This review examines the immunoregulatory functions of interleukin-10 (IL-10)-secreting regulatory B cells (Bregs), specifically focusing on their potential neuroprotective roles and therapeutic implications for central nervous system (CNS) disorders. We conducted a narrative review of the current literature to evaluate the defining characteristics, mechanisms of action, and functional significance of Bregs. We specifically analyzed their roles in modulating immune responses within the CNS following injury and in neurodegenerative contexts. Bregs are a distinct immunosuppressive B cell subset that operates primarily via IL-10 secretion. Their functions include suppressing pro-inflammatory cytokine production and directing T cell differentiation toward regulatory phenotypes. In CNS pathologies, evidence suggests that Bregs can infiltrate the blood-brain barrier following disruption. Once within the CNS, they exert neuroprotection and enhance neuronal survival, thereby mitigating post-injury inflammation. Bregs are essential to immune regulation with significant, although not fully elucidated, neuroprotective potential. Their ability to modulate CNS makes them viable therapeutic targets for the treatment of brain injuries and neurodegenerative diseases. However, clinical applications must consider the complexities of B-cell biology to avoid compromising immune homeostasis. Further research into Breg mechanisms is vital for developing safe, targeted therapies.
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. 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. 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. 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.
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Despite the World Health Organization's prioritization of familial hypercholesterolemia (FH), its global diagnostic rate remains critically low, leading to inadequate treatment and control, thereby increasing the risk of atherosclerotic cardiovascular disease. This study aimed to investigate the comorbidity burden of FH in China and analyze the differences between familial and general hypercholesterolemia (HC) populations. Using a national medical insurance database from 2013 to 2017 including 13,976 patients with FH and 13,976 matched control patients with HC, we utilized case-control methods to compare the composition ratio, comorbidity rates, medical expenses, and healthcare burden of patients with FH to those of control patients. The FH population had a higher comorbidity rate of more than one cardiometabolic disease (83.7% [11,697/13,976]) compared to the HC group (70.3% [9279/13,976]; χ² = 250.45, p < 0.0001). The rates of coronary heart disease, hypertension, stroke, and diabetes were higher in patients with FH (39.2% [5475/13,976], 71.0% [9925/13,976], 14.2% [1982/13,976], and 31.2% [4363/13,976], respectively) compared to those in the HC group (30.4% [4255/13,976], 61.4% [8587/13,976], 11.5% [1601/13,976], and 28.1% [3923/13,976], respectively; all p < 0.0001). In the 40-49 age group, patients with FH had a significantly higher average number of comorbidities compared to control patients with HC (1.2 vs. 0.9; t  = 15.67, p < 0.0001). Notably, the comorbidity count in patients with FH aged 40-49 years even exceeded that in patients with HC aged 50-59 years. Furthermore, the annual per capita medical cost for patients with FH was significantly higher at 5045.5 Chinese yuan (CNY) compared to 4184.7 CNY for patients with HC (t = 12.54, p < 0.0001). With a large number of patients with dyslipidemia, the type and number of comorbidities significantly impact the healthcare burden. FH presents with earlier onset, more comorbidities, and heavier cardiovascular-related medical burdens than HC. Early identification, intervention, and comprehensive management of comorbidities in the FH population are crucial for neuroprotection and prevention of atherosclerotic cardiovascular disease.
This perspective article delineates the significant role of hypoxic pockets-localized, transient reductions in cerebral oxygenation-and their implications for stroke neuroprotection strategies. It posits that preconditioning and postconditioning, through interventions like isoflurane, exercise, remote limb ischemic conditioning, can mitigate these hypoxic pockets, potentially protecting the brain against ischemic events. These strategies exploit the brain's intrinsic adaptive capabilities to resist ischemic damage, underscoring a novel avenue for enhancing recovery and prevention efforts. The study emphasizes the need for further exploration into optimizing these interventions to harness their full potential in combating stroke's debilitating effects, marking a pivotal shift towards targeted neuroprotective measures focused on cerebral microenvironmental optimization.
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.
Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and multiple sclerosis (MS) involve progressive neuronal loss driven by dysregulated neurotransmission, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Cholesterol metabolism has emerged as a critical factor involved with both central and peripheral dysregulation contributing to pathology. This review synthesizes current evidence on cholesterol's role in neurodegeneration and evaluates the therapeutic potential of statins, which act via cholesterol-dependent and other pleiotropic mechanisms. A PubMed search covering 1985-2025 publications was conducted using terms related to neurodegenerative diseases, statins, cholesterol metabolism, neuroinflammation, oxidative stress, mitochondrial dysfunction, and neuroprotection. Studies were selected to highlight mechanistic insights into cholesterol regulation in the nervous system and clinical data on statin use. Neuronal loss in neurodegeneration is driven by processes including excitotoxicity, inflammation, and mitochondrial dysfunction. Excessive reactive oxygen species activate apoptotic pathways involving BAX, BAK, and p53. Dysregulated cholesterol metabolism is a significant contributor: In AD, the ApoE allele ε4 (ApoE4) links elevated cholesterol to amyloid-β (Aβ) accumulation and cognitive decline; in PD, cholesterol shows mixed effects, with some studies suggesting protection and others linking high levels to α-synuclein aggregation and mitochondrial impairment. In HD reduced cholesterol biosynthesis correlates with neuronal loss, while MS associates with elevated cholesterol and cognitive dysfunction. Statins, widely used cholesterol-lowering agents, reduce Aβ production, enhance its clearance, and improve synaptic function. Beyond lipid lowering, they exert anti-inflammatory, antioxidant, and anti-apoptotic effects. Clinical outcomes remain mixed, with benefits influenced by statin type, dose, treatment duration, disease stage, and patient genetics. Statins show multifaceted neuroprotective potential through cholesterol-dependent and independent pathways. While preclinical data are encouraging, clinical evidence is heterogeneous. Long-term, stratified trials are needed to clarify efficacy, and tailoring therapy to disease-specific mechanisms may offer a viable strategy for mitigating neurodegeneration and enhancing neuronal survival.
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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. 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) (n = 6); 6-hydroxydopamine (6-OHDA) lesion, animals that received an injection of 6-OHDA in the STR (n = 7); l-DOPA/carbidopa, lesioned animals that were treated with l-DOPA/carbidopa from day 13 (D13) to day 30 (D30) after the lesion (n = 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 (n = 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. Compared with 6-OHDA treatment, the combined treatment with BV and l-DOPA/carbidopa significantly improved forelimb motor symmetry (H = 15.16, p = 0.001) and reduced contralateral paw dragging (H = 19.91, p < 0.001). In the corridor test, compared with l-DOPA/carbidopa alone, BV cotreatment increased the retrieval index (H = 16.43, p < 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 (H = 17.48, p < 0.001). 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.
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. 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. 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. 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.
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.
Glial cells, alongside neurons, are the major cells of the central nervous system. More than just supporting neurons, glial cells are vital in central nervous system homeostasis and actively shape neurodegenerative disease mechanisms. They exhibit dual roles in promoting neuroprotection through glutamate clearance, mitochondrial transfer, extracellular vesicle signaling, and remyelination, yet also contributing to excitotoxicity, neuroinflammation, and myelin loss. Recent studies emphasize their therapeutic potential, such as enhancing excitatory amino acid transporters, engineering extracellular vesicles, and boosting oligodendrocyte precursor cell function in combating neurodegeneration. This mini review comments on previous articles published in Neuroprotection alongside others, and discusses how enhancing glial protective roles may serve as novel neuroprotective interventions.
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. 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, n = 9) or vehicle (n = 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 t-tests. Rapamycin significantly reduced infarct volume compared with vehicle (44.77 ± 30.93 mm³ vs. 113.44 ± 60.19 mm³, p = 0.0114) and improved Garcia neurological scores (12.78 ± 1.04 vs. 11.67 ± 0.87, p = 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, p = 0.0002). Rapamycin had no significant effect on CBF, BBB disruption, or edema at 72 h (all p > 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, p = 0.1880). 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.
Ischemic postconditioning (IPostC) has emerged as a promising therapeutic strategy for mitigating ischemia-reperfusion injury in ischemic tissues. However, its neuroprotective potential following thrombectomy in acute ischemic stroke (AIS) remains underexplored in clinical settings. To address this gap, we conducted a review to evaluate the feasibility, clinical relevance, and safety of IPostC in AIS patients. This review is structured in four parts. First, we assess the translational success of IPostC from preclinical research to clinical applications in non-neurological organs. Second, we examine data from animal models of cerebral ischemia, including rodents and canines, to evaluate the potential applicability of IPostC in the brain. Based on an integrated synthesis of these findings, we argue that clinical translation of IPostC for stroke treatment is both feasible and potentially beneficial. Furthermore, by incorporating insights from related endovascular interventions, we refine the proposed IPostC protocol to support safer and more effective clinical implementation. Finally, we introduce a novel in situ neurointerventional IPostC technique and discuss its potential clinical implications.
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.
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. 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: n = 6; EE: n = 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). In SE mice, the inflammatory microglial marker Gal3 and the phagocytic marker CD68 correlated positively with infarct size (r = 0.937, p = 0.006; r = 0.845, p = 0.034, respectively), and the accumulation of myelin debris (r = 0.865, p = 0.026) together with loss of myelin coverage (r = -0.907, p = 0.013) followed lesion-driven trajectories. By contrast, these correlations were absent in EE mice (r = -0.028, p = 0.953; r = 0.671, p= 0.099; r = 0.053, p = 0.910; r = 0.292, p = 0.525) indicating that enrichment attenuated lesion-driven inflammatory responses and myelin damage. Importantly, Gal3 expression correlated specifically with peri-infarct myelin debris (r = 0.82, p = 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 (r = 0.890, p = 0.007; ANCOVA p = 0.039). 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-positive microglia as a potential cellular link to functional recovery.
Stroke remains the leading cause of long-term disability worldwide. Approximately 60% of individuals with chronic ischemic stroke experience persistent upper limb impairment that limits daily activities. The Repair Study aims to evaluate the safety and efficacy of vagus nerve stimulation (VNS) paired with rehabilitation in patients with chronic ischemic stroke in developing countries, including those with severe upper limb dysfunction, thereby generating evidence to support broader global application. It is a multicenter, triple-blinded, randomized controlled trial conducted across 13 centers in China. Up to 99 participants with upper limb motor impairment, 9 months to 10 years post-stroke, will be enrolled. All participants will undergo VNS implantation (Model G115R/G115, PINS Medical, Beijing, China) and be randomized 2:1 by a central randomization system to active stimulation (0.8 mA) or sham stimulation (0 mA) paired with standardized upper limb rehabilitation. The blinded phase includes 6 weeks of clinical therapy (three sessions/week, 90-120 min/session, ≥300 stimulation-movement repetitions) followed by 6 weeks of home-based therapy (30 min/day). Post-unblinding, the active VNS group continues home-based therapy, while the sham group receives 6 weeks of clinic-based therapy. The primary outcome is the between-group difference in Fugl-Meyer Assessment for Upper Extremity scores at the end of 6 weeks of clinical therapy. Secondary outcomes include additional motor, functional, and quality-of-life measures. Safety will be assessed through adverse event monitoring. The Repair Study is a multicenter randomized controlled trial targeting chronic ischemic stroke populations in developing countries. It supplements the existing clinical evidence by enrolling patients with more servere motor dysfunction and being conducted in a developing country. ClinicalTrials.gov: NCT06722677.
The human brain functions as a highly integrated system. Interconnected cellular and molecular networks within this system process sensory information, cognitive functions, and motor responses. The brain also exhibits a remarkable potential for plasticity-driven adaptive learning and memory. Importantly, neuroplasticity serves as a key mechanism of neuroprotection while also enabling the brain to compensate for injury through adaptive structural remodeling. Understanding the brain as a dynamic system requires examining how its components interact to produce adaptive physiological responses and complex behaviors, such as social interactions. Key molecules, such as brain-derived neurotrophic factor (BDNF) and oxytocin (OT), play pivotal roles in maintaining the brain's dynamic complexity and integrative functioning. In this review, we introduce the concept of "neurosocial plasticity", which refers to the brain's ability to adapt both neural circuitry and social behavior through the dynamic interaction between BDNF and OT. This concept highlights how BDNF-OT interactions may support both neural plasticity and the capacity for adaptive social functioning. We then explore how their co-localization, co-expression, and co-regulation may regulate neural and social plasticity, ultimately shaping the brain's adaptability and the development of social behaviors across various contexts.
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.
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