Parkinson's disease (PD) is a progressive neurodegenerative disorder clinically characterized by bradykinesia, rest tremor, rigidity, and postural instability. Its core pathological features include the progressive loss of dopaminergic neurons within the substantia nigra pars compacta, striatal dopamine depletion, and intracellular accumulation of misfolded α-Synuclein (α-Syn)-rich Lewy inclusions that trigger neuronal dysfunction and cell death. Despite substantial research efforts, existing pharmacological strategies targeting α-Syn and dopaminergic neurons show limited capacity to halt or reverse PD progression, creating an urgent need for novel alternative therapeutic interventions. Photobiomodulation (PBM) is a non-invasive phototherapy that delivers photonic energy to biological tissues using visible and near-infrared light. Preclinical studies have documented neuroprotective signals linked to PBM in experimental PD models; however, clinical studies to date provide only preliminary and inconsistent evidence regarding safety and possible symptomatic benefit. This narrative review outlines the mechanistic rationale, preclinical findings, clinical observations, and key translational limitations for PBM as an investigational adjunctive intervention in PD. We first elaborate on PD-related pathological mechanisms, followed by an in-depth discussion of PBM-mediated biological actions, and consolidate recent evidence for its anti-PD applications in preclinical settings. Available preclinical data suggest PBM could modulate mitochondrial function, neuroinflammation, dopaminergic-neuron survival, and responses along the microbiota-gut-brain axis in experimental PD models, though direct evidence supporting modification of α-synuclein aggregation or propagation remains sparse. Clinical observations support procedural feasibility and acceptable short-term safety profiles. Nevertheless, definitive clinical efficacy cannot be confirmed given small sample sizes, heterogeneous intervention protocols, and inconsistent outcomes from controlled trials. PBM should currently be regarded as an investigational adjunctive strategy rather than an established therapy for PD.

Remote ischemic preconditioning (RIPC) is an endogenous protective strategy that confers resistance against sustained ischemia-reperfusion injury in distant organs. RIPC induces protective responses through complex neuronal, humoral, and systemic signaling pathways. Increasing evidence suggests that exosomes may serve as important mediators of humoral inter-organ communication during RIPC. Exosomes are small extracellular vesicles released by donor cells that transport biologically active molecules, including lipids, proteins, messenger RNAs, and microRNAs, to recipient cells, thereby modulating cellular responses to injury. Emerging evidence indicates that RIPC-associated exosomes and their molecular cargo contribute to protection against ischemia-reperfusion injury in organs such as the heart, brain, kidney, and spinal cord. Several exosomal molecules, including miRNAs, HSP90, HIF-1α, and NOX2, have been implicated in the regulation of cellular pathways associated with inflammation, oxidative stress, apoptosis, mitochondrial function, and tissue survival. In particular, alterations in exosomal miRNAs and protein and metabolite profiles following RIPC suggest that exosomes may participate in the transmission of protective signals from remote ischemic tissues to target organs. The therapeutic potential of exosomes is further supported by their ability to transport multiple bioactive molecules and their potential application as biomarkers or delivery vehicles for therapeutic cargo. However, the specific exosomal components responsible for RIPC-mediated protection and their causal contribution to inter-organ signaling remain to be fully established. Therefore, the present review summarizes the emerging evidence on the role of exosomes in RIPC-mediated organ protection, with particular emphasis on cardiovascular and cerebral ischemia-reperfusion injury, the molecular cargo involved, underlying protective mechanisms, and their potential therapeutic and translational applications.

Postoperative cognitive dysfunction (POCD) is a common complication after surgery, but its systemic molecular mechanisms remain unclear. Using a murine model combining 2% isoflurane anesthesia and laparotomy, we integrated spatial proteomics (frontal cortex, hippocampus, and hypothalamus), serum proteomics, and serum lipidomics to elucidate the pathophysiology of POCD. POCD mice showed significant behavioral deficits (reduced open field exploration and impaired Morris water maze performance). Proteomics revealed synaptic dysregulation in the frontal cortex (e.g., Sptan1 upregulation) and mitochondrial dysfunction in the hippocampus (e.g., Ogdh downregulation), along with activated MAPK signaling. Serum lipidomics revealed elevated triglyceride and lysophosphatidylcholine (LPC) (22:6) levels and decreased sphingomyelin and ether lipid levels. Integrated pathway analysis revealed neuroinflammation, oxidative stress, and proteostasis disruption. These findings demonstrate that POCD arises from synergistic dysregulation of synaptic integrity, systemic lipid metabolism, and mitochondrial function. Key molecules such as Sptan1 and Ogdh and those with altered TG/LPC (22:6) ratios have emerged as candidate molecules associated with POCD, suggesting potential directions for therapeutic intervention.

Dravet syndrome (DS) is a catastrophic developmental and epileptic encephalopathy caused most often by de novo loss-of-function mutations in SCN1A, the gene encoding the alpha subunit of the voltage-gated sodium channel (Nav1.1). Animal models such as the Scn1a(+/-)tm1Kea mouse display relevant DS phenotypes including sensitivity to hyperthermia-induced seizures and later-life spontaneous seizures. Elevating the body temperature of immature Scn1a(+/-)tm1Kea mice reliably triggers seizures. Typically, researchers evoke only short-lasting seizures by hyperthermia, whereas febrile seizures in DS patients are often prolonged and complex. This study aimed to characterize a more clinically relevant model of hyperthermia-induced seizures in F1.Scn1a(+/-)tm1kea mice and clarify how this affects epilepsy progression, severity, and associated comorbidities in mice of both sexes. A prolonged febrile event (PFE) was achieved by placing P17 pups in a warmed-air stream inside a chamber, with stepped body temperature raising up to 41 °C followed by holding for 30 min, before cooling body temperature to 37 °C. While the PFE procedure induced prolonged and recurrent seizures, bulk cortical Nav1.1 protein abundance remained unchanged across disease progression (P18, P21 and P90). Post-weaning monitoring up to P90 revealed that PFE-exposed F1.Scn1a(+/-)tm1kea mice displayed higher mortality rates and altered survival patterns, with distinct outcomes observed in male and female mice. As adults, PFE-exposed F1.Scn1a(+/-)tm1kea mice displayed increased locomotor and exploratory behavior, whereas PFE-exposed F1.Scn1a(+/+) mice exhibited impaired spatial reference memory. The findings suggest that early-life prolonged hyperthermia-induced seizures influence multiple disease-related phenotypes in this DS model, some of which may exhibit sex-specific differences. The findings extend the range of tools to study DS and provide insights into how a background of prolonged FS may impact later-life outcomes in mice.

Traumatic brain injury (TBI) is one of the leading causes of acquired temporal lobe epilepsy. TBI drives hippocampal circuit rearrangements that may contribute to increased seizure risk, such as altered inhibitory circuit function and aberrant post-traumatic neurogenesis. In the hippocampal dentate gyrus, adult-born dentate granule cells (DGCs) acquire inhibitory synaptic inputs from parvalbumin-expressing (PV) interneurons early in their maturation. PV inputs are important for circuit integration and feedforward inhibition of adult-born DGCs. We used genetically modified mice, retroviral vectors, and optogenetics to study adult-born and mature DGCs after a Controlled Cortical Impact model of TBI. We tested whether TBI altered PV-mediated inhibition of DGCs that were born after TBI. DGCs born after TBI acquired inhibitory synaptic inputs during their maturation, but PV-mediated inhibition of adult-born DGCs was persistently reduced following TBI. In contrast, mature granule cells did not have a reduction in PV-mediated inhibitory synaptic inputs following TBI. The density of PV cells in the dentate gyrus was not different after TBI, therefore functional changes were not due to loss of PV neurons. The deficit in PV-mediated functional innervation of adult-born DGCs was associated with a transient reduction in release probability at these synapses, which normalized as DGCs matured despite ongoing reduction of functional PV input. Surprisingly, although spontaneous inhibitory postsynaptic currents were reduced for mature granule cells after TBI, there was no difference in spontaneous inhibitory postsynaptic currents in adult-born DGCs. Taken together, these data demonstrate distinct differences in the de novo development and maintenance of PV synapses in the dentate gyrus after TBI. The addition of neurons with reduced PV interneuron-mediated feed-forward inhibition to the dentate gyrus could contribute to hippocampal hyperexcitability after severe brain injury.

The ependymal cell layer lining the central canal of the spinal cord forms a key endogenous neural stem cell niche in adult mammals, and enhancing its activity may promote repair following spinal cord injury (SCI). We investigated the independent and combined effects of voluntary free wheel running and PNU-120596 (PNU), a positive allosteric modulator of α7 nicotinic acetylcholine receptors, on functional recovery and endogenous plasticity after chronic thoracic contusion SCI. Four weeks post-injury, female rats received PNU or vehicle, with or without access to running wheels, for six weeks. Free wheel running robustly improved behavioural recovery and sensory function. Partial information decomposition showed that recovery in the combined treatment group was driven mainly by unique contributions from exercise, while kinematic analyses revealed synergistic informational contributions of exercise and PNU on joint coordination and gait symmetry. Exercise predominantly enhanced cell proliferation and glial lineage differentiation caudal to the lesion, while PNU was associated with selective changes rostrally. Recovery was not explained by running distance alone. Specific exercise parameters (bout frequency, duration, and velocity) were associated with behavioural outcomes and biased cell-fate decisions, with running velocity and bout duration linked to astrocytic and oligodendrocytic differentiation, respectively. These findings demonstrate region-specific actions of exercise and cholinergic modulation on functional recovery and endogenous plasticity after chronic SCI. They show that rehabilitation efficacy depends not only on engaging in exercise, but on how exercise is performed and how it interacts with neuro-modulatory state, supporting a minimally invasive strategy for chronic SCI rehabilitation.

Post-traumatic epilepsy (PTE) is a severe complication of traumatic brain injury (TBI). Patients with PTE often experience comorbid neurobehavioral deficits, which further reduce the quality of life and impede the recovery of patients. This review examines behavioral and motor deficits associated with PTE across clinical and preclinical studies, with an emphasis on the need to identify PTE-specific phenotypes that may serve as biomarkers of disease development and progression, as well as distinguish PTE from other forms of epilepsy. Despite growing evidence of post-TBI behavioral and motor abnormalities, their relationship with PTE remains unclear, particularly in preclinical models where direct comparisons are limited between animals that do and do not develop PTE. We further evaluate the application of artificial intelligence (AI) for characterizing these phenotypes throughout post-traumatic epileptogenesis, highlighting its potential to provide automated, objective, and sensitive measures of functional outcomes.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid beta accumulation, Tau hyperphosphorylation, and progressive neuronal injury. DJ-1 participates in regulating neuronal oxidative stress, mitochondrial function, and protein homeostasis, yet whether DJ-1 alleviates AD-like neuronal injury by regulating neurofilament light chain (NEFL) and autophagy remains unclear. This study investigated whether NEFL and autophagic homeostasis contribute to the neuroprotective effects of DJ-1 in AD-like neuronal injury. In aged mice, loss of DJ-1 led to learning and memory impairment, neuronal injury in the hippocampal CA3 region, abnormal APP abundance, and increased Tau phosphorylation, accompanied by decreased hippocampal NEFL expression and autophagic dysfunction. In contrast, DJ-1 overexpression improved AD-like pathological injury in APP/PS1 mice and HT-22 cells treated with Aβ25-35, restored NEFL expression, and alleviated autophagic dysfunction. Immunofluorescence showed overlapping spatial distributions of DJ-1 and NEFL in hippocampal neurons and HT-22 cells. Cycloheximide chase analysis further showed that DJ-1 overexpression slowed NEFL protein decay under Aβ25-35-induced injury. Notably, NEFL knockdown significantly weakened the ability of DJ-1 overexpression to improve AD-like pathological abnormalities and impaired autophagic flux. These findings suggest that NEFL contributes to DJ-1-mediated neuroprotection and autophagic flux regulation in AD-like neuronal injury. These results reveal a functional link among DJ-1, NEFL, and autophagic homeostasis and provide new evidence for understanding the mechanisms underlying DJ-1-mediated neuroprotection in AD-like injury.

Diabetic cognitive dysfunction (DCD) is a severe complication of type 2 diabetes mellitus (T2DM). Ginkgolide B (GB), a primary bioactive terpene lactone of Ginkgo biloba, has proven neuroprotective effects in ischemic stroke, yet its role and underlying mechanisms in DCD remain poorly understood. This study aimed to investigate the protective effects of GB against DCD and to elucidate the underlying mechanisms focusing on the Keap1/Nrf2 pathway. For in vivo experiments, db/db mice and high-fat diet/streptozotocin-induced T2DM mice with AAV-mediated Nrf2 knockdown (sh-Nrf2) or overexpression (OE-Nrf2) were treated with GB. For in vitro studies, HT22 neurons and BV2 microglial cells exposed to high glucose were used to assess the effects of GB. The results showed that GB treatment significantly ameliorated hyperglycemia and lipid metabolic disorders in diabetic mice. Behaviorally, GB reversed deficits in cognitive abilities. At the mechanistic level, GB attenuated hippocampal neuronal loss and restored synaptic plasticity, concomitant with the suppression of oxidative stress and neuroinflammation. These neuroprotective effects were mediated by the inhibition of Keap1, leading to Nrf2 activation and the subsequent downregulation of the NLRP3 inflammasome and NF-κB pathways. Notably, the cognitive benefits and neuroprotective effects of GB were completely abolished in sh-Nrf2 mice, whereas Nrf2 overexpression mimicked GB's effects without further additive benefits. Crucially, Surface-plasmon resonance and molecular docking analyses confirmed a strong direct binding affinity between GB and Keap1. These results indicated that GB alleviates DCD by targeting Keap1 to activate the Nrf2 signaling pathway, subsequently inhibiting oxidative stress and neuroinflammation.

Alzheimer's disease (AD) is associated with hippocampal mitochondrial dysfunction, including impaired mitophagy, biogenesis, dynamics, bioenergetics, and redox homeostasis, which may contribute to amyloid-β (Aβ) accumulation, tau pathology, and cognitive decline. This systematic review examined whether exercise training is associated with changes in hippocampal mitochondrial regulation and cognitive function in transgenic AD rodent models. Following PRISMA 2020 guidelines, PubMed, EMBASE, and Web of Science were searched up to July 2, 2026. Twenty-one studies met inclusion criteria. Exercise modalities included treadmill running, voluntary wheel running, and swimming, with durations from 4 weeks to 8 months. Risk of bias was assessed using the SYRCLE tool. Due to heterogeneity, meta-analysis was not appropriate; a narrative synthesis was performed. Exercise training was associated with changes in markers of mitophagy, biogenesis, dynamics, and function, as well as reduced oxidative stress, decreased Aβ and tau pathology, and improved spatial learning and memory. However, most studies assessed static markers rather than functional flux, and risk of bias was unclear in several domains. The evidence suggests that exercise training may be associated with hippocampal mitochondrial modulation and cognitive benefits in AD models, but conclusions are limited by heterogeneity and incomplete reporting. Further studies with functional mitochondrial assays and clear reporting of methods and results are needed.

Chronic cerebral hypoperfusion is the leading risk factor for the development of vascular dementia and is associated with white matter damage and cognitive impairment. Here, we assessed sex differences in vascular and neural pathology and cognitive impairment in the asymmetric carotid arterial stenosis (ACAS) mouse model of chronic cerebral hypoperfusion. Thirty days of ACAS significantly reduced cerebral blood flow, increased microvascular permeability as evidenced by extravasation of IgG and fibrinogen into brain parenchyma, and impaired MCA vasodilation. ACAS also induced white matter damage in the hippocampus and corpus callosum, with greater damage in the corpus callosum of females compared to males. Spatial memory impairments on the Barnes maze were significantly greater in ACAS males than in females. Finally, miRNA analyses revealed upregulated angiogenic miRNA in the hippocampus and cortex in ACAS females and upregulated neuroinflammatory miRNA in the hippocampus and cortex in ACAS males. Together, these findings indicate that the ACAS model produces robust neuropathology and sex differences in spatial memory and miRNA profiles.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is associated with loss of dopaminergic neurons, mitochondrial dysfunction and disruption of cellular homeostasis. PTEN-induced kinase 1 (PINK1) plays a crucial role in mitochondrial quality control by regulating mitophagy, mitochondrial dynamics, and calcium signaling to maintain neuronal bioenergetic homeostasis. This review critically evaluates the molecular pathways underlying PINK1-mediated mitochondrial integrity and the mechanisms by which loss-of-function mutations contribute to the pathogenesis of PD. Familial early-onset PD is strongly associated with pathogenic PINK1 mutations identified through genetic studies. Therapeutic approaches targeting the PINK1 pathway are examined, including adeno-associated virus (AAV)-based gene delivery, direct small-molecule PINK1 activation (MTK458), and indirect modulation of mitophagy and mitochondrial homeostasis by compounds such as curcumin, resveratrol, cannabidiol, gastrodin, and quercetin. Moreover, the complementary restoration of mitochondrial homeostasis through the modulation of downstream targets, such as transcription factor EB (TFEB) activation and BCL2-interacting protein 3-like (BNIP3L/NIX)-mediated mitophagy, is discussed as an indirect therapeutic strategy. Another important finding is that PD is a biologically and clinically heterogeneous disease that requires biomarker-directed and genotype-stratified therapeutic development. Finally, major translational issues are critically evaluated, including challenges related to blood-brain barrier penetration, target specificity, and long-term safety of mitochondrial modulators.

Secondary injury in cerebrovascular disease involves energy failure, oxidative stress, neuroinflammation, blood-brain barrier disruption and neurovascular unit dysfunction. Novel lysine acylations, including lactylation, succinylation, beta-hydroxybutyrylation and crotonylation, have emerged as interfaces through which metabolic changes in lactate, succinate, ketone bodies and short-chain acyl-CoA species are translated into transcriptional regulation and altered protein function. This review organizes the evidence according to a framework that links metabolic donors, writer and eraser enzymes, modification sites, cell types and disease stages. We distinguish relatively developed experimental evidence in acute ischemic stroke and cerebral ischemia-reperfusion injury from limited findings in haemorrhage and predominantly exploratory evidence in chronic hypoperfusion and vascular cognitive impairment. Proteomic studies have identified 1003 lactylation sites across 469 proteins in rats subjected to cerebral ischemia-reperfusion injury, although most sites have not undergone causal validation. Comparatively strong evidence has accumulated for sites or regulatory axes involving MeCP2, SOD2, NEK7, ACSL4, PLBD1 and ZO-1. Collectively, current findings indicate that the effects of a given acylation cannot be inferred from its global abundance because they depend on substrate function, cellular origin and the therapeutic window. Major limitations include insufficient site-specific causal evidence, difficulty in directly quantifying crosstalk among post-translational modifications, poor correspondence between animal models and clinical heterogeneity and the absence of effective delivery systems and pharmacodynamic biomarkers. Future studies should integrate spatiotemporally resolved multi-omics, endogenous site editing, cell-specific models, measurable target engagement and independent clinical cohorts to evaluate whether selected acylation sites can progress from experimental candidates to independently validated clinical markers or intervention targets.