Neuroprotection最新文献

{"title":"Bee venom enhances dopaminergic function and behavioral recovery in a murine model of Parkinson's disease.","authors":"Silvia Josefina López-Pérez, Marco Antonio Noriega-Ruiz, Alma Karen Lomeli-Lepe","doi":"10.1002/nep3.70038","DOIUrl":"10.1002/nep3.70038","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons, leading to motor dysfunction and cognitive impairment. Although levodopa (l-DOPA)/carbidopa remains the gold standard therapy for PD, its efficacy declines over time, highlighting the need for adjuvant strategies that improve functional outcomes. This study evaluated whether freeze-dried bee venom (BV) enhances the behavioral effects of l-DOPA/carbidopa in a murine model of PD.</p><p><strong>Methods: </strong>Adult male mice (age: 3.0-3.5 months) were randomly assigned using a computer-generated randomization sequence to the following experimental groups: SHAM, animals that were injected with saline in the dorsomedial striatum (STR) (<i>n</i> = 6); 6-hydroxydopamine (6-OHDA) lesion, animals that received an injection of 6-OHDA in the STR (<i>n</i> = 7); l-DOPA/carbidopa, lesioned animals that were treated with l-DOPA/carbidopa from day 13 (D13) to day 30 (D30) after the lesion (<i>n</i> = 7); and l-DOPA/carbidopa + BV, lesioned animals treated with a combination of l-DOPA/carbidopa and BV from D13 to D30 after the lesion (<i>n</i> = 7). Motor asymmetry and paw dragging were assessed using the cylinder test, and lateralized function was assessed using the corridor test. Cognitive performance was evaluated with the novel object recognition (NOR) test. Behavioral data were analyzed using the Kruskal-Wallis test followed by Dunn's post hoc comparisons.</p><p><strong>Results: </strong>Compared with 6-OHDA treatment, the combined treatment with BV and l-DOPA/carbidopa significantly improved forelimb motor symmetry (<i>H</i> = 15.16, <i>p</i> = 0.001) and reduced contralateral paw dragging (<i>H</i> = 19.91, <i>p</i> < 0.001). In the corridor test, compared with l-DOPA/carbidopa alone, BV cotreatment increased the retrieval index (<i>H</i> = 16.43, <i>p</i> < 0.001). Moreover, BV prevented 6-OHDA-induced cognitive impairment in the NOR test, restoring the discrimination index to levels comparable to those of the SHAM group (<i>H</i> = 17.48, <i>p</i> < 0.001).</p><p><strong>Conclusion: </strong>These findings provide behavioral evidence that BV may serve as a promising adjuvant to l-DOPA/carbidopa, improving both motor and cognitive outcomes in a mouse model of PD and supporting further investigation in studies incorporating histological and molecular endpoints.</p>","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"4 2","pages":"169-177"},"PeriodicalIF":4.1,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13306114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148347289","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":"Neuroprotective effects of ursodeoxycholic acid in Parkinson's disease and Alzheimer's disease.","authors":"Ashley En Yi Chong, Andrew Octavian Sasmita, Rhun Yian Koh, Anna Pick Kiong Ling","doi":"10.1002/nep3.70039","DOIUrl":"10.1002/nep3.70039","url":null,"abstract":"<p><p>Neurodegenerative diseases (NDDs) including Parkinson's disease (PD) and Alzheimer's disease (AD), are progressive disorders characterised by shared pathological features, including mitochondrial dysfunction, oxidative stress, apoptosis, neuroinflammation, neurotoxic protein buildup, and impaired protein clearance. Current treatments can only relieve disease symptoms but cannot delay the disease progression. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid traditionally used in hepatology, has recently gained attention for its neuroprotective properties. This review critically evaluates UDCA's mechanisms of action, including the restoration of mitochondrial function, inhibition of apoptosis, reduction of oxidative stress and neuroinflammation, and enhancement of autophagy in both PD and AD models. In vitro and in vivo studies demonstrate UDCA's ability to preserve neuronal integrity, improve motor and cognitive outcomes, and reduce toxic protein aggregates. Although early-phase clinical trials, such as the UDCA for Parkinson's (UP) study in PD, show promising mitochondrial benefits and safety, clinical evidence in AD remains limited. Future directions emphasise the need for large-scale trials, personalised medicine, improved central nervous system (CNS) delivery strategies, or dietary interventions to modulate UDCA production from the gut microbiome. While not a first-line treatment, UDCA represents a compelling mitochondrial stabiliser with disease-modifying potential in NDDs.</p>","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"4 2","pages":"111-130"},"PeriodicalIF":4.1,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13306118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148347478","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":"Post-recanalization administration of rapamycin improves functional outcome and reduces infarct size in a rat model of ischemic stroke.","authors":"Anna M Schneider, Yvonne Couch, James Larkin, Alastair M Buchan, Daniel J Beard","doi":"10.1002/nep3.70035","DOIUrl":"10.1002/nep3.70035","url":null,"abstract":"<p><strong>Aim: </strong>Despite advances in endovascular recanalization for ischemic stroke, many patients experience poor outcomes. Adjunct cerebroprotective therapies are needed to improve recovery. The mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin has shown neuroprotective effects in preclinical stroke models. However, most studies administered rapamycin prior to or during stroke onset, limiting translational relevance. The aim of this study was to determine whether rapamycin administered immediately after recanalization improves infarct size and functional outcome, and whether these effects are associated with changes in cerebral blood flow (CBF) or blood-brain barrier (BBB) integrity.</p><p><strong>Methods: </strong>Male Wistar Han rats were subjected to transient middle cerebral artery occlusion (tMCAO) for 90 min. Animals were randomized using the sealed envelope method to receive intravenous rapamycin (250 μg/kg, <i>n</i> = 9) or vehicle (<i>n</i> = 9) immediately after recanalization. Infarct volume, CBF, and BBB integrity were assessed using magnetic resonance imaging (MRI) at 72 h, alongside validated neurological tests. Group comparisons were performed using unpaired Student's <i>t</i>-tests.</p><p><strong>Results: </strong>Rapamycin significantly reduced infarct volume compared with vehicle (44.77 ± 30.93 mm³ vs. 113.44 ± 60.19 mm³, <i>p</i> = 0.0114) and improved Garcia neurological scores (12.78 ± 1.04 vs. 11.67 ± 0.87, <i>p</i> = 0.0295). In the adhesive removal test, rapamycin-treated animals showed shorter time to notice the stimulus (45.04 ± 11.91 s vs. 72.33 ± 12.17 s, <i>p</i> = 0.0002). Rapamycin had no significant effect on CBF, BBB disruption, or edema at 72 h (all <i>p</i> > 0.05). The p-mTOR/mTOR ratio did not differ significantly between groups at day 3 (0.55 ± 0.32 vs. 0.90 ± 0.41, <i>p</i> = 0.1880).</p><p><strong>Discussion: </strong>Rapamycin administered after recanalization improves functional outcomes and reduces infarct size, without altering sustained perfusion or BBB permeability. These findings highlight a perfusion-independent, time-sensitive cerebroprotective mechanism and support rapamycin's development as an adjunctive therapy in ischemic stroke.</p>","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"4 2","pages":"157-168"},"PeriodicalIF":4.1,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13306121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148347450","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":"Depletion of microglial compensation in glial network: Disease-associated response dynamics in the revised amyloid hypothesis.","authors":"Songtao Lei, Zixuan Huang, Wen Wang, Yan Meng","doi":"10.1002/nep3.70037","DOIUrl":"10.1002/nep3.70037","url":null,"abstract":"<p><p>Microglia mount coordinated, stage-dependent compensatory programs in response to early amyloid β (Aβ) accumulation that preserve proteostasis and neuronal integrity during preclinical Alzheimer's disease. We propose the \"microglial compensation-depletion\" framework that describes a distributed compensatory network whose failure constitutes a mechanistic tipping point. Once compensatory capacity falls below a critical threshold, positive-feedback loops amplify irreversible pathology, eventually leading to cognitive decline. Integrating single-cell transcriptomics, chromatin accessibility, and genetic evidence from human cohorts and animal models, we synthesize evidence for stage-dependent microglial transitions and for glial interactions that shape resilience or vulnerability. The microglial compensation-depletion framework in the revised amyloid hypothesis is a multiscale, dynamical perspective and highlights potential strategies for modeling and clinical intervention. Intercellular ligand-receptor networks may provide quantitative substrates for defining glial-state patterns and even identifying key communication axes that delineate transitions. For example, microglial triggering receptor expressed on myeloid cells 2 (TREM2)-apolipoprotein E (APOE) signaling exemplifies an intercellular axis that modulates microglial phenotype and Aβ handling. Clinically, in vivo imaging and biofluid biomarkers may offer potential means to track glial functional reserve and to detect approaching tipping points.</p>","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"4 2","pages":"131-142"},"PeriodicalIF":4.1,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13306109/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148347438","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":"Increased expression of aromatase after focal cerebral ischemia: Relevance to neuroprotection and functional recovery.","authors":"Lindsay Gallagher, Anna F Dominiczak, Luis M Garcia-Segura, Nobuhiro Harada, J B Hutchison, James M Mullin, Delyth Graham, Peter O'Shaughnessy, Hilary Victoria O Carswell","doi":"10.1002/nep3.70033","DOIUrl":"10.1002/nep3.70033","url":null,"abstract":"<p><strong>Aim: </strong>Aromatase is the key enzyme in the biosynthesis of 17β-estradiol, the most potent estrogen, which has pleiotropic neuroprotective properties. Aromatase levels increase in the brain after stroke, and its gene variants increase susceptibility to stroke. This study aims to determine whether aromatase overexpression improves stroke outcome and whether aromatase inhibition exacerbates outcome after permanent focal cerebral ischemia.</p><p><strong>Methods/design: </strong>All animals (3-4 months old) underwent permanent middle cerebral artery occlusion (MCAO) by diathermy. Time course of aromatase expression following MCAO in female ovariectomized spontaneously hypertensive stroke prone (SHRSP) rats was assessed by semi-quantitative immunohistochemistry and quantitative polymerase chain reaction (qPCR). The effect of aromatase expression on stroke outcome was assessed using a male mouse model over-expressing aromatase (Dax-1 KO mice) and by letrozole treatment. Volume of ischemic damage was assessed by magnetic resonance imaging (MRI) and functional recovery was assessed by the corner test and foot-fault test. All analyses were performed using GraphPad Prism version 9.0.</p><p><strong>Results: </strong>The key findings are that aromatase expression was significantly increased in SHRSP in both the dorsal and ventral peri-infarct zones and hippocampus at 24 h post-MCAO as measured by areas of immunostaining but not qPCR. There was no improvement in stroke outcome by Dax-1 KO, despite significantly higher plasma 17β-estradiol levels and increased brain aromatase immunoreactivity after stroke. There was no exacerbation on stroke outcome by letrozole, despite decreased plasma 17β-estradiol levels.</p><p><strong>Conclusion: </strong>The time course and location of increased aromatase indicate a potential role in neuroprotection and repair; however, manipulation of aromatase expression does not influence outcome after permanent MCAO in male mice.</p>","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"4 2","pages":"143-156"},"PeriodicalIF":4.1,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13306120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148347493","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":"New insights into disease-modifying factors and clinical translation for central nervous system diseases.","authors":"Shen Li, Xunming Ji, Piotr Walczak, Johannes Boltze","doi":"10.1002/nep3.70034","DOIUrl":"10.1002/nep3.70034","url":null,"abstract":"","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"4 1","pages":"1-3"},"PeriodicalIF":4.1,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147791468","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":"Research status and trends of Piezo1 and brain: A bibliometric analysis.","authors":"Yu Liu, Shengzhen Luo, Hao Zhang, Jianqing Lin, Hui Xiao, Yuying Ma, Dongxue Ye, Liang Cong, Yongwang Li","doi":"10.1002/nep3.70031","DOIUrl":"10.1002/nep3.70031","url":null,"abstract":"<p><strong>Aim: </strong>As a key mechanosensitive ion channel, Piezo1 plays a critical role in various brain functions, including the regulation of cerebral blood flow and neuronal excitability, by converting mechanical stimuli into biochemical signals. This study conducted a quantitative and visual analysis of the global research landscape, evolving trends, and knowledge structure of Piezo1 in brain research from 2014 to 2025.</p><p><strong>Methods: </strong>A comprehensive bibliometric analysis was conducted. We conducted a comprehensive literature search in the Web of Science and Scopus databases for publications focusing on Piezo1 in the brain from January 1, 2014, to October 1, 2025. After rigorous screening and deduplication, 173 studies were finally included in the analysis. Scientometric indicators and visualization tools were employed to examine publication trends, core journals, productive authors and countries, and keyword co-occurrence networks.</p><p><strong>Results: </strong>Annual publication output in this field increased rapidly, with an average growth rate of 34.48%. Research publications are concentrated in a limited number of high-impact journals, reflecting a strong academic focus. Keyword analysis identified core research hotspots, including \"mechanotransduction,\" \"ion channels,\" and \"neuroinflammation,\" highlighting the pivotal role of Piezo1 in cerebral hemodynamics and neuropathology. Intellectual structure analysis revealed that foundational mechanistic studies dominate the current literature.</p><p><strong>Discussion: </strong>Although basic research on Piezo1 in the brain has advanced significantly, studies directly targeting its clinical translation are limited. These findings highlight a clear knowledge gap between mechanistic understanding and therapeutic applications. Future research should prioritize bridging this gap by fostering interdisciplinary collaborations that translate fundamental insights into clinical validation, thereby accelerating the development of Piezo1 as a novel therapeutic target for neurological disorders.</p>","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"4 2","pages":"178-187"},"PeriodicalIF":4.1,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13306112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148347480","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":"Exercise, exerkines, and muscle-brain crosstalk in Parkinson's disease.","authors":"Salomón Páez-García, Edgar Alvarado, Alejandro Cuevas, Laura Valverde, Eduardo Salinas, Kevin O'Hara-Veintimilla, María Cruz Rodríguez-Oroz, Miguel Germán Borda","doi":"10.1002/nep3.70032","DOIUrl":"10.1002/nep3.70032","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurodegenerative disorder with motor and non-motor symptoms, driven by dopaminergic loss and α-synuclein accumulation. Beyond neurodegeneration, growing evidence highlights skeletal muscle health as a key determinant of prognosis, with sarcopenia and frailty contributing to greater disability, fall risk, and reduced quality of life. This narrative review synthesizes current evidence on the interplay among exercise, muscle status, and exerkine signaling in PD, emphasizing their potential roles in neuroprotection and functional outcomes. A comprehensive literature search in PubMed and SciELO up to October 2025 identified 129 relevant studies, including experimental, observational, and interventional data. Sarcopenia and reduced muscle strength are highly prevalent in PD and independently associated with disease severity, frailty, and falls, while grip strength has emerged as a simple biomarker of progression. Clinical trials consistently show that aerobic, resistance, and multimodal exercise programs improve gait, balance, mood, cognition, and quality of life, with progressive resistance and balance training yielding the greatest motor benefits. At a mechanistic level, skeletal muscle functions as an active endocrine organ, releasing a variety of exercise-induced signaling molecules known as exerkines. These include brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), irisin, cathepsin B, myostatin, and growth/differentiation factor 15 (GDF15). Together, these exerkines facilitate muscle-brain crosstalk and are thought to contribute to the neuroprotective effects of exercise in PD. Through anti-inflammatory, antioxidant, and mitochondrial regulatory pathways, they support dopaminergic neuron survival and promote synaptic plasticity and neuronal resilience. Current international guidelines recommend individualized, multimodal programs integrating aerobic, resistance, and balance training, initiated early and maintained long-term. Exercise represents a promising, nonpharmacological intervention to mitigate neurodegeneration, sarcopenia, and functional decline in PD, although further high-quality studies are needed.</p>","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"4 2","pages":"99-110"},"PeriodicalIF":4.1,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13306113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148347431","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":"Environmental enrichment modulates chronic poststroke inflammation and links white matter TREM2-positive microglia in recovery in mice.","authors":"Lluís Camprubí-Ferrer, Ömer K Kolbay, Miriana J Quattromani, Tadeusz Wieloch, Karsten Ruscher, Tomas Deierborg","doi":"10.1002/nep3.70028","DOIUrl":"10.1002/nep3.70028","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Environmental enrichment (EE) has been widely reported to improve functional recovery after stroke, yet its effects on chronic inflammation and white matter pathology remain less well defined. The aim of this study was to investigate whether poststroke EE modulates chronic neuroinflammation and white matter pathology and how these changes relate to functional recovery.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Here, we investigated how EE influences the microglial response and myelin integrity during the recovery phase after photothrombotic stroke in male C57Bl/6J mice. Mice were randomized by using a computer-generated sequence into standard environment (SE) or EE housing conditions 2 days poststroke (SE: &lt;i&gt;n&lt;/i&gt; = 6; EE: &lt;i&gt;n&lt;/i&gt; = 7 for histological analyses; behavioral data unavailable for 2 SE mice). Sensorimotor performance was assessed at 7, 14, and 21 days poststroke using paw placement, foot fault, and limb symmetry tests, integrated into a composite Neuroscore. Housing in EE improved and sustained behavioral recovery up to 21 days. To explore whether specific microglial subpopulations are involved in tissue reorganization and functional outcome, immunofluorescence was performed for ionized calcium binding adaptor molecule 1 (Iba1), galectin-3 (Gal3), purinergic receptor P2Y12 (P2RY12), cluster of differentiation 68 (CD68), and triggering receptor expressed on myeloid cells 2 (TREM2), together with Black Gold myelin staining, in peri-infarct and white matter regions. Statistical analyses included correlation analyses and analysis of covariance (ANCOVA).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In SE mice, the inflammatory microglial marker Gal3 and the phagocytic marker CD68 correlated positively with infarct size (&lt;i&gt;r&lt;/i&gt; = 0.937, &lt;i&gt;p&lt;/i&gt; = 0.006; &lt;i&gt;r&lt;/i&gt; = 0.845, &lt;i&gt;p&lt;/i&gt; = 0.034, respectively), and the accumulation of myelin debris (&lt;i&gt;r&lt;/i&gt; = 0.865, &lt;i&gt;p&lt;/i&gt; = 0.026) together with loss of myelin coverage (&lt;i&gt;r&lt;/i&gt; = -0.907, &lt;i&gt;p&lt;/i&gt; = 0.013) followed lesion-driven trajectories. By contrast, these correlations were absent in EE mice (&lt;i&gt;r&lt;/i&gt; = -0.028, &lt;i&gt;p&lt;/i&gt; = 0.953; &lt;i&gt;r&lt;/i&gt; = 0.671, &lt;i&gt;p&lt;/i&gt;= 0.099; &lt;i&gt;r&lt;/i&gt; = 0.053, &lt;i&gt;p&lt;/i&gt; = 0.910; &lt;i&gt;r&lt;/i&gt; = 0.292, &lt;i&gt;p&lt;/i&gt; = 0.525) indicating that enrichment attenuated lesion-driven inflammatory responses and myelin damage. Importantly, Gal3 expression correlated specifically with peri-infarct myelin debris (&lt;i&gt;r&lt;/i&gt; = 0.82, &lt;i&gt;p&lt;/i&gt; = 0.048), reinforcing its role as a pro-inflammatory mediator. Finally, correlation analysis between Neuroscore and both microglial and myelin markers revealed a unique positive association between TREM2 coverage in white matter and improved Neuroscore in EE mice (&lt;i&gt;r&lt;/i&gt; = 0.890, &lt;i&gt;p&lt;/i&gt; = 0.007; ANCOVA &lt;i&gt;p&lt;/i&gt; = 0.039).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;These results support the idea that EE modulates processes of chronic post-stroke inflammation, peri-infarct myelin debris clearance and demyelination, and highlight white matter TREM2-posi","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"4 1","pages":"65-79"},"PeriodicalIF":4.1,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147791472","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":"Re-conceptualizing Parkinson's disease as a lifelong neurobiological trajectory: A framework for prevention.","authors":"Ayodeji Johnson Ajibare, Abraham Olufemi Asuku, Olabode Oluwadare Akintoye","doi":"10.1002/nep3.70030","DOIUrl":"10.1002/nep3.70030","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder. No disease-modifying therapies exist. This review proposes that PD susceptibility begins with epigenetic changes and neuroimmune activity-factors that alter gene expression and immune responses-during the vulnerable PD lifespan. Human evidence is mostly indirect or contradictory. We present this as a testable trajectory, drawing on diverse epidemiologic, experimental, and mechanistic evidence to identify intervention opportunities. We adopt a life-course perspective focused on the brain's plasticity. We focus on critical developmental periods that increase PD vulnerability by rendering dopaminergic neurons more susceptible to damage. Specifically, we examine two key mechanisms: the induction of a pro-inflammatory epigenetic state and mitochondrial dysfunction, frequently triggered by early-life stress, malnutrition, or neurotoxicant exposure. We discuss how these mechanisms can be studied across epidemiologic, experimental, and mechanistic research. Integrated evidence suggests that early adverse exposures may set the stage for higher PD susceptibility. This occurs through epigenetic, neuroimmune programming, and mitochondrial vulnerabilities in dopaminergic systems. In contrast, endogenous neuroplasticity promotes neuroprotection. Long-term physical activity, cognitive training, and enriched environments build strong neurobiological reserves by enhancing neurogenesis, improving synaptic function, and reducing neuroinflammation. A life course perspective shows how factors interact over time to shape neurobiological pathways of vulnerability or resilience to PD. This review synthesizes current mechanistic understanding, identifies preventive strategies, and aims to apply this knowledge to clinical practice and public health policies to reduce the global burden of PD.</p>","PeriodicalId":74291,"journal":{"name":"Neuroprotection","volume":"4 1","pages":"14-29"},"PeriodicalIF":4.1,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147791453","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}