The scavenger receptor class A (SRA), expressed in astrocytes, plays a critical role in hematoma clearance following intracerebral hemorrhage (ICH). This study employed a three-phase approach-cellular, animal, and clinical-to investigate how the Nrf2-SRA signaling axis modulates astrocyte phenotype and promotes hematoma resolution, with emphasis on its potential clinical relevance.

Aicardi-Goutières syndrome (AGS) is a rare leukodystrophy marked by chronic neuroinflammation, white matter (WM) injury, cerebral vasculopathy with calcifications, and progressive neurological decline. A central feature of AGS is sustained overexpression of interferon-alpha (IFN-α), yet its long-term impact on WM integrity remains poorly understood. To investigate this, we used a transgenic mouse model (GIFN) with astrocyte-specific expression of IFN-α that recapitulates key features of AGS.

Repeated mild traumatic brain injuries (rmTBIs) pose a high risk of developing chronic traumatic encephalopathy (CTE). Since this neurodegenerative disease is diagnosed only post-mortem, new biomarkers for early detection are needed. Although age at injury and biological sex are important factors in many brain pathologies, little is known about their relevance to rmTBI-induced CTE-like consequences. Hence, this study explored how biological sex and age at the time of impact affect progression and changes in biomarker candidates after experimental rmTBI.

The incidence of neurodegenerative diseases (NDs) is gradually increasing with the aging. Non-pharmacological treatments have positive effects on delaying the progression of NDs. While regular exercise is known to benefit patients, the therapeutic potential of whole-body vibration (WBV) remains understudied.

Subarachnoid hemorrhage (SAH) is a severe form of hemorrhagic stroke associated with high morbidity and mortality. There are limited pharmacological treatment options available to prevent or treat secondary neurologic injury after SAH. We have previously shown that the immunomodulatory agent fingolimod (FTY720) reduces early adhesion of leukocytes to pial venules, preserves pial arteriolar dilating function, and improves neurologic outcome in a rodent model of SAH. However, the direct effect on cells residing within the brain is less well understood. We employed the endovascular perforation model of SAH in 6-8-week-old male rats to measure blood-brain barrier damage, downstream pro-inflammatory signaling pathways in microglia and astrocytes, and neuronal cell death. Animals were divided into sham, SAH-vehicle, and SAH-FTY720 groups. The SAH-FTY720 group received a single dose of fingolimod (0.5 mg/kg) intraperitoneally, three hours after surgery to replicate timing in which acute interventions can be administered following SAH. Blood-brain barrier dysfunction was seen in SAH-vehicle animals based on Evans blue extravasation and cerebral water content. Microglia and astrocytes increase expression of nitric oxide synthase after SAH, and microglia in particular upregulate NF-ĸB signaling. These changes are associated with neuronal cell death. Treatment with FTY720 improves blood-brain barrier integrity, inhibits pro-inflammatory signaling within microglia and astrocytes, and decreased neuronal apoptosis in the rat cortex and hippocampus. This data further elucidates proinflammatory and neurotoxic pathways activated within the brain following SAH, and suggests that immunomodulation with FTY720 has a beneficial effect on several pathogenic mechanisms of SAH-associated brain injury.

Repetitive transcranial magnetic stimulation (rTMS) is a promising non-invasive therapy for improving cognition in Alzheimer's disease (AD), but the optimal treatment parameters have yet to be elucidated. One important parameter is the treatment schedule. In this study, we used an established rodent low intensity rTMS stimulation protocol to compare cognitive and biochemical effects of an intensive treatment protocol (daily for 12 days) to a distributed protocol (twice a week for six weeks) in 12-month-old 3xTg-AD mice and B6 controls. We found that both protocols improved object place memory function, but only the distributed protocol improved working memory as measured with the Y-Maze. We did not find any effect of either rTMS protocol on BDNF or amyloid pathology, although these measures correlated well with activity and cognitive performance, suggesting rTMS improvement was independent of these mechanisms. Intensive rTMS increased choline acetyltransferase-positive neurons in the anterior bed nucleus of the stria terminalis (BNST), which may be due to the function of this region in mediating cognitive and limbic circuitry. These results indicate that while both treatment protocols can improve specific aspects of recognition memory, only distributed rTMS improves working memory function, possibly due to causing less cognitive fatigue and physiological stress. Future studies should examine region specific changes relating working memory function and stress related signaling to further understand the mechanisms behind this important rTMS treatment parameter.

Alzheimer's disease (AD) is a disorder characterized by progressive cognitive impairment. Syringic acid (SA) is a phenolic compound with many beneficial effects, such as antioxidant, anti-inflammatory, anti-diabetic, anti-carcinogenic, and neuroprotective. Our study aimed to investigate the effects of SA (50 mg/kg/day) on scopolamine (SCO)-induced AD-like condition in rats. Immunohistochemical evaluation was performed using antibodies to postsynaptic density protein 95 (PSD-95), Glycogen synthase kinase-3β (GSK-3β), TNF-α, and caspase-3. The hippocampus was stained with Hematoxylin-Eosin, and the total number of hippocampal neurons and hippocampal volume were calculated using the stereological method. The Y-maze task behavioral test was performed. SCO decreased PSD-95 expression while increasing GSK-3β, TNF-α, and caspase-3 expression. SA treatment increased PSD-95 expression while decreasing GSK-3β, TNF-α, and caspase-3 expression. Compared to the control group, the number of hippocampal neurons was significantly decreased in the Alzheimer's group, but the number of neurons in the SA group was significantly higher than in the Alzheimer's group. Hippocampal volume was lower in the Alzheimer's group, although there was no statistical difference between the groups. SA also improved SCO-induced cognitive impairment. Our study findings suggest that SA may mitigate SCO-induced cognitive impairment in the AD rat model, modulating PSD-95 and GSK-3β and decreasing neuroinflammation and apoptosis.

Hippocampal metabolic reprogramming from oxidative phosphorylation to glycolysis is a pathological feature in postoperative cognitive dysfunction (POCD). However, the relationship between elevated lactate levels and cognitive deficits following surgical trauma needs to be further illuminated. The lactate dehydrogenase-A (LDHA) inhibitor oxamate (OXA) and the lactate transporter inhibitor α-cyano-4-hydroxycinnamate (4-CIN) were delivered by intraperitoneal administration before POCD modeling. Recombinant adeno-associated virus 9 (AAV9)-Syn to knockdown Synaptosomal-associated protein 25 (SNAP25) was used to investigate whether neuronal-specific SNAP25 ablation blunts OXA-mediated phenotypes. Lactate accumulates in the hippocampus and hippocampal neurons after isoflurane anesthesia and aseptic laparotomy. Both OXA and 4-CIN attenuated cognitive impairment arising from anesthesia and surgery, enhanced SNAP25, PINK1, and LC3B protein, increased dendritic spine density and thickness of the postsynaptic densities, and attenuated pyroptosis-pertinent elements including cleaved caspase-3, N-GSDME, IL-1β and IL-18. SNAP25 knockdown counteracted the favorable effects of OXA on cognitive function, as confirmed by impaired synaptic plasticity, insufficient PINK1-mediated mitophagy, and activation of caspase-3/GSDME-mediated pyroptosis. Our findings suggest that pharmacological inhibition of lactate may be considered as a novel neuroprotective strategy for POCD.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by β-amyloid plaque accumulation, neuroinflammation, and dysregulation of sphingolipid metabolism, mainly manifested as irreversible cognitive decline and memory loss. A key pathological hallmark of AD is neuroinflammation, largely fueled by the persistent stimulation of microglia and subsequent pro-inflammatory cytokine production, which worsens disease development. Calcaratarin D (CalD), a ladanane-type diterpenoid sourced from Hedychium flavum rhizomes, has been reported to exhibit significant anti-inflammatory effects. However, its potential therapeutic benefits in AD remain unknown. Therefore, this research focused on exploring the neuroprotective effects of CalD in AD and elucidating its potential mechanisms. We established a mouse model of AD by targeting delivery of Aβ₁₋₄₂ oligomers to the hippocampus. Behavioral tests showed that CalD significantly improved the memory loss and spatial learning ability of AD mice. Western blotting and immunofluorescence staining further confirmed that CalD effectively reduced Aβ deposition and inhibited the excessive activation of microglia. Network pharmacology analysis found that the mechanism of action of CalD mainly involved inflammatory signaling pathways and sphingolipid metabolism. Subsequently, in vivo and in vitro experiments confirmed that CalD could inhibit the excessive activation of the TLR4/NF-κB/NLRP3 signaling pathway and restore the ceramide homeostasis in AD mice. On this basis, molecular docking and small interfering RNA experiments further clarified that CalD played an anti-inflammatory and regulatory role in sphingolipid metabolism by targeting CERT. In summary, these findings indicate that CalD exerts neuroprotective effects by modulating neuroinflammation and ceramide metabolic dysregulation, suggesting that CalD has therapeutic potential in AD.

Iron overload and oxidative stress significantly contribute to the pathophysiology of postoperative cognitive dysfunction (POCD). Our previous findings demonstrated that transcranial near-infrared (NIR) light alleviates POCD by reducing oxidative stress; however, the underlying mechanism remains unclear. This study aimed to investigate whether NIR light ameliorates ferroptosis following POCD and to identify potential regulatory factors involved in this process.

Cognitive impairment is a common sequela of ischemic stroke, primarily driven by disrupted synaptic structural plasticity in the hippocampus. Although bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) are known to promote synaptic plasticity, their heterogeneous effects across hippocampal subregions and associated regulatory mechanisms remain unclear. In this study, BMSC-EVs were intravenously administered 24 h post-reperfusion in a rat model of transient middle cerebral artery occlusion (tMCAO), with additional injections on days 3, 5, and 7. Behavioral assessments (mNSS, Morris Water Maze, Y-maze) showed significant improvements in neurological and cognitive functions (P < 0.05). Histological observation and analyses revealed differential synaptic remodeling. The dentate gyrus (DG) exhibited the most pronounced response, including a significant increase in spine density beyond sham levels (P < 0.01), a shift towards mature spine morphologies, and enhanced axonal integrity as indicated by NF200 expression (P < 0.001). The CA3 region showed improved neuronal survival (P < 0.05), dendritic complexity, and elevated expression of Syn and PSD-95 (P < 0.01 and P < 0.001, respectively). In contrast, the CA1 region displayed limited structural recovery, despite moderate yet significant increases in Syn and PSD-95 expression (P < 0.001). Mechanistically, BMSC-EVs restored ischemia-induced downregulation of Semaphorin 3G (Sema3G), Neuropilin-2 (Nrp2), and PlexinA4 (P < 0.05 to P < 0.001), suggesting a correlation between BMSC-EVs treatment and activation of the Sema3G-Nrp2/PlexinA4 signaling pathway, which may facilitate neurovascular interactions crucial for synaptic remodeling. In conclusion, this study demonstrates that BMSC-EVs enhance hippocampal synaptic plasticity in a region-distinct manner, with the DG and CA3 regions showing the most robust response. These effects are associated with synaptic protein regulation and the Sema3G-Nrp2/PlexinA4 axis.

The cerebellum has largely remained overlooked for its role in Parkinson's disease (PD). Interrogation of this motor system may reveal innovative targets for therapeutics for PD. Here, we investigate longitudinal changes in spatiospectral dynamics in basal ganglia (BG) and cerebellar nuclei to characterize altered patterns of neural activity in both motor-related brain areas in a rodent model of PD. To do so, we used the unilateral 6-hydroxydopamine (6-OHDA) rat model and recorded local field potentials (LFP) before and during treatment with levodopa and benserazide from three to six weeks post-lesion. Beta oscillations (13-35 Hz) emerged in the ipsilateral striatum of hemiparkinsonian animals at three weeks, whereas beta, theta (4-8 Hz) and alpha (8-12 Hz) oscillations appeared in the DN at six weeks. Levodopa decreased striatal beta oscillations at six weeks post-lesion (p = 0.003) compared to untreated PD animals but did not affect theta oscillations in the striatum and dentate nucleus at this time. These findings suggest that the cerebellum may play a variable role in PD depending on dopamine status: a mirroring/pathologic role during dopamine depletion and a compensatory role during dopamine replacement. This is the first time spectral dynamics in BG and cerebellum have been investigated longitudinally in a PD model, and our findings provide clearer insight regarding the dynamic engagement of the cerebellum during dopamine depletion and replacement therapy. A better understanding about the role of the cerebellum in PD pathophysiology may unmask future targets for therapeutic development.

Growing evidence suggests that network hyperexcitability is a pivotal yet under-recognized pathology linking early Alzheimer's disease (AD) with mesial Temporal Lobe Epilepsy (mTLE). This narrative review synthesises pre-clinical and clinical data showing how disruption of excitation-inhibition balance, driven chiefly by the loss or dysfunction of parvalbumin- and somatostatin-positive GABAergic interneurons (INs), emerges early in AD and fosters subclinical epileptiform activity that hastens cognitive decline. We integrate findings that degeneration of Ventral Tegmental Area dopaminergic projections further destabilises hippocampal circuits by diminishing D2-mediated restraint of pyramidal firing and attenuating anti-inflammatory signalling. Convergent co-pathologies, soluble amyloid-β oligomers, tau mis-localisation, glutamate-dependent excitotoxicity and glia-mediated neuroinflammation amplify IN vulnerability and form a self-reinforcing loop of hyperexcitability, plasticity failure and neurodegeneration. Parallels with mTLE, where similar IN and dopaminergic deficits precipitate seizures, provide a mechanistic framework for interpreting EEG abnormalities and seizure susceptibility in prodromal AD. We critically appraise the therapeutic potential of interventions that restore excitation-inhibition balance or neuromodulatory tone, including interneuron-sparing agents, selective D2-like agonists, transcranial stimulation and anti-inflammatory or anti-excitotoxic strategies. By viewing early AD through a circuit-centric lens that bridges neurodegeneration and Epilepsy, we highlight testable biomarkers, propose stage-specific targets and argue that timely suppression of hyperexcitability could slow progression far upstream of irreversible neuronal loss. Such precision approaches may redefine disease modification by stabilizing vulnerable hippocampal networks before cognitive function is irrevocably compromised.

Burn injuries pose a substantial global health concern, impacting patients both acutely and profoundly in the long term. We elucidate key factors driving burn pathophysiology, moving beyond the initial wound to emphasize the resulting systemic cascade, highlighting the significant, often chronic, impact on multiple organ systems, and focusing on the Central Nervous System (CNS) as a critical mediator and target of pathology. Following the burn, the CNS develops persistent neuroinflammation and engages in detrimental, reciprocal interactions with cardiovascular, immune, endocrine, coagulation, skeletomuscular, and digestive systems, creating vicious cycles that can worsen the outcomes. We conclude with proposed future research directions, and stress the urgent need for integrated, interdisciplinary approaches bridging somatic and cerebral fields to fully comprehend the molecular mechanisms of this multi-organ crosstalk and develop effective therapies targeting the devastating long-term neurological and systemic consequences of burn injury.

This study aims to identify the most optimal rehabilitation strategy for acute ischemic stroke recovery by examining the effects of different mobilization intensities and frequencies, and investigating the underlying mechanisms involving the HIF-1α/PLD2/mTOR signaling pathway.

Ischemic stroke causes significant neuronal DNA damage, but the mechanisms regulating DNA repair remain unclear. This study investigates the role of Ten-eleven translocase 3 (TET3) in DNA damage repair and its potential neuroprotective effects in ischemic stroke. Here we show that the TET3 protein level was significantly increased in the peri-infarct cortex of mice with transient middle cerebral artery occlusion (tMCAO). Knockdown of the TET3 gene significantly worsened neurological deficits and increased infarct volume in tMCAO mice, while TET3 overexpression exhibited the opposite effects and significantly enhanced neuronal DNA damage repair. Mechanistically, SUMO2-specific conjugation of TET3 at lysine residues K1188 and K1397 enhanced its nuclear localization, protein stability, and neuronal 5hmC levels. Furthermore, SUMOylated TET3 effectively reduced DNA damage and improved neurological outcomes following ischemic stroke, whereas a SUMO site-deficient mutant failed to confer these protective effects. Our study reveals a novel mechanism by which SUMOylated TET3 regulates neuronal DNA damage repair in ischemic stroke, strongly suggesting that upregulating TET3 SUMOylation in neurons may provide a promising therapeutic strategy to facilitate stroke recovery.

Deep brain stimulation (DBS) is an effective symptomatic therapy for Parkinson's disease (PD). Although unproven in humans, animal studies suggest that DBS, when applied beyond the acute phase of parkinsonism induction, may be neuroprotective. This study investigated motor responses and neuroprotection resulting from DBS initiated 24 h after induction of dopaminergic terminal loss via intrastriatal injection of 6-hydroxydopamine (6-OHDA) in mice. For that, three groups were analyzed: 6-OHDA/DBS-ON (n = 6) and 6-OHDA/DBS-OFF (n = 8), which received ipsilateral-to-lesion subthalamic nucleus (STN) DBS, implanted immediately after neurotoxin infusion, and Naive (n = 5), without interventions. 6-OHDA/DBS-ON received DBS for 4 days, 3  hours per day. The protocol began on day zero (D0). From D1 to D3, the Cylinder test was conducted. On D4, the Rotarod test was performed immediately before stimulation. Body mass was recorded daily until D4 and again on D7, before euthanasia. Tyrosine Hydroxylase (TH) immunohistochemistry was used to assess nigral neuronal loss and dopaminergic axon density in the striatum. The 6-OHDA/DBS-ON group showed less pronounced body mass loss from D0 to D4: -5.92 % (p = 0.22) vs. -18.04 % in 6-OHDA/DBS-OFF (p = 0.03). Additionally, during the 4 days of the protocol, the 6-OHDA/DBS-ON group exhibited a 3.88-fold superior impaired-limb use (p = 0.006) and a 17.14-fold improvement in Rotarod performance (p = 0.02). At the time of euthanasia (D7), the 6-OHDA/DBS-ON group had 82 % more nigral neurons (p = 0.03) and an 18.8 % higher lesioned/healthy striatal TH+ optical density ratio (p = 0.02). Altogether, the results indicate that early DBS attenuates disease progression and may contribute to neuroprotection in potential future premotor PD diagnosis scenarios.

Huntington's disease is a devastating neuropsychiatric hereditary illness. While progressive in nature, there is evidence suggesting the disease can be positively modified through lifestyle changes. The influence of putative protective factors can be modelled in animal models by enriched environments. As of today, there is a wide array of different implementations of environmental enrichment with little comparative information regarding their respective effects. Aiming to better understand the connection between environmental stimulation and disease progression, we examined behavioural and striatal gene expression changes in female BACHD transgenic rats exposed to either a standard environment or one of two environmental enrichment protocols differing in temporal onset. Our results show striking transgenic effects on phenotype and gene expression. Both glial and neuronal functions and cellular pathways were affected. When exposed to environmental enrichment, both protocols markedly reduced striatal dysregulation, yet some differences were observed between the two designs, thus inviting future studies to further examine the differential effects of specific paradigms. Our findings highlight the promising potential of lifestyle interventions to lighten disease burden of patients and improving their quality of life.

Visual evoked potentials (VEPs) represent an accurate, fast, and cost-effective diagnostic tool to evaluate visual function in multiple sclerosis (MS), and its use in preclinical research can support longitudinal monitoring of treatments effects with implications for translational purposes. Anodal transcranial direct current stimulation (tDCS) and physical exercise (PE) are known to exert neuromodulatory effects on the central nervous system, increasing brain activity, promoting plasticity and remyelination. To improve our understanding of the effects of tDCS and PE on demyelination/remyelination processes and refine its therapeutic use in MS, VEPs were employed to monitor the mouse visual pathway during cuprizone (CPZ) demyelination including before and after therapeutic interventions. In CPZ-fed mice, VEP latency delays were associated with MBP loss in the dorsolateral geniculate nucleus (dLGN) confirming VEP as a biomarker of demyelination in the subcortical visual pathway. Combination of anodal tDCS and PE showed a strong beneficial effect on VEP latency during CPZ demyelination. Both VEP latency and behavioural motor function improvements were stronger after combined protocols, highlighting the potential of this multimodal approach in demyelinating conditions. Differential and synergistic contribution by anodal tDCS and PE was associated with reduced microglia/macrophage levels whilst effects on myelin by the first, and reduced cell death and BDNF protein were driven by the second. VEPs efficiency to detect modulation of visual function by brain stimulation and physical activity, strongly correlated with myelin changes in the visual pathway, providing a potent platform for the translatability of preclinical findings to the clinic.

Stroke is associated with autonomic dysfunction and reduced acetylcholine (ACh), a neurotransmitter critical for cognition. ACh signals in part through the alpha-7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel involved in synaptic plasticity, learning, and memory. Impaired α7nAChR signaling has been linked to heightened neuroinflammation and poor acute stroke recovery. Here, we investigated whether α7nAChR contributes to post-stroke cognitive recovery in young male mice. Wild-type (WT) and α7nAChR knockout (α7nKO) mice underwent 60-min middle cerebral artery occlusion (MCAO). In a pharmacology cohort, the α7nAChR agonist GTS-21 was administered immediately after reperfusion and then daily for 20 days. Cognitive performance was assessed by novel object recognition (day 10), object location (day 20), and Barnes maze and open field testing (day 28). Mass spectrometry at 24 h quantified brain ACh. Flow cytometry at 24 h, 7 days, and 30 days measured microglial and brain F4/80 macrophages. Immunohistochemistry at day 30 evaluated gliosis and neurogenesis. WT mice showed reduced ipsilateral ACh and α7nAChR microglia with increased TNF-α versus sham. Compared with WT, α7nKO mice exhibited greater myeloid infiltration at 24 h, fewer IL-6microglia and F4/80macrophages with impaired STAT3/SOCS3 signaling at day 7, and by day 30, reduced reparative microglia, fewer F4/80 macrophages, greater tissue loss, demyelination, gliosis, reduced SVZ neurogenesis, and impaired cognitive recovery. GTS-21 treatment improved cognition and reduced gliosis, supporting a protective role for α7nAChR activation. In conclusion, α7nAChR signaling supports reparative immune programs and promotes neurorepair after stroke, thereby enhancing long-term cognitive recovery.

Fabry disease (FD) is a rare genetic galactosidase alpha (GLA) gene associated lysosomal disorder caused by alpha-galactosidase A (AGAL) deficiency, leading to sphingolipid (globotriaosylceramide, Gb3) accumulation in multiple tissues. Burning pain due to small fiber neuropathy is an early symptom with great impact on health-related quality of life. The pathophysiological role of Gb3 accumulations in sensory neurons of the dorsal root ganglia is incompletely understood. We have differentiated induced pluripotent stem cells of an isogenic GLA knockout line (p.S364del, hemizygous) and its healthy control into sensory-like neurons to model FD in vitro. We have compared both lines on transcriptional and proteomic level and investigated the effects of AGAL enzyme supplementation. FD sensory neurons showed dysregulation of disease-related pathways, including axon guidance at both RNA and protein level and microfluidic assays revealed shorter neurite length. While AGAL did not restore the transcriptomic state, it reduced Gb3 accumulation and lowered protein ephrin 5 A and glycoprotein M6A level. These findings highlight axon guidance alterations in an isogenic human FD sensory neuron model, with potential implications for early central and peripheral innervation in small fiber neuropathy.