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

{"title":"A New Perspective on Mechanisms of Neurodegeneration in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis: the Early and Critical Role of Platelets in Neuro/Axonal Loss.","authors":"Jacqueline Monique Orian","doi":"10.1007/s11481-025-10182-w","DOIUrl":"10.1007/s11481-025-10182-w","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disorder, with limited treatment options. This disease is characterized by differential pathophysiology between grey matter (GM) and white matter (WM). The predominant WM hallmark is the perivascular plaque, associated with blood brain barrier (BBB) loss of function, lymphocytic infiltration, microglial reactivity, demyelination and axonal injury and is adequately addressed with immunomodulatory drugs. By contrast, mechanisms underlying GM damage remain obscure, with consequences for neuroprotective strategies. Cortical GM pathology is already significant in early MS and characterized by reduced BBB disruption and lymphocytic infiltration relative to WM, but a highly inflammatory environment, microglial reactivity, demyelination and neuro/axonal loss. There is no satisfactory explanation for the occurrence of neurodegeneration without large-scale inflammatory cell influx in cortical GM. A candidate mechanism suggests that it results from soluble factors originating from meningeal inflammatory cell aggregates, which diffuse into the underlying cortical tissue and trigger microglial activation. However, the recent literature highlights the central role of platelets in inflammation, together with the relationship between coagulation factors, particularly fibrinogen, and tissue damage in MS. Using the experimental autoimmune encephalomyelitis (EAE) model, we identified platelets as drivers of neuroinflammation and platelet-neuron associations from the pre-symptomatic stage. We propose that fibrinogen leakage across the BBB is a signal for platelet infiltration and that platelets represent a major and early participant in neurodegeneration. This concept is compatible with the new appreciation of platelets as immune cells and of neuronal damage driven by inflammatory cells sequestered in the meninges.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"14"},"PeriodicalIF":6.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effects of Cannabinoids on Ischemic Stroke-Associated Neuroinflammation: A Systematic Review.","authors":"Eman A Alraddadi, Faisal F Aljuhani, Ghadah Y Alsamiri, Salwa Y Hafez, Ghaida Alselami, Daniyah A Almarghalani, Faisal F Alamri","doi":"10.1007/s11481-025-10171-z","DOIUrl":"10.1007/s11481-025-10171-z","url":null,"abstract":"<p><p>Stroke represents a significant burden on global health and the economy, with high mortality rates, disability, and recurrence. Ischemic stroke is a serious condition that occurs when a blood vessel in the brain is interrupted, reducing the blood supply to the affected area. Inflammation is a significant component in stroke pathophysiology. Neuroinflammation is triggered following the acute ischemic ictus, where the blood-brain barrier (BBB) breaks down, causing damage to the endothelial cells. The damage will eventually generate oxidative stress, activate the pathological phenotypes of astrocytes and microglia, and lead to neuronal death in the neurovascular unit. As a result, the brain unleashes a robust neuroinflammatory response, which can further worsen the neurological outcomes. Neuroinflammation is a complex pathological process involved in ischemic damage and repair. Finding new neuroinflammation molecular targets is essential to develop effective and safe novel treatment approaches against ischemic stroke. Accumulating studies have investigated the pharmacological properties of cannabinoids (CBs) for many years, and recent research has shown their potential therapeutic use in treating ischemic stroke in rodent models. These findings revealed promising impacts of CBs in reducing neuroinflammation and cellular death and ameliorating neurological deficits. In this review, we explore the possibility of the therapeutic administration of CBs in mitigating neuroinflammation caused by a stroke. We summarize the results from several preclinical studies evaluating the efficacy of CBs anti-inflammatory interventions in ischemic stroke. Although convincing preclinical evidence implies that CBs targeting neuroinflammation are promising for ischemic stroke, translating these findings into the clinical setting has proven to be challenging. The translation hurdle is due to the essence of the CBs ability to cause anxiety, cognitive deficit, and psychosis. Future studies are warranted to address the dose-beneficial effect of CBs in clinical trials of ischemic stroke-related neuroinflammation treatment.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"12"},"PeriodicalIF":6.2,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NXP032 Improves Memory Impairment Through Suppression of Tauopathy in PS19 Mice and Attenuates Okadaic Acid-Induced Tauopathy in SH-SY5Y Cells.","authors":"Hyeyoon Eo, Seong Hye Kim, In Gyoung Ju, Joo Hee Lee, Myung Sook Oh, Youn-Jung Kim","doi":"10.1007/s11481-025-10175-9","DOIUrl":"https://doi.org/10.1007/s11481-025-10175-9","url":null,"abstract":"<p><p>Tauopathy is widely observed in multiple neurodegenerative diseases such as Alzheimer's disease (AD) and characterized by abnormal tau protein phosphorylation, aggregation and its accumulation as a form of neurofibrillary tangle (NFT) in the brain. However, there are no effective treatments targeting tau pathology in the AD. Vitamin C is known to reduce tauopathy and modulate one of its regulators called glycogen synthase kinase 3 (GSK3) in the body. Nevertheless, vitamin C has a limitation of its stability during metabolism due to its chemical properties. Thus, in the current study, NXP032 (a vitamin C/aptamer complex) was tested as a candidate for tau-targeting treatment because it can preserve antioxidative efficacy of vitamin C before it can reach the target tissue. In this context, the current study aimed to investigate the therapeutic effect of NXP032 on tauopathy in vivo and in vitro. As a result, NXP032 attenuated cognitive and memory decline and reduced NFT and tau hyperphosphorylation in the P301S mutant human tau transgenic mice (or called PS19 mice). In addition, NXP032 suppressed neuroinflammation found in the PS19 mice. Furthermore, NXP032 protected SH-SY5Y human neuroblastoma cells from okadaic acid (OKA)-induced cytotoxicity. Especially, 10 ng/ml of NXP032 reduced tau hyperphosphorylation and GSK3 activation though its phosphorylation at Tyr216 site which were promoted by OKA treatment in the SH-SY5Y cells. Taken together, our results suggest that NXP032 might be a potential therapy for AD and tauopathy-related neurodegenerative disorders as well.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"10"},"PeriodicalIF":6.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comparative Study of Nanoconjugates of a Synthetic and a Natural Drug Against T2DM-Induced Cognitive Dysfunction.","authors":"Sweta Priyadarshini Pradhan, Anindita Behera, Pratap Kumar Sahu","doi":"10.1007/s11481-025-10170-0","DOIUrl":"https://doi.org/10.1007/s11481-025-10170-0","url":null,"abstract":"<p><p>Type II Diabetes Mellitus (T2DM) is one of the risk factors for the development of dementia leading to cognitive dysfunctions. The present study evaluates the efficacy of a synthetic drug (Vildagliptin, VLD) and a natural glycosidic compound (Hesperidin, HSP) against T2DM-induced cognitive dysfunction in rats. The drugs were conjugated with metal nanoparticles like gold (Au) and selenium (Se) to enhance their efficacy. The synthesis of the monometallic and bimetallic nanoparticles of VLD and HSP was established via the turkevich method and characterised by different spectroscopical techniques like UV (Ultraviolet)-visible, FTIR (Fourier Transform Infrared Spectroscopy), zeta potential, particle size, HR-TEM (High Resolution Transmission Electron Microscopy), SAED (Selected Area Electron Diffraction) and SEM-EDX (Scanning Electron Microscopy with Energy Dispersive X-ray Analysis). Both Streptozotocin (STZ) of 65 mg/kg (Group I-X) and Alloxan (ALX) of 150 mg/kg (Group I-X) were injected into 120 Wistar rats to induce cognitive dysfunction. After the induction, the BGL levels were evaluated and rats with BGL > 250 mg/dl were used in the study. Then the test drug and nanoformulations were administered for 21 days. Neurobehavioral assessment, antioxidant studies, and estimation of AChE (acetylcholinesterase) and nitrite levels were done. The VLD and HSP with its nanoconjugates significantly attenuated the effect of STZ and ALX by improving the memory and learning function in Y-maze, radial arm maze (RAM), and elevated plus maze (EPM), increased antioxidant levels of SOD (superoxide dismutase), CAT (catalase), and GSH (glutathione); decreased lipid peroxidation and reduced the AChE and nitrite levels in the rat brain. The bimetallic nanoconjugates of both VLD and HSP were more effective than the monometallic forms of VLD and HSP. However, VLD and its nanoconjugates exhibited better neuroprotective activity than HSP and its nanoconjugates in STZ and ALX animal models. VLD and its nanoformulations were more effective against long-term memory than HSP and its nanoconjugates. Both VLD and HSP may be a potential lead for cognitive and neurodegenerative diseases.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"11"},"PeriodicalIF":6.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of Intestinal Inflammation and Protection of Dopaminergic Neurons in Parkinson's Disease Mice through a Probiotic Formulation Targeting NLRP3 Inflammasome.","authors":"Liping Zhou, Ka Ying Wong, Hongxiang Xie","doi":"10.1007/s11481-024-10163-5","DOIUrl":"10.1007/s11481-024-10163-5","url":null,"abstract":"<p><p>Emerging evidence highlights the significance of peripheral inflammation in the pathogenesis of Parkinson's disease (PD) and suggests the gut as a viable therapeutic target. This study aimed to explore the neuroprotective effects of the probiotic formulation VSL#3^® and its underlying mechanism in a PD mouse model induced by MPTP. Following MPTP administration, the striatal levels of dopamine and its metabolites, as along with the survival rate of dopaminergic neurons in the substantia nigra, were significantly reduced in PD mice. MPTP also significantly increased the mRNA expression of pro-inflammatory cytokines TNF-α and IL-1β, while reducing anti-inflammation mediators, like glia cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in the striatum. These pathological changes were notably mitigated by VSL#3^® treatment, suggesting its neuroprotective and anti-inflammatory effects in the brain. Additionally, VSL#3^® significantly lowered the circulating levels of pro-inflammatory cytokines, and reduced TNF-α and IL-1β mRNA expression in the liver, indicating an inhibition of cytokine transfer. In the intestine, the probiotic treatment markedly decreased the mRNA expression of pro-inflammatory cytokines, (TNF-α, IL-1β, IL-6 and IL-17), and the other two key components of the NLRP3 inflammasome, caspase-1 and NLRP3, demonstrating an inhibition of VSL#3^® on gut NLRP3 inflammasome. VSL#3^® exerts neuroprotective effects in PD mice through the suppression of intestinal inflammation, particularly inhibiting the intestinal NLRP3 inflammasome. This study supports the therapeutic potential of targeting intestinal inflammation and utilizing probiotics in PD treatment.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"9"},"PeriodicalIF":6.2,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143017788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The High-Affinity IL-2 Receptor Affects White Matter Damage after Cerebral Ischemia by Regulating CD8 + T Lymphocyte Differentiation.","authors":"Yuqian Li, Qian Jiang, Xiaokun Geng, Haiping Zhao","doi":"10.1007/s11481-025-10169-7","DOIUrl":"https://doi.org/10.1007/s11481-025-10169-7","url":null,"abstract":"<p><p>IL-2/IL-2R inhibition improved the prognosis of ischemic stroke by regulating T cells, while the respective contribution of T cells with high/medium/low-affinity IL-2 receptors remained unclear. Single-cell RNA sequencing data of ischemic brain tissue revealed that most of the high-affinity IL-2R would be expressed by CD8 + T cells, especially by a highly-proliferative subset. Interestingly, only the CD8 + T cells with high-affinity IL-2R infiltrated ischemic brain tissues, highly expressing 32 genes (including Cdc20, Cdca3/5, and Asns) and activating 7 signaling pathways (including the interferon-alpha response pathway, a key mediator in the proliferation, migration, and cytotoxicity of CD8 + T cells). Its interaction with endothelial cells and the ligand-receptor interaction analysis also suggested an augmented brain infiltration after cerebral ischemia. In IL-2Rα KO mice, who would have no high- or low-affinity IL-2R in CD8 + T cells, the RNA-seq, qPCR, immunofluorescence, and multiplex assays found that the expression of CD8b, CD122, CD132, and Vcam-1 was upregulated in the acute phase of cerebral ischemia, with decreasing H2-k1 positive cells and increasing Vcam-1 and CD8b positive cells in brain tissue. However, inflammation pathways in brain were inhibited and peripheral inflammatory cytokine levels were reduced, indicating that CD8 + T cells changed into an anti-inflammatory phenotype. The IL-2Rα KO mice after cerebral ischemia also performed better in behavioral tests and had more favorable results in diffusion tensor imaging, electrophysiology, and MBP testing. Our findings suggested that the CD8 + T cells with high-affinity IL-2R, as well as IL-2Rα, might be targeted to improve the clinical management of ischemic stroke.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"8"},"PeriodicalIF":6.2,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143017790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncRNA NEAT1, an Important Biomarker Involved in the Pathological and Physiological Processes of Parkinson's Disease.","authors":"Runsen Chen, Yuxi Zhang, Yang Shen, Kede Wu, Xuming Mo, Zhaocong Yang","doi":"10.1007/s11481-024-10168-0","DOIUrl":"https://doi.org/10.1007/s11481-024-10168-0","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a complex progressive neurodegenerative disorder and the pathogenesis and treatment methods are unknown. This aim is to investigate the effects of long non coding RNA NEAT1 (LncRNA NEAT1) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD). Immunoprecipitation and western blot were used to search for the effects of LncRNA NEAT1 on PD. Tyrosine hydroxylase (TH) and brain derived neurotrophic factor (BDNF) were evaluated in substantia nigra (SN) region of the brain by immunohistochemical staining. Compared with the control group, the relative expression level of LncRNA NEAT1 in the MPTP group was significantly increased. LncRNA NEAT1 is negatively correlated with miR-376b-3p. LncRNA NEAT1 significantly increased oxidative stress, neuroinflammation along with enhanced neurotrophic potential via NLR family Pyrin domain protein 3 (NLRP3) pathway. In conclusion, these results indicated that LncRNA NEAT1 participated in the pathophysiological of PD and its mechanism via the miR-376b-3p/NLRP3 signaling pathway.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"7"},"PeriodicalIF":6.2,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ghrelin Induces Ferroptosis Resistance and M2 Polarization of Microglia to Alleviate Neuroinflammation and Cognitive Impairment in Alzheimer's Disease.","authors":"Yaoxue Guo, Junli Zhao, Xing Liu, Pu Lu, Furu Liang, Xueyan Wang, Jing Wu, Yan Hai","doi":"10.1007/s11481-024-10165-3","DOIUrl":"https://doi.org/10.1007/s11481-024-10165-3","url":null,"abstract":"<p><p>Microglial polarization and ferroptosis are important pathological features in Alzheimer's disease (AD). Ghrelin, a brain-gut hormone, has potential neuroprotective effects in AD. This study aimed to explore the potential mechanisms by which ghrelin regulates the progression of AD, as well as the crosstalk between microglial polarization and ferroptosis. Mouse BV2 microglial cells and male mice were treated with beta-amyloid (Aβ) (1-42) to simulate the AD environment. Microglia ferroptosis was measured by detecting levels of ferroptosis-related proteins (SLC7A11, GPX4, FTL1, and FTH1), metabolic markers (ROS, MDA, GSH, SOD), and observing mitochondrial morphological changes. Microglial polarization was evaluated by measuring levels of inflammatory markers and surface markers. The impact of ghrelin on Aβ_1-42-exposed microglia was assessed by coupling with the ferroptosis activator Erastin. Cognitive impairment in AD mice was evaluated through behavioral tests. Tissue staining was applied to determine neuronal damage. In Aβ_1-42-exposed microglia, ghrelin upregulated the protein expression of SLC7A11, GPX4, FTL1 and FTH1, reduced ROS and MDA levels, and elevated GSH and SOD levels through the BMP6/SMAD1 pathway. Ghrelin alleviated mitochondrial structural damage. Additionally, ghrelin reduced levels of pro-inflammatory factors and CD86, while increasing levels of anti-inflammatory factors and CD206. Erastin reversed the effects of ghrelin on ferroptosis and phenotypic polarization in Aβ_1-42-exposed microglia. In AD mice, ghrelin ameliorated abnormal behavior, neuroinflammation, and plaque deposition. Ghrelin attenuated iNOS/IBA1-positive expression and enhanced Arg-1/IBA1-positive expression in the hippocampus. Ghrelin induces microglial M2 polarization by inhibiting microglia ferroptosis, thereby alleviating neuroinflammation. Our results indicate that ghrelin may serve as a promising potential agent for treating cognitive impairment in AD.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"6"},"PeriodicalIF":6.2,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Empagliflozin Mitigates PTZ-Induced Seizures in Rats: Modulating Npas4 and CREB-BDNF Signaling Pathway.","authors":"Heba A Abdelaziz, Mohamed F Hamed, Hamdy A Ghoniem, Manar A Nader, Ghada M Suddek","doi":"10.1007/s11481-024-10162-6","DOIUrl":"https://doi.org/10.1007/s11481-024-10162-6","url":null,"abstract":"<p><p>Empagliflozin (EMPA) is one of the sodium/glucose cotransporter 2 (SGLT2) inhibitors that has been recently approved for the treatment of diabetes mellitus type II. Recently, EMPA has shown protective effects in different neurological disorders, besides its antidiabetic activity. Kindling is a relevant model to study epilepsy and neuroplasticity. This study aimed to investigate the potential protective effects of EMPA (1 and 3 mg/kg orally) against convulsant effects induced by pentylenetetrazole (PTZ) using a modified window- (win-) PTZ kindling protocol. The biochemical dysfunction and hippocampal damage induced by PTZ were profoundly reversed by EMPA treatment in a dose-dependent manner, as evidenced by the significant increase in reduced glutathione (GSH) and decrease in malondialdehyde (MDA) hippocampal contents. Furthermore, EMPA counteracted PTZ-induced neuronal damage in the hippocampal region, as confirmed by histopathological examination of the hippocampal tissues. EMPA impaired astrocytosis and showed an antiapoptotic effect through a significant reduction of glial fibrillary acidic protein (GFAP) and BCL2-Associated X Protein (BAX) expressions, respectively. Interestingly, EMPA exhibited an antiepileptic effect against PTZ-induced seizures through significantly reducing neuronal PAS domain Protein 4 (Npas4), cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) hippocampal expressions, and enhancing the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) pathway, which are found to be involved in epileptogenesis, eventually leading to significant improvement of behavioral impairments induced by PTZ. Hence, these results showed further prospective insights for EMPA as a neuroprotective agent.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"5"},"PeriodicalIF":6.2,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142959858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Memantine/Rosuvastatin Therapy Abrogates Cognitive and Hippocampal Injury in an Experimental Model of Alzheimer's Disease in Rats: Role of TGF-β1/Smad Signaling Pathway and Amyloid-β Clearance.","authors":"Esraa F Zidan, Nesrine S El-Mezayen, Safaa H Elrewini, Elham A Afify, Mennatallah A Ali","doi":"10.1007/s11481-024-10159-1","DOIUrl":"10.1007/s11481-024-10159-1","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder of complex pathogenesis and multiple interacting signaling pathways where amyloidal-β protein (Aβ) clearance plays a crucial role in cognitive decline. Herein, the current study investigated the possible modulatory effects of memantine/ rosuvastatin therapy on TGF-β1/p-Smad/p21 signaling pathway and their correlation to the blood brain barrier transporters involved in Aβ-clearance and microRNAs as a novel molecular mechanism in AD treatment. AD was induced by a single intracerebroventricular streptozotocin injection (ICV-STZ, 3 mg/kg) in rats and drug therapy was continued for 28 days after AD induction. Efficacy was monitored by applying a battery of behavioral assessments, as well as biochemical, histopathological, molecular and gene expression techniques. The upregulated TGF-β1-signaling in the untreated rats was found to be highly correlated to transporters and microRNAs governing Aβ-efflux; ABCA1/miRNA-26 and LRP1/miRNA-205 expressions, rather than RAGE/miRNA-185 controlling Aβ-influx; an effect that was opposed by the tested drugs and was found to be correlated with the abolished TGF-β1-signaling as well. Combined memantine/rosuvastatin therapy ameliorated the STZ evoked decreases in escape latency and number of crossovers in the Morris water maze test, % spontaneous alternation in the Y-maze test, and discrimination and recognition indices in the object recognition test. The evoked behavioral responses were directly related to the β-amyloid accumulation and the alteration in its clearance. Additionally, drug treatment increased brain glutathione and decreased malondialdehyde levels. These findings were histopathologically confirmed by a marked reduction of gliosis and restoration of neuronal integrity in the CA1 region of the hippocampus of the AD rats. These findings implicated that the memantine/rosuvastatin combination could offer a new therapeutic potential for AD management by abrogating the TGF-β1/p-Smad2/p21 pathway and regulating Aβ-clearance.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"4"},"PeriodicalIF":6.2,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}