J Neuroimmune Pharmacol [JOURNAL]
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200 papers
Melatonin Promotes B-Cell Maturation and Attenuates Post-Ischemic Immunodeficiency in a Murine Model of Transient Focal Cerebral Ischemia.
Tai SH, Hsu HH, Huang SY … +5 more , Chen YN, Chen LY, Lee AH, Lee AC, Lee EJ
J Neuroimmune Pharmacol · 2025 Jun · PMID 40455093 · Publisher ↗
In this study, we investigated the immunomodulatory effects of melatonin on B-cell maturation and its potential to mitigate immunodeficiency following transient focal cerebral ischemia in mice. Transient middle cerebral...
In this study, we investigated the immunomodulatory effects of melatonin on B-cell maturation and its potential to mitigate immunodeficiency following transient focal cerebral ischemia in mice. Transient middle cerebral artery occlusion (MCAO) was induced in adult C57BL/6 mice, followed by melatonin administration. We evaluated the effects of melatonin on neutrophil infiltration, macrophage and microglial activation in the ischemic brain, and B-cell maturation in both the central nervous system and peripheral blood. Melatonin treatment significantly reduced pro-inflammatory cell infiltration in the ischemic hemisphere and promoted B-cell maturation, reflecting robust immunomodulatory activity. These immune changes coincided with improved neurological outcomes and reduced cerebral edema. Collectively, our findings suggest that melatonin may serve as a promising therapeutic candidate in ischemic stroke, addressing both immunodeficiency and neuronal injury.
The Sympathetic Nervous Influence on Hematopoiesis Up To Date.
Maestroni G
J Neuroimmune Pharmacol · 2025 May · PMID 40447962 · Publisher ↗
Hematopoiesis is a tightly regulated process taking place in specialized bone marrow structures called hematopoietic niches. In these structures, hematopoietic stem cells produce all hematopoietic lineages by their self-...
Hematopoiesis is a tightly regulated process taking place in specialized bone marrow structures called hematopoietic niches. In these structures, hematopoietic stem cells produce all hematopoietic lineages by their self-renewal and differentiation abilities. Sympathetic nerve fibers, entering the bone marrow in association with blood vessels, regulate on a circadian basis the hematopoietic stem cells and leukocytes migration in and out the bone marrow. This cellular traffic, that is mainly regulated by beta-adrenergic receptors expressed on mesenchymal stem cells, is needed to maintain an efficient hematopoietic niche and for immunosurveillance against infections. Both alpha- and beta-adrenergic receptors seem involved in the regeneration of hematopoiesis after myeloablative treatments. Likewise, the effects of psychogenic stress and of ageing on the hematopoietic system are also mediated by adrenergic signals. Yet, the exact mechanisms regulating hematopoietic regeneration and the differentiation ratio between lymphoid and myeloid cells are still obscure. A comprehensive understanding of the adrenergic influence on hematopoiesis holds the potential for novel therapeutic approaches in a variety of hematological diseases.
TNF-Stimulated Gene-6, Part of Extracellular Vesicles in Adipose Tissue-Derived Mesenchymal Stem Cell Concentrated Conditioned Medium, Affects Microglial Activity.
Hossain MS, Rasiah PK, Seetharaman ATM … +5 more , Alvarado D, Luo M, Wohlschlegel JA, Pentecost M, Gangaraju R
J Neuroimmune Pharmacol · 2025 May · PMID 40439794 · Full text
Identifying the specific bioactive molecules produced by mesenchymal stem cells (MSCs) and the signaling pathways and cell types upon which they act is critical to developing MSC-based therapeutics for inflammatory disea...
Identifying the specific bioactive molecules produced by mesenchymal stem cells (MSCs) and the signaling pathways and cell types upon which they act is critical to developing MSC-based therapeutics for inflammatory diseases with high unmet needs. Our study aimed to investigate the impact of extracellular vesicle (EV)-derived TNF-Stimulated Gene-6 (TSG-6, from adipose tissue-derived mesenchymal stem cell concentrated conditioned medium, ASC-CCM or TSG-6 overexpression in ASC using ORF expression-ready clone) on microglia and its potential anti-inflammatory effects. EV but not non-vesicular secretome prepared by ultracentrifugation confirmed the expression of TSG-6 exclusively in the small EV (sEV) fraction. sEV ranged from 50-150 nm as determined by Zetasizer, demonstrated bilipid membrane evidenced by transmission electron microscopy, expressed positive exosomal (e.g. CD63) markers, and were endocytosed by BV2 cells confirmed by DiI fluorescently labeled exosomes. BV2 microglia cultured under serum-free conditions stimulated with TLR4 agonists (LPS and IFNγ) for 12 h in the presence of p-ASC-EV (sEV derived from ASC after cytokine stimulation) and TSG-6-ORF-EV significantly reduced nitrite release (p < 0.001), phagocytic activity (p < 0.001) and reduced CD44 expression (p < 0.05). CD44 knockdown in BV2 cells ablated TSG-6-ORF-EV mediated nitrite release, IL1β downregulation, and phagocytosis with TLR4 agonists. Our results revealed that under cytokine stimulation, the EV portion of ASC-CCM becomes enriched with TSG-6. Overexpressing TSG-6 in ASC leads to an increased concentration of TSG-6 in sEVs. This enriched EV fraction, containing TSG-6, regulates microglial dynamics through a feedback loop with CD44. EV-associated TSG-6 can influence immune cell behavior and signaling, mitigating excessive inflammation or immune dysfunction.
RIPK1: A Promising Target for Intervention Neuroinflammation.
Yan F, Qiao Y, Pan S … +3 more , Kang A, Chen H, Bai Y
J Neuroimmune Pharmacol · 2025 May · PMID 40418439 · Publisher ↗
Necroptosis is a novel mode of cell death that differs from traditional apoptosis, characterized by distinct molecular mechanisms and physiopathological features. Recent research has increasingly underscored the pivotal...
Necroptosis is a novel mode of cell death that differs from traditional apoptosis, characterized by distinct molecular mechanisms and physiopathological features. Recent research has increasingly underscored the pivotal role of necroptosis in various neurological diseases, including stroke, Alzheimer's disease and multiple sclerosis. A defining hallmark of these conditions is neuroinflammation, a complex inflammatory response that critically influences neuronal survival. This review provides a comprehensive analysis of the mechanistic underpinnings of necroptosis and its intricate interplay with neuroinflammation, exploring the interrelationship between the two processes and their impact on neurological disorders. In addition, we discuss potential therapeutic strategies that target the intervention of necroptosis and neuroinflammation, offering novel avenues for intervention. By deepening our understanding of these interconnected processes, the development of more effective treatments approaches holds significant promise for improving patient outcomes in neurological disorders.
COVID-19 Alters Inflammatory, Mitochondrial, and Protein Clearance Pathway Genes: Potential Implications for New-onset Parkinsonism in Patients.
Nwabufo CK
J Neuroimmune Pharmacol · 2025 May · PMID 40404934 · Full text
Several preclinical and clinical studies have shown that SARS-CoV-2 infection is associated with new-onset Parkinson's disease (PD). The overall goal of this study is to uncover how the COVID-19 severity gradient impacts...
Several preclinical and clinical studies have shown that SARS-CoV-2 infection is associated with new-onset Parkinson's disease (PD). The overall goal of this study is to uncover how the COVID-19 severity gradient impacts the conventional pathological pathway of PD to inform the identification of at-risk patients and the development of personalized treatment strategies. Transcriptomics analysis of 43 PD pathogenic genes was conducted on nasopharyngeal swabs from 50 COVID-19 patients with varying severity including 17 outpatients, 16 non-ICU, and 17 ICU patients, compared to 13 SARS-CoV-2 negative individuals. The study shows that COVID-19 severity gradient differentially dysregulates PD pathological genes. Dysfunctional lysosomal and mitochondrial processes in outpatients and non-ICU COVID-19 patients was identified as the convergent network of COVID-19-PD interactions. These dysfunctions were later abrogated by the upregulation of the ubiquitin-proteasome system and autophagy-lysosome system in ICU COVID-19 patients. A potential synergistic co-expression and clustering of protein clearance pathway genes with other pathological genes was observed in ICU patients, indicating a possible overlap in biological pathways. Dysregulation of the PD pathopharmacogene, SLC6A3 was observed in ICU patients, suggesting potential COVID-19-gene-drug interactions. Nasopharyngeal swabs express major PD pathological genes as well as clinically relevant drug processing genes, which could advance studies on PD, including diagnosis, pathogenesis, and the development of disease-modifying treatments. Outpatients and non-ICU COVID-19 patients may face a higher risk of developing new-onset PD, whereas ICU COVID-19 patients may be more susceptible to COVID-19-gene-drug interactions.
Exploring Dapagliflozin's Influence on Autophagic Flux in Mania-like Behaviour: Insights from the LKB1/AMPK/LC3 Pathway in a Mouse Model.
Saleh NK, Farrag SM, El-Yamany MF … +1 more , Kamel AS
J Neuroimmune Pharmacol · 2025 May · PMID 40402300 · Full text
Mania-like episodes are neuropsychiatric disturbances associated with bipolar disorder (BD). Autophagic flux disturbance evolved as one of the molecular mechanisms implicated in mania. Recently, Dapagliflozin (DAPA) has...
Mania-like episodes are neuropsychiatric disturbances associated with bipolar disorder (BD). Autophagic flux disturbance evolved as one of the molecular mechanisms implicated in mania. Recently, Dapagliflozin (DAPA) has corrected autophagic signaling in several neurological disorders. Yet, no endeavours examined the autophagic impact of DAPA in mania-like behaviours. This study aimed to investigate the effect of DAPA on disrupted autophagic pathways in a mouse model of mania-like behaviour. Mania-like behaviour was induced through paradoxical sleep deprivation (PSD) using the multiple-platform method for a duration of 36 h. Mice were divided into three groups, with DAPA (1 mg/kg/day, orally) administered for one week. Behavioural assessments were conducted on the 7th day. DAPA mitigated anxiety-like behaviour in the open field test and improved motor coordination and muscle tone in the rotarod test. Mechanistically, DAPA activated hippocampal autophagy-related markers; liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) pathway, autophagy related gene 7 (ATG7), and microtubule-associated protein light chain 3II (LC3II). This was associated with reduced levels of the autophagosome receptor p62 protein, which subsequently enhanced GABA receptor-associated protein (GABARAP), facilitating the surface presentation of GABA receptors. Additionally, DAPA upregulated the GABA receptor R2 subunit through trophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Furthermore, DAPA mitigated elevated serum stress hormones and restored the balance between proinflammatory and anti-inflammatory cytokines in both cortical and hippocampal tissues. These findings highlight the role of autophagic flux modulation by DAPA and its therapeutic potential in mitigating mania-like behaviours.
Clonidine Ameliorates Neuroinflammation in the Rat Model of Tourette Syndrome.
Ke Z, Huang Y, Wang A … +1 more , Chen Y
J Neuroimmune Pharmacol · 2025 May · PMID 40392363 · Publisher ↗
Neuroinflammation plays a vital role in the etiology and pathogenesis of Tourette syndrome (TS). The postmortem report of TS patients clarified that IL-2 is elevated in the basal ganglia region, supporting neuroinflammat...
Neuroinflammation plays a vital role in the etiology and pathogenesis of Tourette syndrome (TS). The postmortem report of TS patients clarified that IL-2 is elevated in the basal ganglia region, supporting neuroinflammation of TS. α receptor agonist (clonidine) is one of the primary drugs for treating tic disorders; supported by clinical and animal experiments, α receptor agonists have potential anti-inflammatory effects. This article aims to explore the impact of clonidine on neuroinflammation with TS and to reveal the possible mechanism of clonidine-mediated neuroinflammation with TS. Thirty P21 SD rats were randomly divided into a TS rat group (n = 20) and a normal control group (n = 10). After successful TS modelling, rats were randomly divided into the clonidine intervention group (n = 10) and the TS group (n = 10). The clonidine intervention group received clonidine 0.1 mg/kg by gavage daily for seven consecutive days. After behavioural evaluation on day 8, the brain was removed from the head. The striatum was separated from one side of the brain and subjected to ELISA to detect cytokines. The other side of the brain was subjected to immunohistochemical detection for microglial activation, and the integral optical density value was calculated using image software for comparison between the groups. Compared to the normal group, IL-2 cytokine levels in TS rats were significantly higher (P < 0.05). In the clonidine group, IL-2 levels (213.82 ± 121.48 pg/ml) were significantly lower than in the TS group (322.61 ± 79.27 pg/ml) (P < 0.05) but not significantly different from the normal control group (257.40 ± 95.80 pg/ml) (P > 0.05). Immunohistochemical analysis showed significant microglial activation in TS rats (IOD = 22.10 ± 6.67) compared to the normal group (IOD = 11.58 ± 4.36) (P < 0.05). Clonidine administration reduced microglial activation, with a significant difference between the TS + clonidine group (IOD = 15.97 ± 8.03) and TS rats (P < 0.05). Clonidine can suppress the neuroinflammatory response in Tourette syndrome, and its inhibitory effect on the neuroinflammatory response may be a potential beneficial effect of this treatment.
Limettin and PD98059 Mitigated Alzheimer's Disease Like Pathology Induced by Streptozotocin in Mouse Model: Role of p-ERK1/2/p-GSK-3β/p-CREB/BDNF Pathway.
Hassan RM, Elsayed NS, Assaf N … +3 more , Budzyńska B, Skalicka-Wożniak K, Ibrahim SM
J Neuroimmune Pharmacol · 2025 May · PMID 40381124 · Full text
Sporadic Alzheimer's disease (SAD) represents one of the major memory deficits that is characterized by tau hyperphosphorylation and amyloid beta (Aβ) deposition in the brain. Both are considered AD hallmarks which are m...
Sporadic Alzheimer's disease (SAD) represents one of the major memory deficits that is characterized by tau hyperphosphorylation and amyloid beta (Aβ) deposition in the brain. Both are considered AD hallmarks which are mediated through neuroinflammation, oxidative stress, and cholinergic circuit interruption. This study aimed to show how limettin and PD98059 exert a neuroprotective effect against SAD and the possible role of the extracellular regulated kinase (p-ERK1/2) and glycogen synthase kinase-3 beta (p-GSK-3β) (Ser9)/cAMP-response element binding protein (p-CREB) (Ser133)/brain derived neurotrophic factor (BDNF) pathway. Control animals (Group I) received the vehicles, group II received PD98059 (10 mg/kg/i.p), while group III was administered limettin (15 mg/kg/i.p). Additionally, the other three groups received a single dose of streptozotocin (STZ; 3 mg/kg/ICV), where group IV served as the SAD group, while groups V and VI received PD98059 and limettin daily for 3 weeks, respectively. The SAD animals receiving PD98059 and limettin increased the number of arm entries, % alternations in Y-maze, with reduction in mean escape latency, increase in time spent in target quadrant and platform crossing in Morris Water Maze, compared to the SAD group. Additionally, PD98059 and limettin administration to the STZ group downregulated persistent activation of p-ERK1/2 which in turn increased p-GSK-3β (Ser9), leading to enhanced p-CREB (Ser133) and BDNF expressions, as well as reducing inflammatory markers viz., nuclear factor-kappa B and interleukin-6, leading to decreased Aβ deposition. Both treatments reduced immunohistochemical p-tau expression, brain edema, and increased intact neuron cells remarkably. Thus, based on these findings, PD98059 and limettin may have promising effects in protecting against SAD. Using blockers/inhibitory molecules are recommended to confirm effect through the corresponding pathway.
COP1 Overexpression Attenuates Nociceptive Behaviors and Neuroinflammation in Cancer-Induced Bone Pain by Suppressing c/EBPβ.
Li DY, Liu L, Gao SJ … +7 more , Liu DQ, Zhang LQ, Wu JY, Song FH, Dai XY, Zhou YQ, Mei W
J Neuroimmune Pharmacol · 2025 May · PMID 40377783 · Publisher ↗
Patients with advanced cancer often have bone metastases, causing bone destruction and cancer-induced bone pain (CIBP). The CCAAT/enhancer binding protein β (c/EBPβ) mediated the regulation of various pro-inflammatory mo...
Patients with advanced cancer often have bone metastases, causing bone destruction and cancer-induced bone pain (CIBP). The CCAAT/enhancer binding protein β (c/EBPβ) mediated the regulation of various pro-inflammatory molecules in microglia. To investigate the specific effect and regulatory mechanism of c/EBPβ in CIBP, a mice model of Lewis lung cancer (LLC) cells implantation was constructed. Our data demonstrated that the c/EBPβ was remarkably elevated in the spinal cord of CIBP mice. Specific knocking down c/EBPβ relieved the mechanical allodynia and thermal hyperalgesia of CIBP mice by suppressing the microglia activation and pro-inflammatory cytokines generation. Besides, overexpressing c/EBPβ could prompt severe pain behaviors with spinal neuroinflammation in naïve mice. Notably, the upstream regulator constitutive photomorphogenic 1 (COP1) was gradually reduced in the spinal cord of CIBP mice. Upregulating the expression of COP1 effectively alleviated the nociceptive behaviors of CIBP mice by inhibiting the accumulation of c/EBPβ and subsequent neuroinflammation. However, knocking down COP1 caused the rapid increase of c/EBPβ and exacerbation of spinal neuroinflammation, ultimately leading to behavioral damage in naïve mice. In conclusion, the absence of COP1 promoted the accumulation of c/EBPβ and neuroinflammatory molecules in the spinal cord of CIBP mice, which extends the future therapeutic approach for CIBP.
Protective Effect of HMG-CoA Reductase Inhibitor Rosuvastatin on Doxorubicin-Induced Cognitive Impairment, Oxidative Stress and Neuroinflammation: Possible Role of CREB, ERK1/2, and BDNF.
Yeni Y, Cicek B, Hacimuftuoglu A … +2 more , Ozkaraca M, Lacin BB
J Neuroimmune Pharmacol · 2025 May · PMID 40358798 · Full text
During or after chemotherapy, cognitive impairments characterized by forgetfulness, difficulty concentrating, and depressive and anxiety-like symptoms are observed. There is limited research examining the effects of rosu...
During or after chemotherapy, cognitive impairments characterized by forgetfulness, difficulty concentrating, and depressive and anxiety-like symptoms are observed. There is limited research examining the effects of rosuvastatin (RVS), an HMG-CoA reductase inhibitor, in the context of neuroinflammation-related cognitive disruption. Here, we aimed to investigate the neuroprotective potential of RVS against doxorubicin (DOX)-induced cognitive impairments. Experimental groups were planned as control (normal saline, intraperitoneal), DOX (total cumulative dose 10 mg/kg, intraperitoneal), RVS (10 mg/kg, oral, 20 days), and RVS + DOX. Efficacy was monitored by applying a battery of behavioral assessments, as well as biochemical, genetic, histopathological, and immunohistochemical examinations. Results from Morris water maze (MWM), passive avoidance, locomotion activity, and elevated plus maze (EPM) tests showed that DOX administration caused behavioral disorders. Moreover, DOX increased the levels of inducible nitric oxide synthase (iNOS), malondialdehyde (MDA), and tumor necrosis factor-α (TNF-α), while decreasing the levels of interleukin-10 (IL-10), glutathione (GSH), superoxide dismutase, catalase (SOD), endothelial nitric oxide (eNOS), and catalase (CAT). Co-treatment with RSV significantly attenuated DOX-induced behavioral changes and oxidative stress markers. In addition, similar to the immunohistochemical results, we determined that it increased the expression levels of extracellular signal-related kinases 1/2 (ERK1/2), cyclic adenosine monophosphate response element binding protein (CREB), and brain-derived neurotrophic factor (BDNF) and restored the histopathological structure of the brain. Therefore, these results indicated that RSV has a neuroprotective effect against DOX-induced cognitive impairment by reducing neurobehavioral impairments, exerting antioxidant and anti-inflammatory effects, and modulating brain growth factors.
HucMSCs-Derived Extracellular Vesicles Deliver RPS27A Protein to Manipulate the MDM2-P53 Axis and Ameliorate Neurological Dysfunction in Parkinson's Disease.
Xu J, Lei H, Yang C … +2 more , Qiu Y, Wu X
J Neuroimmune Pharmacol · 2025 May · PMID 40338442 · Publisher ↗
Extracellular vesicles released from mesenchymal stem cells (MSCs-EV) have shown anti-inflammatory effects in Parkinson's disease (PD). This study was designed to assess the neuroprotective effects of human umbilical cor...
Extracellular vesicles released from mesenchymal stem cells (MSCs-EV) have shown anti-inflammatory effects in Parkinson's disease (PD). This study was designed to assess the neuroprotective effects of human umbilical cord MSCs (hucMSCs) and the possible mechanisms involved. SH-SY5Y cells were induced with MPP, and the impact of hucMSCs-EV on the damage to SH-SY5Y cells was examined. Mice were induced with PD-like symptoms by MPTP and the effects of hucMSCs-EV on neurological damage in mouse brain tissue were detected as well. HucMSCs-EV inhibited apoptosis and oxidative stress in MPP-induced SH-SY5Y cells. HucMSCs-EV suppressed behavioral deficits and neuronal apoptosis in MPTP-induced mice, with an increased number of dopamine neurons in brain tissues and decreased p-alpha-syn expression in dopamine neurons. The expression of ribosomal protein S27A (RPS27A) in SH-SY5Y cells was elevated after co-culture of neurons and hucMSCs-EV, and RPS27A silencing abated the effect of hucMSCs-EV in vivo and in vitro. RPS27A bound to the MDM2 promoter, thus promoting P53 ubiquitination and degradation. MDM2 overexpression strengthened the therapeutic effect of hucMSCs-EV. We conclude that hucMSCs-EV promote the interaction between RPS27A and MDM2 by delivering RPS27A, which regulates the MDM2-P53 axis to promote degradation of P53 to ameliorate neurological damage in PD.
Possible Interaction of Suramin with Thalamic P2X Receptors and NLRP3 Inflammasome Activation Alleviates Reserpine-Induced Fibromyalgia-Like Symptoms.
Mohamed MM, Zaki HF, Kamel AS
J Neuroimmune Pharmacol · 2025 May · PMID 40329125 · Full text
The high pain sensitivity in fibromyalgia (FM) is processed by the thalamus that presents as a key component in the pain pathway in FM patients. Noteworthy, Purinergic receptors, specifically P2X, are implicated in pain...
The high pain sensitivity in fibromyalgia (FM) is processed by the thalamus that presents as a key component in the pain pathway in FM patients. Noteworthy, Purinergic receptors, specifically P2X, are implicated in pain signaling and neuroinflammation via inflammasome signaling. However, there is no available data on the impact of pharmacological intervention on the P2X receptor in thalamic pain transmission in FM. To investigate this aspect, the clinically tested P2X inhibitor, Suramin (SURM), was utilized. FM was induced over three days using Reserpine (1 mg/kg/day, s.c.), followed by a single dose of SURM (100 mg/kg, i.p.). At the molecular level, SURM countered the overexpression of P2X7 and P2X4 receptors accompanied by reduced NLRP3 inflammasome complex and pyroptotic markers like gasdermin-D. This was associated with the suppression of the p38-MAPK and NF-κB pathways, along with a decrease in pro-inflammatory cytokines and tumor necrosis factor-α as observed by increased CD86 expression on M1 microglia phenotype, a neuroinflammatory marker. Concurrently, blocking the P2X receptor shifted microglia polarization towards the M2 phenotype, marked by elevated CD163 expression, as a neuroprotective mechanism. This was outlined by increased neurotrophic and anti-inflammatory IL-10 with normalization of disturbed neurotransmitters. Behaviorally, SURM ameliorated the heightened pain processing, as observed in mechanical and thermal pain tests. Furthermore, it lowered Reserpine-induced motor impairment in the rotarod and open-field tests. This improvement in the somatosensory experience was reflected in alleviating depressive-like behavior in the forced swimming test. These findings highlight the therapeutic potential of blocking thalamic P2X receptors in alleviating fibromyalgia symptoms.
Lycopene Supplemented Mediterranean Diet Ameliorates Experimental Autoimmune Encephalomyelitis (EAE) in Mice and Changes Intestinal Microbiome.
Atuk Kahraman T, Yılmaz M, Aslan K … +5 more , Canatan H, Kara A, Nalbantoglu OU, Gundogdu A, Eken A
J Neuroimmune Pharmacol · 2025 May · PMID 40323426 · Full text
This study aimed to determine the effects of the Mediterranean diet (MD) and lycopene on the development of EAE and on inflammatory markers. In the 43-day study, 72 female C57BL/6 mice were randomly divided into eight gr...
This study aimed to determine the effects of the Mediterranean diet (MD) and lycopene on the development of EAE and on inflammatory markers. In the 43-day study, 72 female C57BL/6 mice were randomly divided into eight groups according to whether they were EAE or naive (control) mice, fed a Western diet or a MD, and whether they received lycopene. During the study, mice were fed ad libitum, and lycopene groups were given 10 mg/kg/day lycopene per mouse every other day for 28 days in oral gavage. The mice were scored for EAE, sacrificed and their spleen, lymph nodes, and spinal cords were removed. We observed slightly delayed EAE onset in the MD-Lyc group compared to the others, and the EAE clinical scores were also lower than in the other groups. T-cell counts in the spleen and lymph nodes of the MD-Lyc group were significantly lower than in other groups. The production of IFN-γ and IL-22 was higher than in the other groups. IL-17 A cytokine produced in the spleen was lower in the MD-Lyc group than in the other groups. In addition, the highest myelination score was seen in the MD-Lyc group. MD-Lyc group also had a unique microbiome profile compared with the remaining groups. In summary, MD and lycopene administration positively impacted EAE scores and myelination. However, more comprehensive studies at the in vitro and in vivo levels are needed to reveal the effect of this intervention on cell numbers in the CNS.
Exploring Anticonvulsant Effects of Pomalidomide by Targeting Oxidative Stress and Nrf2-Ho1 Signaling Pathway in Male Wistar Rats: A New Insight in Seizure Control.
Khorasanian E, Rajabi-Maham H, Azizi V … +1 more , Hosseini A
J Neuroimmune Pharmacol · 2025 May · PMID 40310605 · Publisher ↗
Current medications for seizure symptoms can reduce seizure severity but do not stop or slow their progression. These drugs often have unpleasant side effects and may not work for all patients. The search for new therape...
Current medications for seizure symptoms can reduce seizure severity but do not stop or slow their progression. These drugs often have unpleasant side effects and may not work for all patients. The search for new therapeutic targets for seizure progression can be expedited through drug repurposing, which leverages existing approved medications, ultimately reducing clinical trial costs. This study investigates the neuroprotective properties of pomalidomide, an immunomodulatory drug, in a male rat model of pentylenetetrazol-induced seizures. Pomalidomide pretreatment significantly decreased the frequency and severity of seizures and delayed their onset. It elevated glutathione peroxidase (GPX) and superoxide dismutase (SOD) levels while lowering malondialdehyde (MDA), showcasing its antioxidant effects. Furthermore, it activated the Nrf2/HO-1 signaling pathway by increasing gene expression in the hippocampus, providing neuroprotection in the CA1 and CA3 regions. These findings suggest that pomalidomide may enhance the antioxidant defense system, support the Nrf2/HO-1 pathway, and protect the hippocampus, indicating its potential for treating patients with seizures, particularly intractable ones.
Unraveling the Immune Puzzle: Role of Immunomodulation in Alzheimer's Disease.
Ashvin, Dhapola R, Kumari S … +4 more , Sharma P, Vellingiri B, Medhi B, HariKrishnaReddy D
J Neuroimmune Pharmacol · 2025 Apr · PMID 40299221 · Publisher ↗
Alzheimer's disease (AD) is a complex neurodegenerative disorder with growing evidence highlighting the dual role of immunomodulation in its pathogenesis and potential therapeutic strategies. Disturbance in the immune sy...
Alzheimer's disease (AD) is a complex neurodegenerative disorder with growing evidence highlighting the dual role of immunomodulation in its pathogenesis and potential therapeutic strategies. Disturbance in the immune system increases the inflammatory cytokines that cause tau hyperphosphorylation and neuroinflammation. Also, immune checkpoint inhibition further increases the amyloid-beta deposition. Therefore, this review examines the intricate interplay between the immune system and AD, focusing on how immunomodulatory mechanisms influence key pathological hallmarks, including amyloid-beta aggregation, tau hyperphosphorylation, neuroinflammation, and cholinergic dysfunction. We analyse critical signaling pathways involved in immune regulation, such as Toll-like receptor (TLR), Janus kinase/signal transducer and activator of transcription (JAK/STAT), phosphoinositide 3-kinase/Akt (PI3K/Akt), Wnt/β-catenin, tumor necrosis factor (TNF), and triggering receptor expressed on myeloid cells (TREM), along with immune checkpoints like programmed cell death protein 1 (PD-1). Preclinical studies of immunomodulatory agents, including salidroside, festidinol, astragalin, sulforaphane, BM-MSC, simvastatin, Ab-T1, hTREM2, and XENP345, demonstrate promising effects. Additionally, clinical investigations of drugs such as simufilam, AL002, TB006, VGL101, DNL919, XPro1595, astragalus, and IBC-Ab002 underscore the therapeutic potential of targeting immune pathways in AD. This review emphasizes how neuroinflammation, microglial activation, and peripheral immune responses contribute to disease progression. By exploring immunomodulatory mechanisms, the article sheds light on potential therapeutic targets that could help mitigate AD pathology which may pave the way for novel interventions preventing neurodegeneration in AD.
Current Understanding of the Exosomes and Their Associated Biomolecules in the Glioblastoma Biology, Clinical Treatment, and Diagnosis.
Ramezani A, Rahnama M, Mahmoudian F … +6 more , Shirazi F, Ganji M, Bakhshi S, Khalesi B, Hashemi ZS, Khalili S
J Neuroimmune Pharmacol · 2025 Apr · PMID 40299204 · Publisher ↗
Glioblastoma is the most common and aggressive brain tumor with a low survival rate. Due to its heterogeneous composition, high invasiveness, and frequent recurrence after surgery, treatment success has been limited. In...
Glioblastoma is the most common and aggressive brain tumor with a low survival rate. Due to its heterogeneous composition, high invasiveness, and frequent recurrence after surgery, treatment success has been limited. In addition, due to the brain's unique immune status and the suppressor tumor microenvironment (TME), glioblastoma treatment has faced more challenges. Exosomes play a critical role in cancer metastasis by regulating cell-cell interactions that promote tumor growth, angiogenesis, metastasis, treatment resistance, and immunological regulation in the tumor microenvironment. This review explores the pivotal role of exosomes in the development of glioblastoma, with a focus on their potential as non-invasive biomarkers for prognosis, early detection and real-time monitoring of disease progression. Notably, exosome-based drug delivery methods hold promise for overcoming the blood-brain barrier (BBB) and developing targeted therapies for glioblastoma. Despite challenges in clinical translation, the potential for personalized exosome = -054321`therapies and the capacity to enhance therapeutic responses in glioblastoma, present intriguing opportunities for improving patient outcomes. It seems that getting a good and current grasp of the role of exosomes in the fight against glioblastoma would properly serve the scientific community to further their understanding of the related potentials of these biological moieties.
Unmasking a Paradox: Roles of the PD-1/PD-L1 Axis in Alzheimer's Disease-Associated Neuroinflammation.
Moadab A, Khorramdelazad H, Javar MTA … +6 more , Nejad MSM, Mirzaie S, Hatami S, Mahdavi N, Ghaffari S, Yazdian FA
J Neuroimmune Pharmacol · 2025 Apr · PMID 40285967 · Publisher ↗
Alzheimer's disease (AD) represents the most prevalent form of dementia, characterized by progressive cognitive impairment and chronic neuroinflammation. Immune checkpoint inhibitors (ICIs), including anti-programmed cel...
Alzheimer's disease (AD) represents the most prevalent form of dementia, characterized by progressive cognitive impairment and chronic neuroinflammation. Immune checkpoint inhibitors (ICIs), including anti-programmed cell death (PD)-1 and anti-PD-L1, signify a revolutionary advancement in cancer treatment by preventing T-cell exhaustion; however, their therapeutic application in AD presents a conundrum. Hypothesis: Recent preclinical studies indicate that PD-1 inhibition in AD mouse models induces an interferon-gamma (IFN-γ)-mediated response, leading to increased recruitment of monocyte-derived macrophages into the brain, enhanced clearance of amyloid-beta (Aβ) plaques, and improved cognitive performance. Nonetheless, this therapeutic effect is counterbalanced by the potential for exacerbated neuroinflammation, as PD-1/PD-L1 blockade may potentiate pro-inflammatory T helper (Th)1 and Th17 responses. In this review, we critically discuss the pertinent pro-inflammatory and neuroprotective facets of T cell biology in the pathogenesis of AD, emphasizing the potential for modulation of the PD-1/PD-L1 axis to influence both Aβ clearance and the dynamics of neuroinflammatory processes. In summary, we determine that ICIs are promising tools for reducing AD pathology and improving cognition. However, it is essential to refine treatment protocols and carefully select patients to optimize neuroprotective effects while adequately considering inflammatory risks.
Human Umbilical Cord Mesenchymal Stem Cells Ameliorated Chronic Unpredictable Mild Stress-Induced Depression and Anxiety by Alleviating Neuroinflammation.
Liu G, Miao L, Niu H … +13 more , Wang H, Yan L, Chen Y, Zhang C, Li X, Mi Y, Xu L, Wang D, Zhou J, Xu X, Li G, Long H, Liu Y
J Neuroimmune Pharmacol · 2025 Apr · PMID 40272640 · Publisher ↗
Inflammation, neurotransmitters, and apoptotic neurons are crucial elements in the progression of Major Depressive Disorder (MDD). Previous studies have demonstrated that mesenchymal stem cells (MSCs) had a positive impa...
Inflammation, neurotransmitters, and apoptotic neurons are crucial elements in the progression of Major Depressive Disorder (MDD). Previous studies have demonstrated that mesenchymal stem cells (MSCs) had a positive impact on neuroinflammation and neuroprotection. In this context, human umbilical cord mesenchymal stem cells (hUC-MSCs) were administered into chronic unpredictable mild stress model (CUMS) mice to evaluate their effects on inflammation, neurotransmitters, microglia, neurons activation, and neuronal apoptosis. The distribution of hUC-MSCs within the brain was detected by CM-Dil-labelled hUC-MSCs. Our results indicated that hUC-MSCs infiltrated the brains of CUMS mice to protect the integrity of the blood-brain barrier (BBB). Furthermore, hUC-MSCs inhibited microglia activation to result in decreased inflammation levels and increased neurotransmitters, ultimately alleviating neuronal damage and regulating neuronal activity. These findings suggest that hUC-MSCs can maintain the BBB integrity and reduce neuroinflammation and neuronal damage, thereby effectively alleviating depression-like and anxiety-like behavior.
Cranberry Extract Ameliorates Diabetic Cognitive Impairment in Rats Via LncRNA GAS-5 Downregulation and Pyroptosis Pathway Inhibition.
Abo-Saif MA, Ragab AE, Talaat IM … +3 more , Saber-Ayad M, Ibrahim AO, Selim HM
J Neuroimmune Pharmacol · 2025 Apr · PMID 40257540 · Full text
The pathophysiology of diabetes-induced brain injury involves pyroptosis, an inflammatory programmed cell death. This study aimed to investigate the potential protective effect of cranberry extract (CE) against diabetes-...
The pathophysiology of diabetes-induced brain injury involves pyroptosis, an inflammatory programmed cell death. This study aimed to investigate the potential protective effect of cranberry extract (CE) against diabetes-induced brain injury. Type 1 diabetes was induced by intraperitoneal injection of streptozotocin in rats. Brain tissue samples were investigated for biochemical determination of the reduced glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), and the quantitative RT-PCR for the gene expression of glial cell-derived neurotrophic factor (GDNF), lncRNA GAS-5, and pyroptosis markers. ELISA was used to determine the caspase-1 level and immunohistochemical staining for assessing IL-1β. Prophylactic dosing of the CE in diabetic rats improved cognitive behavior and significantly suppressed MDA concentration, pyroptosis genes expression (gasdermin D and caspase 1), and lncRNA GAS-5. In addition, CE significantly elevated GSH concentration, SOD activity, and gene expression of GDNF and markedly reduced IL-1β positive stained cells score in the brain. Phytochemical characterization of the CE by FT-IR and UPLC-PDA-MS/MS revealed cyanidin arabinoside, procyanidins, quercetin, and isorhamnetin as key components. CE protects against diabetes-induced cognitive dysfunction in rats by targeting redox-related signaling pathways and inducing an anti-inflammatory effect. LncRNA GAS-5 downregulation and pyroptosis pathway inhibition may contribute to its beneficial effects, suggesting its therapeutic potential.
Novel Trajectories Towards Possible Effects of Semaglutide for Amelioration of Reserpine-induced Fibromyalgia in Rats: Contribution of cAMP/PKA/p-CREB and M1/M2 Microglia Polarization.
Shafiek MZ, Zaki HF, Mohamed AF … +1 more , Ibrahim WW
J Neuroimmune Pharmacol · 2025 Apr · PMID 40240584 · Full text
Fibromyalgia (FM) is a pain disorder characterized by pervasive musculoskeletal pain associated with exhaustion, depression, and irregular sleep patterns. Semaglutide, an innovative glucagon-like peptide-1 (GLP-1) agonis...
Fibromyalgia (FM) is a pain disorder characterized by pervasive musculoskeletal pain associated with exhaustion, depression, and irregular sleep patterns. Semaglutide, an innovative glucagon-like peptide-1 (GLP-1) agonist, has shown analgesic effects by modulating pain hypersensitivity in animal models of inflammatory pain. The objective of this study is to ascertain semaglutide's therapeutic potential against FM-like symptoms caused by reserpine. Reserpine (1 mg/kg/day; SC) was administered into rats for 3 consecutive days, then they were treated daily with semaglutide intraperitoneally in low (5 nmol/kg), intermediate (10 nmol/kg), or high doses (20 nmol/kg), respectively, for 14 consecutive days. Semaglutide alleviated reserpine induced histopathological and immunohistopathological changes in spinal cord of rats evidenced by a remarkable rise in immuno-expression of cluster of differentiation 163 (CD163) contrary to a significant diminution in CD86 level as compared with reserpine group. Semaglutide also had an analgesic effect and improved motor incoordination, and depression brought on by reserpine. Furthermore, it had an anti-inflammatory impact via stimulating cyclic adenosine monophosphate (cAMP)/ protein kinase A (PKA)/ cAMP response element (CRE)-binding protein (CREB) signaling pathway and shifting M1/M2 macrophage polarization towards the M2. Semaglutide's anti-inflammatory actions were manifested through inhibition of inducible nitric oxide synthase and reduction in dorsal root ganglia concentrations of tumor necrosis factor-α together with elevation in the levels of arginase-1 and interleukin-4.
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