Metabolic brain disease最新文献

{"title":"Pharmacological modulation of PI3K/PTEN/Akt/mTOR/ERK signaling pathways in ischemic injury: a mechanistic perspective.","authors":"Heena Khan, Aditi Singh, Yashvardhan Singh, Diksha Sharma, Kamal Dua, Amarjot Kaur Grewal, Thakur Gurjeet Singh","doi":"10.1007/s11011-025-01543-8","DOIUrl":"https://doi.org/10.1007/s11011-025-01543-8","url":null,"abstract":"<p><p>Ischemia, also known as ischemia, relates to the reduced blood movement to a cells, muscle group, or organ in the body, culminating in an insufficient amount of oxygen required for cellular metabolism and the maintenance of tissue viability. There are different types of stroke (ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage), and different causes of stroke (e.g., cardioembolic, atherothrombotic, lacunar ischemic strokes, aneurysmal subarachnoid hemorrhage). It also includes other disorders affecting the blood vessels in the brain (e.g., vascular malformations, unruptured aneurysms). Each of these conditions has different characteristics in terms of how common they are and how they are managed. Stroke is the primary and catastrophic clinical presentation of all cerebrovascular diseases. In this review we focused about the importance of PI3K/AKT signaling pathways which are important in the onset of ischemia-reperfusion (I/R) injury. In addition, mTOR, a target that is activated by the PI3K/Akt signaling pathway, is both required and capable of providing enough protection to the heart against harm caused by I/R. Moreover, the signaling pathways that involve PI3K/Akt/Erk/PTEN/mTOR play a crucial role in facilitating the proliferation and maintenance of neurons following an ischemic stroke. The current review summarizes the molecular mechanisms of various signaling pathways in ischemic diseases and suggests targeting its receptors as a preventive approach based on pre-clinical and clinical studies.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 3","pages":"131"},"PeriodicalIF":3.2,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the mTOR pathway modulation by SGLT2 inhibitors: a novel approach to Alzheimer's disease in type 2 diabetes.","authors":"Prakash Ramakrishan, Jayaraman Rajangam, Shaheedha Shabudeen Mahinoor, Shradha Bisht, Sabareesh Mekala, Dinesh Kumar Upadhyay, Viswas Raja Solomon, Govindaraj Sabarees, Ranakishor Pelluri","doi":"10.1007/s11011-025-01555-4","DOIUrl":"https://doi.org/10.1007/s11011-025-01555-4","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurological condition causing cognitive deterioration, leading to severe consequences. As the global prevalence of AD increases, new treatment approaches are needed to supplement current conventional therapies, as traditional treatments are not meeting the increasing demand for alternative treatments. It is increasingly evident that treating metabolic disorders like diabetes mellitus, obesity, and AD by blocking mechanistic target of rapamycin (mTOR) signalling is advantageous. Chronic mTOR activation may cause AD's metabolic, lysosomal, and mitochondrial dysfunction, tau hyperphosphorylation, amyloid plaque development, and disruption of the blood-brain barrier through endothelial cell malfunction. Chronic glucose loss through sodium-glucose transporter 2 (SGLT2) inhibitions can restore mTOR cycling, potentially halting or slowing AD pathogenesis. Chronic activation of mTOR is implicated in pathophysiological aspects of AD, such as metabolic dysfunction, tau hyperphosphorylation, amyloid plaque formation, and disruption of the blood-brain barrier. SGLT-2 inhibitors, commonly used in treating Type 2 Diabetes, have been shown to reduce mTOR activation and restore circadian regularity, a new finding in cognitive decline and metabolic disorders. Conversely, SGLT2 inhibitors decrease oxidative damage, inflammation, insulin signaling pathways, and proliferation of endothelial cells to enhance vascular tone, flexibility, and contractility. Along with reducing the formation of plaque containing amyloid and improving brain function, neural plasticity, acetylcholinesterase (AChE) activity, damage to the brain, and cognitive decline, they also regulate the mTOR pathway in the brain. Thus, repurposing SGLT-2 inhibitors, primarily used in diabetes treatment, presents a promising avenue for changing the way that AD is managed. The purpose of this review was to focus on the mTOR signalling cascade of SGLT 2 inhibitors to AD management in Type 2 Diabetes mellitus.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 3","pages":"132"},"PeriodicalIF":3.2,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Untargeted metabolomics unveils critical metabolic signatures in novel phenotypes of acute ischemic stroke.","authors":"Yao Jiang, Qian Wu, Yingqiang Dang, Lingling Peng, Ling Meng, Chongge You","doi":"10.1007/s11011-024-01451-3","DOIUrl":"https://doi.org/10.1007/s11011-024-01451-3","url":null,"abstract":"<p><p>This study aimed to identify metabolic footprints associated with distinct phenotypes of acute ischemic stroke (AIS) using untargeted metabolomics. We included 20 samples each from AIS phenotype A (n = 251), B (n = 213), and C (n = 43) groups, along with 20 age- and gender-matched healthy controls (HCs). Plasma metabolic profiles were analyzed using liquid chromatography-mass spectrometry (LC-MS). Weighted gene correlation network analysis (WGCNA) evaluated associations between metabolite clusters and clinical traits, including the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS). We identified three, five, and six key differential metabolites for diagnosing phenotypes A, B, and C, respectively, demonstrating high diagnostic performance. These metabolites were focused on fatty acids, sex hormones, amino acids, and their derivatives. WGCNA identified 12 core metabolites involved in phenotype progression. Notably, phenylalanylphenylalanine and phenylalanylleucine were inversely correlated with disease severity and disability. Metabolites related to energy supply and inflammation were common across phenotypes, with additional changes in ionic homeostasis in phenotype A and decreased neurotransmitter release in phenotype C. Biosynthesis of unsaturated fatty acids and the pentose phosphate pathway (PPP) were relevant across all phenotypes, while the folate biosynthesis pathway was linked to phenotype C and clinical scales. Key metabolites, including phenylalanylphenylalanine and phenylalanylleucine, and pathways such as folate biosynthesis, significantly contribute to AIS severity and differentiation of phenotypes. These findings offer new insights into the pathogenesis and mechanisms underlying AIS phenotypes.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 3","pages":"130"},"PeriodicalIF":3.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α-asarone activates mitophagy to relieve diabetic encephalopathy via inhibiting apoptosis and oxidative stress.","authors":"Xiao-Dan Yan, Rong-Hua Fan, Yu Wang, Xiao-Xu Duan, Xuan Wei, Lin-Sen Li, Qing Yu","doi":"10.1007/s11011-025-01556-3","DOIUrl":"https://doi.org/10.1007/s11011-025-01556-3","url":null,"abstract":"<p><p>Diabetic encephalopathy (DE) is a common complication of diabetes that may result in cognitive impairment. Currently, there is limited effective therapy for DE. Herein, we explored the beneficial effect of α-Asarone on DE and its potential mechanisms. DE was induced in Type 2 diabetes mellitus mice and high-glucose (HG)-exposed PC-12 cells. Cognitive function was evaluated by MWM test. Pathological changes in the brain tissues were observed by HE staining. Cell viability was detected by CCK-8. Apoptosis was assessed by Hoechst 33,342 staining, Annexin V/PI staining and TUNEL. Mitochondrial membrane potential was analyzed by JC-1 probe. ROS production was measured by DCFH-DA staining. Target protein levels were analyzed by Western blotting. Network pharmacology was used to elucidate the beneficial mechanisms of α-Asarone in DE. Our study showed that α-Asarone enhanced cell viability and suppressed apoptosis in HG-stimulated PC-12 cells. Furthermore, α-Asarone relieved HG-induced reduction in mitochondrial membrane potential and ROS overproduction. In addition, mitophagy was triggered by α-Asarone, which was responsible for the inhibitory effect of α-Asarone on apoptosis and oxidative stress. Consistently, the in vivo experiments showed that α-Asarone treatment relieved cognitive dysfunction, apoptosis, and oxidative stress of DE mice via mitophagy induction. However, inhibition of mitophagy by Mdivi-1 counteracted the beneficial action of α-Asarone. Mechanistically, network pharmacology analysis identified 10 key targets of α-Asarone. Molecular docking substantiated a strong affinity of α-Asarone with CASP3, EGFR, NFKB1, and ESR1 proteins. Taken together, α-Asarone protected against mitochondrial dysfunction, oxidative stress and apoptosis via activating mitophagy, thereby alleviating DE. Our findings suggest α-Asarone as a potential drug for DE.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"126"},"PeriodicalIF":3.2,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective effects of L-carnitine towards oxidative stress and inflammatory processes: a review of its importance as a therapeutic drug in some disorders.","authors":"Gilian Guerreiro, Marion Deon, Graziela Schmitt Becker, Bianca Gomes Dos Reis, Moacir Wajner, Carmen Regla Vargas","doi":"10.1007/s11011-025-01545-6","DOIUrl":"https://doi.org/10.1007/s11011-025-01545-6","url":null,"abstract":"<p><p>L-carnitine (LC) is a natural compound crucial for transporting long-chain fatty acids into mitochondria for ATP production. It is found mainly in red meat, fish, and dairy products, in addition to being synthesized by the body. LC is supplemented in patients with organic acidemias since it corrects secondary carnitine deficiency and accelerates the removal of the accumulated acyl organic acid derivative groups. Recently, it was also shown to behave as an antioxidant and an anti-inflammatory agent in various pathological conditions like hypertension, diabetes, and neurodegenerative diseases. Inflammation is a complex response to tissue damage or infection associated with oxidative stress. LC has been implicated in reducing inflammatory cytokines and other biomarkers. Recent studies suggest that LC supplementation reduces inflammation in chronic kidney disease, cardiovascular disease, and neuroinflammation. LC supplementation has been effective in reducing inflammatory markers like C-reactive protein (CRP) and interleukins (IL-6, TNF-α) in various pathologies, including septic shock and polycystic ovary syndrome (PCOS). It has also been shown to reduce cardiovascular events in patients with end-stage renal disease. In experimental models, LC revealed neuroprotective effects, improving memory and reducing neuronal death. Additionally, in spinal cord ischemia-reperfusion injury and acute myocardial infarction, LC treatment diminished inflammation and oxidative stress while improving neurological and cardiac functions. In conclusion, LC supplementation demonstrates significant potential properties in reducing inflammation and improving health outcomes in various pathological conditions, making it a subject of increasing interest in medical research. This article aims to review the literature on the anti-inflammatory and antioxidant effects of LC in different pathologies.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"127"},"PeriodicalIF":3.2,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lights and shadows of clozapine on the immune system in schizophrenia: a narrative literature review.","authors":"Jian Liu, Weimin Zhao, Yitong Wang","doi":"10.1007/s11011-025-01558-1","DOIUrl":"https://doi.org/10.1007/s11011-025-01558-1","url":null,"abstract":"<p><p>Schizophrenia is a chronic mental disorder and one of the main causes of disability in the world. Approximately 1% of the general population suffers from this disorder, and almost 30% of cases are unresponsive to antipsychotic therapies. Clozapine is a Food and Drug Administration (FDA)-approved antipsychotic drug for treatment-resistant schizophrenia (TRS). Clozapine is also approved for the prevention of suicide associated with schizophrenia. However, clozapine is not the preferred first-line medication because of its potential AEs, including agranulocytosis, metabolic syndromes, and myocarditis. Clozapine prescription requires weekly absolute neutrophil count (ANC) monitoring for the first six months, followed by biweekly monitoring until the patient has finished one year of treatment. Several psychiatric disorders have been reported to be associated with inflammatory biomarkers. Dysregulation of the immune system and the elevation of pro-inflammatory cytokines were also reported to be associated with schizophrenia, highlighting the necessity of further research into the etiology of the disease and the relationship between the immune system and clozapine-responsiveness to support better management of symptoms and potential AEs. In this framework, we searched PubMed using the medical subject headings (MeSH) terms \"clozapine\", \"antipsychotics\", \"schizophrenia\", \"treatment-resistant schizophrenia\", \"immune system\", \"inflammation\", \"neuroinflammation\", \"biomarker\", \"cytokine\", and \"chemokine\" with the aim of overview the impact of clozapine on the immune system in individuals with treatment-responsive and treatment-resistant schizophrenia.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"128"},"PeriodicalIF":3.2,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unlocking NAC's potential ATF4 and m6A dynamics in rescuing cognitive impairments in PTSD.","authors":"Yanling Zhou, Xiuhong Yuan, Min Guo","doi":"10.1007/s11011-024-01485-7","DOIUrl":"https://doi.org/10.1007/s11011-024-01485-7","url":null,"abstract":"<p><p>In this study, we investigated the therapeutic potential of N-acetylcysteine (NAC) in a mouse model of post-traumatic stress disorder (PTSD) induced by a single prolonged stress (SPS) protocol. Our findings demonstrate that NAC treatment significantly improved cognitive function and mitigated hippocampal neuronal apoptosis in PTSD model mice. These positive effects were accompanied by a reduction in m6A methylation levels and activating transcription factor 4 (ATF4) expression. Silencing ATF4 further attenuated hippocampal neuronal apoptosis and cognitive dysfunction, while ATF4 overexpression partially reversed the beneficial effects of NAC. It suggests that NAC's efficacy in PTSD may be mediated by its regulation of ATF4 expression and m6A methylation levels. Overall, our study provides valuable insights into the potential mechanism of action for NAC in PTSD treatment, offering promising avenues for future therapeutic strategies.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"129"},"PeriodicalIF":3.2,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ST3 beta-galactoside alpha-2,3-sialyltransferase 4 (St3gal4) deficiency reveals correlations among alkaline phosphatase activity, metabolic parameters, and fear-related behavior in mice.","authors":"Siriporn Tangsudjai, Akiko Fujita, Toshiya Tamura, Takaya Okuno, Mika Oda, Keiko Kato","doi":"10.1007/s11011-025-01551-8","DOIUrl":"10.1007/s11011-025-01551-8","url":null,"abstract":"<p><p>ST3 beta-galactoside alpha-2,3-sialyltransferase 4 (ST3GAL4) is a sialyltransferase involved in the biosynthesis of alpha2,3-sialic acid on glycoproteins and glycolipids. In mice, St3gal4 gene expression plays a crucial role in modulating epilepsy and anxiety/depression through its expression in thalamic neurons. Genome-wide association studies (GWAS) have identified several peripheral metabolic traits strongly associated with ST3GAL4 in humans. However, whether the symptoms observed in mice are associated with metabolic changes remains unclear. This study investigated the effects of St3gal4 deficiency on the same metabolic parameters in mice as those in humans. The parameters examined included body weight, plasma biochemistry, specifically alkaline phosphatase (ALP), protein, and cholesterol levels, and free amino acids profiles, resulting in elevated ALP and reduced tryptophan and total cholesterol (T-Cho) levels in St3gal4-knockout (KO) mice. Additionally, clearance of blood glucose was delayed in KO male mice. These findings suggest mouse St3gal4 deficiency correlated with modulated ALP, tryptophan, and T-Cho levels in the plasma. Next, brain ALP activity was compared between St3gal4-KO mice and wild-type (WT) mice, focusing on the thalamus. Fear conditioning tests assessed the relationship between behavior and ALP activity in plasma and brain. In KO mice, the enhanced tone freezing positively correlated with plasma ALP levels. Conversely, thalamic ALP activity was greatly reduced in KO mice, negatively correlating with plasma ALP. These findings suggest that mouse St3gal4 deficiency influences ALP activity in both thalamus and plasma, associating with emotional behaviors and metabolic changes.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"125"},"PeriodicalIF":3.2,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11828824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel approach to metabolic profiling in case models of MECP2-related disorders.","authors":"Jessica A Cooley Coleman, Bridgette A Moffitt, William C Bridges, Kelly Jones, Melanie May, Cindy Skinner, Michael J Friez, Steven A Skinner, Charles E Schwartz, Luigi Boccuto","doi":"10.1007/s11011-025-01546-5","DOIUrl":"10.1007/s11011-025-01546-5","url":null,"abstract":"<p><p>Genetic abnormalities of the MECP2 gene cause several conditions grouped under the umbrella term of MECP2-related disorders and characterized by a variety of phenotypes. We applied a functional approach to identify metabolic profiles in two patients with Rett syndrome (RTT) and one patient with MECP2 duplication syndrome (MRXSL). Such an approach is based on the Phenotype Mammalian Microarray (PM-M) technology, which is designed to assess the cellular production of energy in the presence of different compounds generating distinct metabolic environments. The findings in the three case models were compared versus 50 controls. Although the small number of samples prevented most results from reaching significant p-values when adjusted with the Benjamini-Hochberg correction, some interesting trends emerged. Some compounds indicated metabolic trends shared by the two conditions, like increased energy production in the presence of energy sources such as pectin, adenosine, and pyruvic acid, or decreased metabolic response to certain hormones. Other compounds showed opposite trends for the two disorders, like interleukin-1 beta (IL-1 beta), which caused decreased energy production in the RTT group but increased energy production in the patient with MRXSL. The response to IL-1 beta also offers valuable insights into the pathogenic mechanism and potential therapeutic approaches. The metabolic profiling of MECP2-related disorders bears a remarkable translational potential since it may be helpful to investigate the molecular abnormalities underlying the phenotypical variety in this spectrum of conditions, develop biomarkers for the identification of ideal candidates for treatments like the recently approved trofenatide, and identify potential targets for the development of novel therapeutic approaches.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"124"},"PeriodicalIF":3.2,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143409174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the role of Nrf2 in dopaminergic neurons: a review of oxidative stress and mitochondrial dysfunction in Parkinson's disease.","authors":"Manpreet Kaur, Khadga Raj Aran","doi":"10.1007/s11011-025-01552-7","DOIUrl":"https://doi.org/10.1007/s11011-025-01552-7","url":null,"abstract":"<p><p>Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcriptional factor, involved in the regulation of countenance of various anti-oxidant enzymes and cytoprotective genes that respond to mitochondrial dysfunctions, oxidative stress, and neuroinflammation, thus potentially contributing to several neurodegenerative diseases (NDDs), including Parkison's disease (PD). PD is the second most prevalent progressive NDD, characterized by gradual neuronal death in substantia nigra pars compacta (SNpc), depletion of dopamine level, and a wide range of motor symptoms, including bradykinesia, tremor, tingling, and muscle fatigue. The etiopathology of PD is caused by multifactorial intertwined with the onset and progression of the disease. In this context, Nrf2 exhibits neuroprotective action by preserving dopaminergic neurons in the striatum and retarding the disease progression; thus, Nrf2 activation plays a crucial role in PD. Additionally, Nrf2 binds with the antioxidant response element, which is located in the promoter region of most of the genes that are responsible for coding antioxidant enzymes. Moreover, protein kinase C (PKC) mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) are also involved in the regulation of Keap1 pathway-mediated Nrf2 activation. As Nrf2 revealed its defensive and protective role in the central nervous system (CNS), it is gaining enough interest in treating PD. The treatments that are currently available are intended to alleviate the symptoms of PD; however, they are unable to halt the progression and severity of the disease. Therefore, in this review we delve deeper into various molecular mechanisms associated with oxidative stress, mitochondrial dysfunction, and neuroinflammation in PD. Additionally, we elaborated on the substantial role that NRF2 plays in mitigating these adverse effects and its potential as a therapeutic target.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 2","pages":"123"},"PeriodicalIF":3.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}