J Neuroimmune Pharmacol [JOURNAL]
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200 papers
The Role of Microglial Exosomes in Clozapine Treatment: Effect on Cognition in Schizophrenia.
Hewitt K, Huang XF
J Neuroimmune Pharmacol · 2025 Apr · PMID 40238023 · Full text
Schizophrenia is a complex neuropsychiatric disorder characterized by a spectrum of symptoms including cognitive impairments and psychotic episodes. Clozapine, an atypical antipsychotic drug, is a widely recognised treat...
Schizophrenia is a complex neuropsychiatric disorder characterized by a spectrum of symptoms including cognitive impairments and psychotic episodes. Clozapine, an atypical antipsychotic drug, is a widely recognised treatment option for patients with drug-resistant schizophrenia, due to it having the highest efficacy out of all the antipsychotic drugs. Despite its efficacy, clozapine's impact on cognition and brain structure in schizophrenia patients remains a subject of ongoing research and debate, with accumulating evidence indicating negative impacts on cognitive performance and changes in brain volume. Changes in the immune system are linked to variations in cognitive functioning in schizophrenia. Previous research has indicated that microglia, the primary innate immune cells of the brain, have been associated with decreased cognitive performance when dysfunctional. Evidence suggests that brain structure may mediate the observed relationship between microglia and cognition. Microglial exosomes, integral to neuroinflammation and cellular communication, could provide insight into the neurobiological mechanisms underpinning the effects of clozapine treatment. This review focuses on the proposition that alterations in microglial exosome composition, particularly miRNAs, are involved in mediating clozapine's diverse effects on cognition by influencing brain macrostructure. This review aims to highlight new directions for future research that could lead to more effective and targeted therapeutic approaches in the management of schizophrenia.
Preparation and In vitro/In vivo Evaluation of Fingolimod hydrochloride Loaded Polymeric Mixed Nano-Micelles for Treatment of Multiple Sclerosis.
Dayani L, Haddadi F, Aliomrani M … +1 more , Taheri A
J Neuroimmune Pharmacol · 2025 Apr · PMID 40237870 · Publisher ↗
Fingolimod (FYN) is one of the approved medicines for treatment of multiple sclerosis (MS) while exhibiting several side effects such as liver enzyme elevation and cardiac damage. This study was aimed to prepare the mixe...
Fingolimod (FYN) is one of the approved medicines for treatment of multiple sclerosis (MS) while exhibiting several side effects such as liver enzyme elevation and cardiac damage. This study was aimed to prepare the mixed micelles of ascorbyl palmitate (AP) and alpha-tocopherol polyethylene glycol succinate (TPGS) as a delivery system for FYN. The mixed micelles were prepared by thin film hydration method at different ratios of AP/TPGS. Saturation solubility of the micelles was compared with the pure drug. The optimized formulation was characterized by scanning electron microscopy (SEM) and subjected for stability study at 5 ± 3 °C for 3 months. The effect of the prepared fingolimod loaded micelles (FYN-Micelle) was finally assessed by experimental autoimmune encephalomyelitis (EAE) model at the dose of 0.3, 1, and 3 mg/kg of fingolimod, which was administrated intraperitoneally. The results indicated that the prepared mixed micelles at the AP/TPGS ratio of 1:5 showed a particle size, zeta potential, and an entrapment efficiency of 116.86 ± 2.41 nm, 23.61 ± 4.56 mV, and 63.28 ± 5.31%, respectively. Also, this formulation was stable after a 3-month incubation at 5 ± 3 °C. SEM images displayed an amorphous state of the drug in the micelles. Animal studies confirmed that this formulation at the dose of 1 mg/kg could enhance the myelin density of the brain while reducing cardiac and hepatic impairment. Therefore, these findings suggested that FYN-Micelle could be exploited as an effective delivery system for fingolimod hydrochloride to treat MS.
Modafinil Ameliorated Fibromyalgia Syndrome in Rats by Modulating Mast Cells and Microglia Activation Through Dopamine/Substance P/MRGPRX/Histamine and PI3K/p-Akt/NF-κB Signaling Pathways.
Kamal MM, Essam RM, Abdelkader NF … +1 more , Zaki HF
J Neuroimmune Pharmacol · 2025 Apr · PMID 40234306 · Full text
Fibromyalgia syndrome (FMS) is characterized by prolonged, widespread musculoskeletal pain accompanied by various physical and psychological disturbances. Modafinil, a wake-promoting drug, manages pain symptoms in severa...
Fibromyalgia syndrome (FMS) is characterized by prolonged, widespread musculoskeletal pain accompanied by various physical and psychological disturbances. Modafinil, a wake-promoting drug, manages pain symptoms in several diseases by inhibiting dopamine reuptake and exhibiting anti-inflammatory and immunomodulatory effects, including the impairment of cytokine production, microglia, and mast cell activation. Central inflammation may involve microglial activation, which is correlated with mast cell activation. Restoring dopamine levels and modulating the communication between mast cells and microglia may represent a promising approach to managing pain symptoms in FMS. Thus, this study intended to explore the interplay between brain mast cells and microglia as an underlying mechanism in the pathophysiology of FMS and how this interaction is controlled by modafinil, with a focus on dopamine/SP/MRGPRX2/histamine and PI3K/p-Akt/NF-κB signaling pathways. Rats were arbitrarily distributed between 4 groups. Group 1 served as normal control. Reserpine (1 mg/kg/day; s.c) was injected into the remaining groups for three consecutive days. In groups 3 and 4, modafinil (100 mg/kg/day; p.o) was administered either alone or in conjunction with haloperidol (1 mg/kg/day; ip), respectively, for the following 21 days. Modafinil ameliorated reserpine-induced thermal/mechanical allodynia (1.3-fold, 2.3-fold) and hyperalgesia (0.5-fold), attenuated depression (0.5-fold), and enhanced motor coordination (1.2-fold). It mitigated the histopathological alterations and increased dopamine levels in the thalamus of rats by 88.5%. Modafinil displayed anti-inflammatory effects via inhibiting mast cells and microglia activation, manifested by reductions in SP/MRGPRX2/IL-17/histamine (52%, 58%, 56.7%, and 63.7%) and PI3K/p-Akt/t-Akt/NF-κB/TNF-α/IL-6 (31.7%, 55.5%, 41%, 47.6%, and 76.9%), respectively. Ultimately, modafinil alleviated FMS behavioral, histopathological, and biochemical abnormalities and suppressed mast cell-microglial neuroinflammation in the thalamus of rats exposed to reserpine. This study highlights the potential of repurposing modafinil to improve FMS symptoms.
Abscisic Acid Rescues Behavior in Adult Female Mice in Attention Deficit Disorder with Hyperactivity Model of Dopamine Depletion by Regulating Microglia and Increasing Vesicular GABA Transporter Expression.
Meseguer-Beltrán M, Sánchez-Sarasúa S, Kerekes N … +3 more , Landry M, Real-López M, Sánchez-Pérez AM
J Neuroimmune Pharmacol · 2025 Apr · PMID 40234284 · Full text
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental syndrome typically diagnosed in childhood that may persist into adulthood. Its etiology encompasses both genetic and environmental factors, with gen...
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental syndrome typically diagnosed in childhood that may persist into adulthood. Its etiology encompasses both genetic and environmental factors, with genetic studies indicating catecholamine dysfunction and epidemiological evidence emphasizing neuroinflammation as a potential trigger. To investigate the roles of inflammation and development processes in ADHD, we conducted a longitudinal behavioral study using female Swiss mice with a dopamine deficit model. We explored the impact of neonatal dopaminergic lesions, treatment with abscisic acid (ABA)-an anti-inflammatory hormone-and developmental changes by comparing behavioral patterns in juvenile and adult mice. Postmortem analyses assessed neuroinflammation through microglial morphology, NLRP3, cytokine expression, and the excitatory/inhibitory (E/I) ratio in specific brain regions. Neonatal dopaminergic lesions induced hyperactivity and hypersensitivity in juvenile mice that persisted into adulthood. In adults, increased social interaction and memory impairment were observed in lesioned mice. Brain development mitigated impulsivity, while ABA treatment reduced locomotor activity, downregulated pain sensitivity, and influenced social interaction, although it did not completely resolve cognitive deficits in lesioned adult mice. In brain regions such as the anterior cingulate cortex (ACC), posterior insular cortex (pIC), and hippocampus, lesions significantly altered microglial morphology. In the ACC, lesions increased IL-1β and TNFα levels, decreased Arg1 mRNA levels, and disrupted the E/I balance. Importantly, ABA treatment restored microglial morphology, normalized IL-1β and Arg1 expression and upregulated vGAT levels. This study demonstrates that dopamine deficits lead to microglia alterations and E/I imbalance, contributing to ADHD symptoms. While some symptoms improve with brain development, targeting microglial health in specific brain regions emerges as a promising therapeutic approach for managing ADHD.
Evaluation of the Anti-Inflammatory Effects of Novel Fatty Acid-Binding Protein 4 Inhibitors in Microglia.
Low YL, Kreutzer E, Chandrashekaran IR … +7 more , Adams LA, Pun J, Doak BC, Pan Y, Short JL, Scanlon MJ, Nicolazzo JA
J Neuroimmune Pharmacol · 2025 Apr · PMID 40234265 · Full text
Fatty acid-binding protein 4 (FABP4) is a key lipid binding protein expressed in microglia, which has been demonstrated to play a critical role in microglial-mediated neuroinflammation, a component of many neurodegenerat...
Fatty acid-binding protein 4 (FABP4) is a key lipid binding protein expressed in microglia, which has been demonstrated to play a critical role in microglial-mediated neuroinflammation, a component of many neurodegenerative diseases. Compounds able to inhibit the function of FABP4 have shown promise in reducing microglial-mediated neuroinflammation, however, their physicochemical properties would prevent their ability to be easily formulated and traverse the blood-brain barrier (BBB) in order to access microglial FABP4. To this end, this study assessed the ability of a series of FABP4 inhibitors, with more desirable physicochemical properties, to attenuate microglial inflammation in an in vitro setting. Four inhibitors with varying affinity to FABP4, as measured by isothermal titration calorimetry (MFP-0011462, MFP-0012314, MFP-0012318, and MFP-0012328), were assessed for their ability to induce toxicity and attenuate reactive oxygen species (ROS) generation and tumour necrosis factor-α (TNF-α) release from lipopolysaccharide (LPS)-activated BV-2 microglia. All FABP4 inhibitors were determined to be soluble in the aqueous buffers at the highest concentration used in the assays (100 µM). Isothermal titration calorimetry demonstrated that the compounds had varying affinities for FABP4 (K values of 316 nM to > 100 µM). The ability of FABP4 inhibitors to reduce LPS-mediated ROS production aligned with their K for FABP4, with the most effective inhibitor (MFP-0012328) also able to reduce TNF-α production (by RT-qPCR) and TNF-α release from LPS-activated BV-2 cells by 17% and 25%, respectively. These studies have demonstrated that a series of FABP4 inhibitors with more appropriate physicochemical properties for BBB penetration are able to reduce microglial-mediated inflammation, which may be of benefit in diseases where overactivation of microglia leads to neurodegeneration.
Experimental autoimmune encephalomyelitis pathogenesis alters along animal age: impact of S100B expression.
Ribeiro AR, Pereira R, Barros C … +9 more , Barateiro A, Alberro A, Basto AP, Graça L, Pinto MV, Santos FMF, Gois PMP, Howlett SE, Fernandes A
J Neuroimmune Pharmacol · 2025 Apr · PMID 40227512 · Full text
Multiple Sclerosis (MS) is the leading inflammatory and non-traumatic cause of disability in young adults, with late-onset MS emerging in middle-aged patients often resulting in poorer treatment responses and worse progn...
Multiple Sclerosis (MS) is the leading inflammatory and non-traumatic cause of disability in young adults, with late-onset MS emerging in middle-aged patients often resulting in poorer treatment responses and worse prognoses. The calcium-binding protein S100B is elevated in MS patients, and its targeting has shown promise in reducing disease severity in experimental autoimmune encephalomyelitis (EAE) models. However, most studies on MS pathology have focused on young animal models, leaving a gap in understanding the effects of age and S100B ablation on disease progression throughout the lifespan. This study aimed to characterize EAE in mice of different ages, examining demyelination, inflammation, and immune responses to determine whether S100B ablation could mitigate MS pathogenesis across the lifespan. EAE was induced in six cohorts of C57BL/6 mice: young adults (3 months), older adults (6 months), and middle-aged (12 months), including corresponding S100B knockout (KO) groups, followed for 23 days. Upon sacrifice, spinal cords were assessed via immunohistochemistry and Real-Time qPCR, while splenocytes were analyzed for immune cell characterization. Results indicated a more severe disease course in 12-month-old mice, marked by increased gliosis, inflammation, and impaired microglial phagocytic activity. Notably, S100B absence reduced gliosis and inflammatory markers across all ages, with 12-month-old S100B KO mice showing increased regulatory T cells. These findings highlight the exacerbating role of age and elevated S100B in MS progression, underscoring the importance of identifying age-specific MS markers and therapeutic targets.
Antioxidant-Effective Quercetin Through Modulation of Brain Interleukin-13 Mitigates Autistic-Like Behaviors in the Propionic Acid-Induced Autism Model in Rats.
Kılıç KD, Garipoğlu G, Çakar B … +2 more , Uyanıkgil Y, Erbaş O
J Neuroimmune Pharmacol · 2025 Apr · PMID 40220083 · Full text
Overproduction of reactive oxygen species occurs when inflammation induces oxidative stress in macrophages and microglia, leading to a self-sustaining cycle of cellular damage and neuroinflammation. Oxidative stress and...
Overproduction of reactive oxygen species occurs when inflammation induces oxidative stress in macrophages and microglia, leading to a self-sustaining cycle of cellular damage and neuroinflammation. Oxidative stress and neuroinflammation are well-established contributors to the pathophysiology of autism spectrum disorders, which are associated with impaired neuronal function, neuronal loss, and behavioral deficits. Damaged cells, through microglial activation, release additional inflammatory mediators under conditions of oxidative stress, exacerbating neuronal damage. Quercetin, a powerful dietary antioxidant, has been shown to scavenge free radicals, reduce oxidative stress, and inhibit inflammatory pathways. Given these properties, we hypothesize that quercetin may improve learning and social skills in individuals with autism spectrum disorders by alleviating oxidative stress and reducing brain levels of inflammatory cytokines. In this study, an autism model was established in 30 rats by intraperitoneal injection of 250 mg/kg/day propionic acid (PPA) for five days. The study groups were as follows: Group 1: Normal ontrol (n = 10); Group 2: PPA + saline (PPAS, n = 10); Group 3: PPA + Quercetin (PPAQ, n = 10). All treatments were administered for 15 days. At the end of the treatment, histological and biochemical analyses of brain tissue and behavioral tests related to autistic-like behaviors were performed. Malondialdehyde, tumor necrosis factor-alpha, and interleukin-13 levels in brain homogenates were significantly higher in the PPAS group compared to the control group, indicating elevated oxidative stress and inflammation following PPA exposure. The PPAQ group significantly reduced oxidative stress parameters and inflammatory biomarkers, demonstrating its antioxidant and anti-inflammatory effects. This biochemical improvement was accompanied by preserving Purkinje cells and neuronal populations, significantly reduced in the PPAS group. Moreover, quercetin-treated rats exhibited improved social behavior and learning, which were severely impaired in the PPAS group. These findings, when interpreted together, suggest that quercetin exerts its neuroprotective effects by targeting oxidative stress and neuroinflammation, thereby preventing neuronal cell loss and alleviating behavioral deficits associated with autism spectrum disorders.
Yi-Nao-Jie-Yu Prescription Relieves Post-Stroke Depression by Mitigating Ferroptosis in Hippocampal Neurons Via Activating the Nrf2/GPX4/SLC7A11 Pathway.
Zhang Y, Tang Q, Yao J … +5 more , Liu H, Xu C, Guo Z, Liu S, Zhao R
J Neuroimmune Pharmacol · 2025 Apr · PMID 40214929 · Full text
Post-stroke depression (PSD) poses a serious impact on patients' life quality. Effective drugs to treat this annoying disease are still being sought. Yi-nao-jie-yu (YNJY) prescription has been found to relieve PSD; howev...
Post-stroke depression (PSD) poses a serious impact on patients' life quality. Effective drugs to treat this annoying disease are still being sought. Yi-nao-jie-yu (YNJY) prescription has been found to relieve PSD; however, the underlying mechanisms remain unelucidated. This work elucidated the therapeutic effects and mechanisms underlying YNJY prescription in PSD. PSD rat model was treated with YNJY prescription and ML385. Depression-like behaviors of rats was appraised. Hematoxylin-eosin, Nissl, and NeuN immunofluorescence staining were performed to observe hippocampal neuronal damage. Transmission electron microscopy was used to assess hippocampal mitochondrial damage. Commercial kits and western blotting were adopted to research ferroptosis-related factors and Nrf2/GPX4/SLC7A11 signals. In vitro experiments were performed using rat hippocampal neurons to explore the mechanism by which YNJY prescription relieves PSD. In PSD rats, YNJY prescription relieved depression-like behaviors, attenuated hippocampal neuronal damage, mitigated hippocampal ferroptosis and mitochondrial damage, and activated hippocampal Nrf2/GPX4/SLC7A11 pathway. By in vitro experiments, erastin treatment exacerbated hippocampal neuronal damage, ferroptosis, mitochondrial damage, and lipid peroxidation; however, YNJY prescription abolished these erastin-induced effects. In the erastin-treated hippocampal neuronal model of PSD, ML385 treatment increased ferroptosis, hippocampal neuronal damage, and lipid peroxidation; however, YNJY prescription counteracted these ML385-induced effects. By in vivo study, ML385 reversed the relief of YNJY prescription on depressive-like behaviors of PSD rats, and the inhibition on ferroptosis in PSD rats' hippocampus. YNJY prescription relieves PSD by blocking ferroptosis via activating the Nrf2/GPX4/SLC7A11 pathway. It may be a promising agent for treating PSD clinically.
Irisin Regulates Microglia M1/M2 Polarization and Promotes Autophagy Through the Sirt3 Pathway to Alleviate POCD.
Li C, Cong Y, Song W … +3 more , Wu Y, Gou X, Qi S
J Neuroimmune Pharmacol · 2025 Apr · PMID 40214830 · Publisher ↗
Cognitive impairment following surgical procedures, termed postoperative cognitive dysfunction (POCD), is a significant complication affecting the central nervous system. This condition stems from the combined impacts of...
Cognitive impairment following surgical procedures, termed postoperative cognitive dysfunction (POCD), is a significant complication affecting the central nervous system. This condition stems from the combined impacts of anesthesia and surgical intervention, with microglial-induced neuroinflammation identified as the primary pathological mechanism. Irisin, a recently identified hormone released during physical exercise, has shown remarkable anti-inflammatory and neuroprotective properties, largely through its ability to modulate microglial activation in various central nervous system disorders. In this study, we explored the protective effects of irisin and its underlying mechanisms in a mouse model of POCD and BV2 microglial cells. Our results demonstrated that irisin effectively mitigated hippocampal-dependent cognitive deficits in mice subjected to exploratory laparotomy. Additionally, irisin facilitated the phenotypic shift of microglia from the pro-inflammatory M1 state to the anti-inflammatory and reparative M2 state. Furthermore, irisin upregulated the expression of Sirt3 in the postoperative hippocampus of mice. Importantly, pharmacological inhibition of Sirt3 activity using 3-TYP nullified the neuroprotective effects of irisin. In vitro studies revealed that irisin increased the expression of Sirt3 and autophagy-related proteins in lipopolysaccharide-activated BV2 microglial cells. Notably, Sirt3 knockout impeded irisin-induced autophagy enhancement and inhibited the polarization of microglia toward the M2 phenotype. Collectively, these findings highlight irisin's ability to attenuate POCD by driving the phenotypic transition of microglia from M1 to M2 through a mechanism involving Sirt3-mediated autophagy. This novel pathway underscores the therapeutic potential of irisin as a promising candidate for managing POCD.
( +)-Catechin Alleviates CCI-Induced Neuropathic Pain by Modulating Microglia M1 and M2 Polarization via the TLR4/MyD88/NF-κB Signaling Pathway.
Jing B, Zhao JJ, Chen ZN … +6 more , Si WM, Chang SQ, Zheng YC, Zhuang ZF, Zhao GP, Zhang D
J Neuroimmune Pharmacol · 2025 Apr · PMID 40195186 · Publisher ↗
The aim of this research endeavor was to explore the therapeutic potential of ( +)-catechin in mitigating neuropathic pain. A total of thirty-two Sprague‒Dawley rats were randomly allocated into four groups: the sham gro...
The aim of this research endeavor was to explore the therapeutic potential of ( +)-catechin in mitigating neuropathic pain. A total of thirty-two Sprague‒Dawley rats were randomly allocated into four groups: the sham group, the chronic constriction injury (CCI) group, the CCI + ibuprofen group, and the CCI + ( +)-catechin group. The results of the in vivo experiment show that ( +)-catechin has the potential to improve mechanical hyperalgesia induced by CCI and reduce the infiltration of inflammatory cells in the injured sciatic nerve. CCI induces the upregulation of nNOS, iNOS, IL-1β, and COX-2 within the rat sciatic nerve and leads to an elevation in the levels of IL-1β, PGE2, and TNF-α in the serum of rats, while simultaneously diminishing the secretion of IL-10. Moreover, immunofluorescence analysis reveals that CCI enhances the expression of CD32 (an M1 polarization marker) in the rat spinal cord, while diminishing the expression of CD206 (an M2 polarization marker). However, the administration of ( +)-catechin effectively counteracts these effects. Western blot analysis further demonstrates that ( +)-catechin significantly reduces the protein expression of IBA-1, IL-1β, MyD88, p-NF-κB, p-JNK, p-ERK, p-p38MAPK, COX-2, and TLR4 within the spinal cord. The findings of the BV2 cell experiment revealed the attenuating effects of ( +)-catechin on M1 polarization markers (such as IL-1β, TNF-α, iNOS, and CD32), while concurrently boosting the levels of M2 polarization markers (including CD206, IL-10, and Arg-1). Notably, administration of LPS significantly heightened the accumulation of IBA-1, IL-1β, MyD88, p-NF-κB, p-JNK, p-ERK, p-p38MAPK, TLR4, COX-2, and iNOS, while concurrently suppressing Arg-1 expression. However, the administration of ( +)-catechin effectively reversed these alterations. Overall, these findings suggest that ( +)-catechin alleviates neuropathic pain by modulating the M1 and M2 phenotypes of microglia through the TLR4/MyD88/NF-κB pathway.
Dapagliflozin Ameliorate Type-2 Diabetes Associated Neuropathy via Regulation of IGF-1R Signaling.
Kaur P, Singh T, Jena L … +6 more , Gupta T, Rana MK, Singh S, Singh R, Kumar P, Munshi A
J Neuroimmune Pharmacol · 2025 Apr · PMID 40178648 · Publisher ↗
Dapagliflozin, an approved SGLT2 inhibitor, has been shown to have extra-glycemic effects like cardio-reno protection. However, the neuroprotective effects of SGLT2 inhibitors against diabetic neuropathy (DN) have not be...
Dapagliflozin, an approved SGLT2 inhibitor, has been shown to have extra-glycemic effects like cardio-reno protection. However, the neuroprotective effects of SGLT2 inhibitors against diabetic neuropathy (DN) have not been explored. The current study aimed to determine the neuroprotective potential of Dapagliflozin against STZ-NAD-induced DN in Wistar rats via IGF-1 signaling. DN was induced by STZ-NAD in male Wistar rats. After 60 days of induction, behavioural tests were conducted to access DN, and treatment with Dapagliflozin (0.75 mg/kg & 1.50 mg/kg) was initiated for 30 days. At the end of the study, the brain and sciatic nerve were isolated and expression analysis of IGF-1R signaling molecules was carried out using western blotting, qRTPCR, and immunohistochemistry. Structural changes in the brain and sciatic nerve were ascertained by histopathology. The results showed that treatment with Dapagliflozin improved behavioural parameters in STZ-NAD-induced DN rats. The decreased expression levels of IGF1R signaling pathway molecules and increased expression of p-AKT were found to increase and decrease in the brain and sciatic nerve, respectively after the treatment. Histological studies demonstrated the restoration of normal architecture of the brain and sciatic nerve after treatment with dapagliflozin. The altered expression of IGF-1R signaling molecules established the neuroprotective potential of dapagliflozin against DN.
Pentoxifylline Prevents Neuroinflammation and Modifies PTEN/TrkB Signaling in an LPS-Induced Depression Model.
Ali T, Luo Y, Zheng C … +4 more , Rahman SU, Murtaza I, Feng J, Li S
J Neuroimmune Pharmacol · 2025 Apr · PMID 40175765 · Publisher ↗
Neuroinflammation affects patients with major depressive disorder and is linked to severe, treatment-resistant symptoms, making it a promising therapeutic target for improving depressive symptoms. This study highlighted...
Neuroinflammation affects patients with major depressive disorder and is linked to severe, treatment-resistant symptoms, making it a promising therapeutic target for improving depressive symptoms. This study highlighted the neuroprotective role of pentoxifylline (PTX) against lipopolysaccharide (LPS)-induced neuroinflammation and associated behavioral deficits. Mice were injected with LPS (1 mg/kg, i.p) to induce neuroinflammation and treated with PTX (10 mg/kg, i.p). Behavioral and biochemical analyses were performed to evaluate depressive-like behaviors and examine hippocampal protein expression associated with neuroinflammation and synaptic plasticity. LPS administration increased proinflammatory cytokine production (IL-1, IL6, and TNF-α), microglial activation (IBA-1/GFAP), and dysregulation of key synaptic proteins, including BDNF and TrkB, in the hippocampus of mice. Concomitantly, LPS reduced Phosphatase and tensin homolog (PTEN) phosphorylation, potentially contributing to increased neuroinflammation. PTX treatment effectively attenuated LPS-induced effects by suppressing inflammatory responses, restoring BDNF/TrkB signaling, and rescuing synaptic impairments. Mechanistically, PTX treatment increased PTEN phosphorylation and was reversed by the TrkB inhibitor K252a, suggesting that PTX upregulates TrkB/BDNF signaling, leading to increased PTEN phosphorylation and subsequent inhibition of PTEN activity. These findings highlight the potential of PTX as a therapeutic agent for neuroinflammatory conditions, possibly exerting its effects by modulating the PTEN/TrkB/BDNF signaling axis and suggest a novel mechanism of action involving the modulation of the PTEN/TrkB/BDNF signaling pathway.
Revisiting Migraine Pathophysiology: from Neurons To Immune Cells Through Lens of Immune Regulatory Pathways.
Subalakshmi S, Rushendran R, Vellapandian C
J Neuroimmune Pharmacol · 2025 Apr · PMID 40172704 · Publisher ↗
Migraine is a prevalent neurological disorder characterized by severe, recurrent headaches accompanied by symptoms, such as nausea, photophobia, and phonophobia, significantly affecting the quality of life of millions of...
Migraine is a prevalent neurological disorder characterized by severe, recurrent headaches accompanied by symptoms, such as nausea, photophobia, and phonophobia, significantly affecting the quality of life of millions of people worldwide. Although the neurovascular pathway, involving blood vessel dilation and neurogenic inflammation, has been a cornerstone in understanding migraine pathophysiology. Emerging evidence suggests that immune dysregulation plays a pivotal role in the onset and progression of migraine. This review uniquely synthesizes recent advances linking immune regulatory pathways to migraine, an area that has not been widely explored in the literature. Specifically, we highlighted the involvement of CD4 + CD25 + regulatory T (Treg) cells, interleukins, and pro-inflammatory and anti-inflammatory cytokines, which have been implicated in pain signaling and immune imbalance in patients with migraine. Furthermore, genetic studies have provided compelling evidence by identifying associations between migraine susceptibility and immune-related polymorphisms, particularly in forkhead box P3 (FOXP3) and nuclear factor of activated T cells (NFAT). Moreover, the higher prevalence of migraine in individuals with comorbid autoimmune diseases further supports the hypothesis of a shared pathophysiological mechanism. Despite the growing recognition of immune involvement in migraine, its precise mechanisms remain unclear. By integrating key immune biomarkers and genetic insights, this review proposes a novel framework for understanding the immune-mediated pathways in migraine progression. Future research should focus on elucidating the specific immunological mechanisms underlying migraine, which could open new avenues for innovative, targeted therapeutic strategies.
IL-17 A Exacerbated Neuroinflammatory and Neurodegenerative Biomarkers in Intranasal Amyloid-Beta Model of Alzheimer's Disease.
Gautam AS, Pandey SK, Balki S … +2 more , Panda ES, Singh RK
J Neuroimmune Pharmacol · 2025 Mar · PMID 40163129 · Publisher ↗
Proinflammatory cytokines, especially interleukin-17 A (IL-17 A) have been found to be significantly associated with AD patients. IL-17 A amplifies neuroinflammation during AD pathology. This study highlighted the abilit...
Proinflammatory cytokines, especially interleukin-17 A (IL-17 A) have been found to be significantly associated with AD patients. IL-17 A amplifies neuroinflammation during AD pathology. This study highlighted the ability of IL-17 A to exacerbate amyloid-beta-induced pathology in animals. The AD pathology was induced with repeated intranasal administration of Aβ along with recombinant mouse IL-17 A (rmIL-17) at 1, 2 and 4 µg/kg for seven alternate days. Although, the combination of rmIL-17 and Aβ did not have severe effects on memory of the animals, but it drastically increased the IL-17 A mediated signaling, level of proinflammatory cytokines, oxidative stress and reduced antioxidants in the hippocampus and cortex regions of the animal brains. Interestingly, combining rmIL-17 with Aβ also triggered the expression of AD structural markers like pTau, amyloid-beta and BACE1 in the brain regions. Furthermore, rmIL-17 with Aβ exposure stimulated astrocytes and microglia leading to activation of proinflammatory signaling in the brain of the animals. These results showed the propensity of IL-17 A to promote severity of AD pathology and suggest IL-17 A as potent therapeutic target to control AD progression.
Correction: Low-Dose Aspirin Upregulates Tyrosine Hydroxylase and Increases Dopamine Production in Dopaminergic Neurons: Implications for Parkinson's Disease.
Rangasamy SB, Dasarathi S, Pahan P … +2 more , Jana M, Pahan K
J Neuroimmune Pharmacol · 2025 Mar · PMID 40138106 · Publisher ↗
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Modulating Multiple Molecular Trajectories by Nutraceuticals and/or Physical Activity in Attention-Deficit/Hyperactivity Disorder (ADHD)-Like Behaviors in Rat Pups.
Abu-Elfotuh K, Kamel GAM, Najm MAA … +14 more , Hamdan AME, Koullah MT, Fahmy RKE, Aboelsoud HA, Alghusn MA, Albalawi BR, Atwa AM, Abdelhakim KR, Elsharkawy AMA, Mohamed EK, Abdou NS, Almotairi R, Salem HA, Gowifel AMH
J Neuroimmune Pharmacol · 2025 Mar · PMID 40102360 · Full text
Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition affecting cognitive and social functions all over childhood. Monosodium glutamate (MSG) is a common food additive associated with ADHD-lik...
Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition affecting cognitive and social functions all over childhood. Monosodium glutamate (MSG) is a common food additive associated with ADHD-like symptoms in children. Nutraceuticals, like sesamol (SE) and astaxanthin (AST), or physical activity (PHA) were reported to possess beneficial effects on human health. Meanwhile, still their neuroprotective effect against ADHD has been poorly investigated. This study aimed to investigate the impact of SE, AST and PHA either separately or combined on ADHD-like behaviors induced by MSG in rat pups. Eighty-four male Sprague Dawley rat pups were randomly allocated into seven groups; control, MSG, (PHA + MSG), (SE + MSG), (AST + MSG), (SE + AST + MSG), and (COMB [PHA + SE + AST] + MSG) and treated for eight weeks. MSG-induced ADHD-like behavior was evaluated, via assessing behavioral outcomes; neurotransmitters' levels; five pathway biomarkers, coupled with histopathological and immunohistochemical studies. Rats exposed to PHA or treated with SE or AST either separately or combined exhibited enhanced attention, locomotor, and cognitive abilities, compared to MSG-intoxicated group. All treatments remarkably improved MSG-induced abnormalities in neurotransmitters' levels; biochemical markers; along with histological findings, via modulating HMGB1/RAGE/JAK-2/STAT-3, PI3K/AKT/CREB/BDNF, AMPK/SIRT-1 and PERK/CHOP pathways. Nevertheless, the combination of PHA with nutraceuticals (SE and AST) elicited more favorable effects in all measured parameters and histological findings, compared to other treated groups. In conclusion, this study revealed the superiority of the combination of nutraceuticals with PHA, over other standalone treatments, in amelioration of MSG-induced ADHD-like behaviors in rat pups, via fine-tuning of HMGB1/RAGE, PI3K/AKT/CREB/BDNF, AMPK/SIRT-1 and PERK/CHOP pathways.
Intranasal Delivery of Lithium Salt Suppresses Inflammatory Pyroptosis in the Brain and Ameliorates Memory Loss and Depression-like Behavior in 5XFAD Mice.
Bhuiyan P, Zhang W, Liang G … +9 more , Jiang B, Vera R, Chae R, Kim K, Louis LS, Wang Y, Liu J, Chuang DM, Wei H
J Neuroimmune Pharmacol · 2025 Mar · PMID 40095208 · Full text
BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegenerative disease (AD) and has no treatment that can cure or halt the disease progression. This study explored the therapeutic potential of lithium salt disso...
BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegenerative disease (AD) and has no treatment that can cure or halt the disease progression. This study explored the therapeutic potential of lithium salt dissolved in Ryanodex formulation vehicle (RFV) and delivered to the brain by intranasal application. We first compared lithium concentrations in the brain and blood of wild-type mice following intranasal or oral administration of lithium chloride (LiCl) dissolved in either RFV or water. The beneficial and side effects of intranasal versus oral LiCl in RFV in these mice were assessed and potential mechanisms underlying the efficacy of anti-inflammation and anti-pyroptosis in the brains were also investigated in both wild-type and 5XFAD Alzheimer's Disease (AD) mice brains. METHODS: For the study of brain versus blood lithium concentrations, wild-type (WT) B6SJLF1/J mice at 2 months of age were treated with intranasal or oral LiCl (3 mmol/kg) dissolved in RFV or in water. Brain and blood lithium concentrations were measured at various times after drugs administration. Brain/blood lithium concentration ratios were then determined. For studying therapeutic efficacy versus side effects and their underlying mechanisms, 5XFAD and WT B6SJLF1/J mice were treated with intranasal LiCl (3 mmol/kg) daily, Monday to Friday each week, in RFV beginning at 2 or 9 months of age with a 12-week treatment duration. Animal behaviors were assessed for depression (tail suspension), cognition (fear conditioning and Y maze), olfaction (buried food test), and motor functions (rotarod) at the age of 5 and 12 months. Blood and brain tissue were harvested from these mice at 13 months. Blood biomarkers for the functions of thyroid (thyroid stimulating hormone, TSH) and kidney (creatinine) were measured using ELISA. Changes in protein expression levels of the endoplasmic reticulum Ca release channels type 1 InsP receptors (InsPR-1), malondialdehyde (MDA)-modified proteins and 4-hydroxy-2-nonenal (4-HNE), pyroptosis regulatory proteins (NLR family pyrin domain containing 3 (NLRP3), cleaved caspase-1, N-terminal of Gasdermin D (GSDMD)), cytotoxic (IL-1β, IL-18, IL-6, TNF-α) and cytoprotective (IL-10) cytokines and synapse proteins (PSD-95, synapsin-1) were determined using immunoblotting. Mouse body weights were monitored regularly. RESULTS: Compared to oral LiCl in RFV nanoparticles, intranasal treatment of WT mice with LiCl in RFV markedly decreased blood concentrations at the time range of 30-120 min. The ratio of brain/blood lithium concentration after intranasal lithium chloride in RFV significantly increased, in comparison to those after oral administration lithium chloride in RFV or intranasal administration of lithium chloride in water. Intranasal lithium chloride in RFV inhibited both memory loss and depressive behavior in adult and aged 5XFAD mice. Additionally intranasal treatment of aged 5XFAD mice with LiCl in RFV effectively suppressed the increases in InsPR-1, intracellular oxidative stress markers (4-HNE-bound and MDA-modified proteins), pyroptosis activation proteins (NLRP3, cleaved caspase-1, N-terminal GSDMD) and cytotoxic cytokines (IL-1β, IL-6, TNF-α), but reversed the down-regulation of cytoprotective cytokine IL-10. Intranasal LiCl in RFV also alleviated the loss of the postsynaptic synapse proteins PSD-95, but not synapsin-1, in aged 5XFAD mice. Blood level of the kidney function marker creatinine was significantly increased in 5XFAD than in WT mice in an age-dependent manner and this elevation was abolished by intranasal delivery of LiCl in RFV. Intranasal LiCl in RFV for 12 weeks in both WT or 5XFAD mice did not affect blood biomarkers for thyroid function, nor did it affect smell or muscle function or body weight. CONCLUSION: Intranasal administration of LiCl in RFV significantly decreased lithium blood concentrations and increased brain/blood lithium concentration ratio, in comparison to its oral administration. Intranasal administration of LiCl in RFV robustly protected against both memory loss and depressive-like behavior, while had no side effects concerning thyroid and kidney toxicity in 5XFAD mice. These lithium-induced beneficial effects were strongly associated with lithium's suppression of InsPR-1 Ca channel receptor increase, pathological neuroinflammation and activation of the pyroptosis pathway, as well as the loss of the synaptic protein PSD-95. Intranasal delivery of lithium salt in RFV could become an effective and potent inhibitor of pathological inflammation/pyroptosis in the CNS and serve as a new treatment for both AD-associated dementia and depression with minimal unwanted side effects including peripheral organ toxicity.
Correction: Reduction of Lewy Body Pathology by Oral Cinnamon.
Raha S, Dutta D, Roy A … +1 more , Pahan K
J Neuroimmune Pharmacol · 2025 Mar · PMID 40072646 · Publisher ↗
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Mitigating Remote Organ-Induced Brain Injury in Renal Ischemia-Reperfusion: The Role of Oleuropein in Inhibiting Oxidative Stress, Inflammation, Ferroptosis, and Apoptosis in Male Rats.
Ghaffarinasab M, Kaeidi A, Hassanshahi J
J Neuroimmune Pharmacol · 2025 Mar · PMID 40056289 · Publisher ↗
Renal ischemia-reperfusion (RIR) induces brain damage as a distant organ. Oleuropein has antioxidant properties. This study aimed to explore oleuropein's protective effects against brain injury following RIR in rats. Thi...
Renal ischemia-reperfusion (RIR) induces brain damage as a distant organ. Oleuropein has antioxidant properties. This study aimed to explore oleuropein's protective effects against brain injury following RIR in rats. Thirty-six male Wistar rats were divided into six groups (n = 6) including sham, oleuropein (200 mg/kg), RIR, and RIR groups treated with oleuropein (50, 100, and 200 mg/kg). 48 h after injury, blood urea nitrogen (BUN) and creatinine levels were surveyed. The western blotting analysis was performed to assay the interleukin-1 beta (IL-1β), IL-10, tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa-light-chain-enhancer of activated B cells p65 (NF-κB p65), Bcl-2 associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), cleaved caspase-3, glutathione peroxidase-4 (GPX4), nuclear factor erythroid-related factor-2 (NRF2), solute carrier family 7, member 11 (SLC7A11), and anti-acyl-CoA synthetase long-chain family 4 (ACSL4) proteins in kidney and/or brain tissues. Also, malondialdehyde (MDA) and total antioxidant capacity (TAC) levels, the activity of GPx, catalase, and superoxide dismutase (SOD) were evaluated. Kidney and brain tissues damage scores (KTDS and BTDS) were determined by H&E staining method. Prussian blue staining was conducted to identify iron accumulation. RIR significantly increased BUN, serum creatinine levels, KTDS, BTDS, iron deposition, MDA concentration, Bax, cleaved caspase-3, IL-1β, TNF-α, NF-κB p65, ACSL4 proteins expression levels, while decreasing TAC content, SOD, GPx, and catalase activity, Bcl-2, GPX4, SLC7A11 and NRF2 proteins expression in kidney and/or brain tissue of RIR group versus the sham (P < 0.05). Moreover, oleuropein attenuated these indicators in the RIR + oleuropein (200 mg/kg) group versus the RIR group (P < 0.05). Our study showed that RIR induced brain damage, and oleuropein exhibited protective effects against brain injury induced by RIR, through inhibiting oxidative stress, inflammation, ferroptosis, and apoptosis mechanisms.
A Comprehensive Review on Utilizing Human Brain Organoids to Study Neuroinflammation in Neurological Disorders.
Rubio AD, Hamilton L, Bausch M … +4 more , Jin M, Papetti A, Jiang P, Yelamanchili SV
J Neuroimmune Pharmacol · 2025 Feb · PMID 39987404 · Full text
Most current information about neurological disorders and diseases is derived from direct patient and animal studies. However, patient studies in many cases do not allow replication of the early stages of the disease and...
Most current information about neurological disorders and diseases is derived from direct patient and animal studies. However, patient studies in many cases do not allow replication of the early stages of the disease and, therefore, offer limited opportunities to understand disease progression. On the other hand, although the use of animal models allows us to study the mechanisms of the disease, they present significant limitations in developing drugs for humans. Recently, 3D-cultured in vitro models derived from human pluripotent stem cells have surfaced as a promising system. They offer the potential to connect findings from patient studies with those from animal models. In this comprehensive review, we discuss their application in modeling neurodevelopmental conditions such as Down Syndrome or Autism, neurodegenerative diseases such as Alzheimer's or Parkinson's, and viral diseases like Zika virus or HIV. Furthermore, we will discuss the different models used to study prenatal exposure to drugs of abuse, as well as the limitations and challenges that must be met to transform the landscape of research on human brain disorders.
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