Synergistic Effects of Bioactive Plant Compounds Via the CREB-BDNF Signaling Pathway.
Li J, Sun L, Fang F … +1 more , Morshedi M
J Neuroimmune Pharmacol · 2025 Jun · PMID 40587022 · Publisher ↗
The hippocampus, a vital brain region, orchestrates numerous critical functions including memory, learning, stress response, and emotional regulation. Structural changes in the hippocampus due to prolonged stress exposur...
The hippocampus, a vital brain region, orchestrates numerous critical functions including memory, learning, stress response, and emotional regulation. Structural changes in the hippocampus due to prolonged stress exposure can precipitate cognitive decline and behavioral deficits. Recent studies have illuminated the restorative influence of physical fitness on the hippocampus; notably, exercise enhances memory, learning, hippocampal architecture, neurogenesis, and synaptic plasticity. A key mediator in these processes is the brain-derived neurotrophic factor (BDNF), which facilitates synaptic improvements and overall brain health following exercise. Concurrently, bioactive plant compounds such as curcumin, resveratrol, and crocin have emerged as potent therapeutic agents for neurodegenerative disorders, credited with improving memory, synaptic plasticity, and overall brain function, without the adverse effects associated with synthetic drugs. These natural compounds potentially exert their neuroprotective effects through various mechanisms including neurotransmitter regulation, oxidative stress alleviation, and stimulation of the BDNF-cyclic AMP response element binding protein (CREB) signaling pathway. Given the individual benefits of exercise and bioactive plant compounds, this review proposes a synergistic approach combining both modalities, aimed at developing novel, efficacious neuroprotective interventions. By harnessing the intertwined benefits of physical activity and plant-derived therapies, we outline a compelling case for their combined utility in fortifying hippocampal function and combating neurodegenerative conditions. In this review, we combined the benefits of exercise and therapy with bioactive plant components to create a neuroprotective drug.
Stimulant Use, HIV, and Plasma Metabolites Among Men.
Cherenack EM, Larson ME, Murray K … +5 more , Mayer ZJ, Guerrero C, Broedlow CA, Klatt NR, Carrico AW
J Neuroimmune Pharmacol · 2025 Jun · PMID 40533682 · Full text
Metabolomics can be used to identify biological targets to mitigate the negative impacts of HIV and stimulant use on neuroimmune and cardiometabolic functioning. However, studies are needed to characterize the plasma met...
Metabolomics can be used to identify biological targets to mitigate the negative impacts of HIV and stimulant use on neuroimmune and cardiometabolic functioning. However, studies are needed to characterize the plasma metabolome among sexual minority men (SMM) in the context of independent and co-occurring HIV and stimulant use. From 2020 to 2022, we collected plasma samples and assessed biologically confirmed HIV status and stimulant use among 61 community-recruited SMM in Miami, Florida. Cross-sectional bivariate analyses and multivariable regressions correcting for false discovery rate compared 390 mass spectrometry-based plasma metabolites across four HIV/stimulant use groups: (1) living without HIV and no stimulant use (HIV-STIM-), (2) living with HIV and no stimulant use (HIV + STIM-), (3) living without HIV with stimulant use (HIV-STIM +), and (4) living with HIV with stimulant use (HIV + STIM +). Six metabolites showed differences between HIV/stimulant use groups at p < 0.05 in both Kruskal-Wallis tests and linear regressions: choline, tryptophan, two lysophosphatidylcholines, one triacylglyceride, and one dihexosylceramide. After correcting for false discovery rate, in linear regressions controlling for BMI and age, the HIV + STIM + group had lower aspartic acid than the HIV-STIM- group, higher lysophosphatidylcholine a C18:1 than the HIV-STIM + group, and higher triacylglyceride(20:3_34:0) than the HIV-STIM- and HIV + STIM- groups. In SMM, co-occurring stimulant use and HIV were associated with perturbations in certain metabolites. Metabolites such as aspartic acid and lysophosphatidylcholines are potentially involved in immune dysregulation, addiction, energy use, and cardiovascular disease. Trials of interventions to reduce stimulant use could elucidate its causal relationship to metabolites.
Puerarin Improves Cancer-Induced Bone Pain by Recovering Mitochondrial Dysfunction in the Spinal Cord.
Sheng G, Wu Y, Liu H … +5 more , Zhang P, Zhang Z, Yu L, Cheng M, Zhu H
J Neuroimmune Pharmacol · 2025 Jun · PMID 40493135 · Publisher ↗
Cancer metastases induce bone pain and central sensitization in the spinal cord. Mitochondrial dysfunction is associated with pian signal transmission and involved in cancer-induced bone pain. Pueratin (Pue) is a natural...
Cancer metastases induce bone pain and central sensitization in the spinal cord. Mitochondrial dysfunction is associated with pian signal transmission and involved in cancer-induced bone pain. Pueratin (Pue) is a natural isoflavone compound that works as a potential natural neuroprotective agent. However, the mechanisms of Pue on cancer pain remain unclear. In this study, a cancer-induced bone pain (CIBP) rat model was established and Pue was administered intrathecally. As a result, CIBP model rats exhibited as the evoked mechanical pain, thermal pain, and spontaneous pain, the elevated neurological damage and mitochondrial dysfunction in the spinal cord. Pue administration improved pain related behaviors, decreased the neuronal activity, reduced NLRP3 inflammasome-mediated inflammation, and elevated mitochondrial dysfunction in the spinal cords of CIBP rats. Proteomical data showed that in the spinal synaptosomes, 59 differentially expressed proteins (DEPs) were significantly up-regulated while 128 DEPs were down-regulated. Among them, 5 genes were found to be overlapped for CIBP and Pue-potential targets and Src was belonged to the hub genes. Database analysis and experimental assay showed that Pue bound with Src at the affinity of 7.9 ± 0.2 µM, and decreased Src level and phosphorylation in the spinal cord of CIBP rats and in primary astrocytic cells. In addition, Pue also recovered levels of mitochondrial membrane potential and reactive oxygen species, and decreased inflammation in primary astrocytic cells. To summarize, Pue inhibits spinal Src activity, restores mitochondrial function, reduces central sensitization in the spinal cord, and relieves cancer-induced bone pain. This study may provide a basis for the application of Pue on the relief of cancer pain.
The Dopaminergic and Anti-Neuroinflammatory Properties of Functionalized Nanoliposomes Containing Levodopa and Ibuprofen and Conjugated with Anti-Alpha-Synuclein Aptamer.
Mostafa-Tehrani S, Saffari M, Balali E … +2 more , Khadivi R, Jebali A
J Neuroimmune Pharmacol · 2025 Jun · PMID 40489035 · Publisher ↗
The purpose of this study was to design, synthesize, characterize, and evaluate the functionalized nanoliposomes containing levodopa and ibuprofen and conjugated with Anti-alpha-synuclein aptamer (FNLLICAASA). In this st...
The purpose of this study was to design, synthesize, characterize, and evaluate the functionalized nanoliposomes containing levodopa and ibuprofen and conjugated with Anti-alpha-synuclein aptamer (FNLLICAASA). In this study, different aptamer sequences were designed and the best aptamer was selected. Then, the FNLLICAASA was synthesized, characterized, and the amount of dopamine level changes in SH-SY5Y cells after exposure to FNLLICAASA was evaluated. Also, the interferon-gamma (INFG) expression was assessed. The binding of FNLLICAASA to SH-SY5Y cells was also investigated using a fluorescent microscope and flow cytometry. The results of molecular docking and molecular dynamics simulation showed that aptamer APT46 with GAGGAG sequence was the best-chosen aptamer. The FNLLICAASA have a size range of 120 to 310 nm with an average positive zeta potential of 30 mV. The dopamine level change was increased in treated SH-SY5Y nerve cells, indicating the dopaminergic property of FNLLICAASA. Also, the expression of INFG was decreased in treated SH-SY5Y nerve cells, indicating the anti-neuroinflammatory property of FNLLICAASA. The binding tests showed the targeted binding of synthesized nanoliposomes to alpha-synuclein molecules on the cell surface of SH-SY5Y cells.
Extracellular Vesicles from Peripheral Blood Mononuclear Cells of Hyperammonemic Rats Induce Neuroinflammation in Hippocampus, Impairing Memory and Learning in Normal Rats.
Izquierdo-Altarejos P, López-Gramaje A, Pedrosa MA … +5 more , Sebestyén VE, Vazquez L, Martinez-Garcia M, Llansola M, Felipo V
J Neuroimmune Pharmacol · 2025 Jun · PMID 40481977 · Publisher ↗
Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE), with mild cognitive impairment. Studies in patients and animal models show that MHE is triggered by a shift in peripheral inflammation. Periphe...
Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE), with mild cognitive impairment. Studies in patients and animal models show that MHE is triggered by a shift in peripheral inflammation. Peripheral extracellular vesicles (EVs) seem to mediate transmission of deleterious effects to the brain. However, it is not known which cell types produce the pathological EVs. The aim of this study was to assess if EVs released from cultured peripheral blood mononuclear cells from hyperammonemic rats with MHE (HA-PBMC-EVs) transmit pathological signals to the brain when injected into normal rats and to analyze the underlying mechanisms. We found that HA-PBMC-EVs induce neuroinflammation in hippocampus and cognitive impairment in normal rats, indicating that hyperammonemia alters the EVs released by PBMCs, which mediate cognitive impairment induction. We also identified underlying mechanisms: HA-PBMC-EVs enhance membrane expression and activation of TNFR1 and of S1PR2, increasing IL-1β and phosphorylation of Src, which increases CCL2 and BDNF content and membrane expression of the GLUN2B subunit of the NMDA receptor. BDNF activates TrkB, leading to phosphorylation and activation of Akt, which further increases BDNF. The increased activation of GLUN2B alters membrane expression of GluA1 and GluA2 subunits of AMPA receptors, which would be responsible for the induction of cognitive impairment. Moreover, blocking TNFα in the HA-PBMC-EVs prevents the activation of the TNFα-TNFR1-S1PR2-IL-1β-Src-BDNF-TrkB pathway and the changes in membrane expression of NMDA and AMPA receptors. EVs from PBMC may be therefore a therapeutic target on which to act to reverse cognitive impairment in patients with MHE.
Motor-Related Neural Dynamics are Modulated by Regular Cannabis Use Among People with HIV.
Webert LK, Schantell M, Horne LK … +9 more , John JA, Glesinger R, O'Neill J, Kubat M, Coutant AT, Ende GC, Bares SH, May-Weeks PE, Wilson TW
J Neuroimmune Pharmacol · 2025 Jun · PMID 40473990 · Full text
Recent work has shown that people with HIV (PWH) exhibit deficits in cognitive control and altered brain responses in the underlying cortical networks, and that regular cannabis use has a normalizing effect on these neur...
Recent work has shown that people with HIV (PWH) exhibit deficits in cognitive control and altered brain responses in the underlying cortical networks, and that regular cannabis use has a normalizing effect on these neural responses. However, the impact of regular cannabis use on the neural oscillatory dynamics underlying motor control deficits in PWH remains less understood. Herein, 102 control cannabis users, control nonusers, PWH who regularly use cannabis, and PWH who do not use cannabis performed a motor control task with and without interference during high-density magnetoencephalography. The resulting neural dynamics were examined using whole-brain, voxel-wise statistical analyses that examined the impact of HIV status, cannabis use, and their interaction on the neural oscillations serving motor control, spontaneous activity during the baseline period, and neurobehavioral relationships. Our key findings revealed cannabis-by-HIV group interactions in oscillatory gamma within the prefrontal cortices, higher-order motor areas, and other regions, with the non-using PWH typically exhibiting the strongest gamma interference responses. Cannabis-by-HIV interactions were also found for oscillatory beta in the dorsal premotor cortex. Spontaneous gamma during the baseline was elevated in PWH and suppressed in cannabis users in all regions exhibiting interaction effects and the left primary motor cortex, with spontaneous levels being correlated with behavioral performance. These findings suggest that regular cannabis use has a normalizing effect on the neural oscillations serving motor control and the abnormally elevated spontaneous gamma activity that has been widely replicated in PWH, which may suggest that cannabis has at least some therapeutic utility in PWH.
Efficacy of 6-nitrobenzo[d]thiazol-2 Amine Derivative (N3) in Mitigating PTZ-Induced Epileptic Conditions Via Modulation of Inflammatory and Neuroprotective Pathways in-vivo Zebrafish.
Ramamurthy K, Nayak SPRR, Madesh S … +8 more , Panda SP, Manikandan K, Rajagopal R, Alfarhan A, Palaniappan S, Guru A, Kathiravan MK, Arockiaraj J
J Neuroimmune Pharmacol · 2025 Jun · PMID 40473889 · Publisher ↗
Epilepsy, a chronic neurological illness affecting 50 million people worldwide, causes recurring seizures due to abnormal brain activity. Current anti-epileptic medications have serious side effects and low efficacy, req...
Epilepsy, a chronic neurological illness affecting 50 million people worldwide, causes recurring seizures due to abnormal brain activity. Current anti-epileptic medications have serious side effects and low efficacy, requiring alternative treatments. The current study investigated the anti-inflammatory, antioxidant, and neuroprotective effects of 6-nitrobenzo[d]thiazol-2-amine (N3) derivatives in a zebrafish larvae model of epilepsy caused by 6 mM pentylenetetrazole (PTZ). Furthermore, N3 was tested for its safety, potential to reduce oxidative stress, inflammation, and neurodegeneration, and effects on motor coordination and neurotransmitter levels. The study utilized in vitro hemolysis assays to evaluate the membrane-stabilizing properties of N3. Zebrafish larvae were pre-treated with N3 at varying concentrations and subsequently exposed to PTZ to induce epilepsy-like conditions. Antioxidant enzyme activities superoxide dismutase (SOD), catalase CAT), glutathione (GSH) levels, lactate dehydrogenase (LDH) activity, and reactive oxygen species (ROS) levels were analyzed. Gene expression for pro-inflammatory and neuroprotective markers was quantified using qPCR, while histological assessments were performed to evaluate amyloid plaque formation, collagen accumulation, and calcium deposition. Behavioral tests measured motor coordination, and gamma-aminobutyric acid (GABA) levels were quantified using high-performance liquid chromatography. N3 demonstrated dose-dependent hemolysis inhibition, confirming its membrane-stabilizing and anti-inflammatory properties up to 43.47 ± 1.36%. It enhanced antioxidant enzyme activities, increased GSH levels 0.76 ± 0.03 nmol/mg, reduced LDH and ROS levels 7.47 ± 0.07 U/mg protein, and suppressed pro-inflammatory gene expression. Histological analysis revealed reduced neurodegenerative markers, including amyloid plaques and calcium deposition. Behavioral improvements were observed, including enhanced motor coordination and increased GABA levels. The findings suggest that N3 derivatives have significant therapeutic potential in epilepsy by reducing oxidative stress, inflammation, and neurodegeneration. Further studies are needed to optimize dosing and confirm safety for clinical applications.
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