Exp. Neurol. [JOURNAL]
Sun
200 papers
Isoquercetin-ligustrazine co-polymorph attenuates hypoxia-accelerated Alzheimer's disease by suppressing PERK-CHOP-mediated ER stress.
Long X, Shen R, Yang Y … +8 more , Xu Y, Wang Y, He Y, Xie Y, Xie X, Gao D, Pang X, Du L
Exp Neurol · 2026 May · PMID 42214747 · Publisher ↗
Alzheimer's disease (AD), a neurodegenerative disorder predominantly affecting the elderly population, is frequently associated with hypoxic conditions, including obstructive sleep apnea and other age-related comorbiditi...
Alzheimer's disease (AD), a neurodegenerative disorder predominantly affecting the elderly population, is frequently associated with hypoxic conditions, including obstructive sleep apnea and other age-related comorbidities. Arising from various pathological conditions, chronic hypoxia may contribute to the acceleration of AD progression. However, the precise mechanisms underlying hypoxia-induced cellular stress responses, particularly those involving ER stress and the PERK pathway, remain insufficiently explored. In this study, the therapeutic effects of a co-polymorph combining Isoquercetin and Ligustrazine (ILCP) on AD-related pathologies aggravated by chronic hypoxia were investigated. ApoE3/4 transgenic mice were exposed to hypoxic conditions for four weeks; results on oxidative stress levels, β-amyloid (Aβ) deposition, and neuronal apoptosis were assessed. Chronic hypoxia was found to intensify PERK pathway activity, elevate neuronal damage, and further aggravate AD-associated cognitive deficits. ILCP administration was associated with reduced PERK pathway activation, resulting in reduced oxidative stress, alleviated neuronal damage, and preserved synaptic plasticity. These findings support a role for PERK-CHOP signaling in hypoxia-driven AD pathology and suggest a potential link between ILCP treatment and modulation of this pathway.
Epigenetic histone deacetylase inhibition by sodium butyrate reduces neuroinflammation, improves neurological dysfunction and promotes disease modification of epileptogenesis following traumatic brain injury.
Golub VM, Ramakrishnan S, Reddy DS
Exp Neurol · 2026 May · PMID 42214746 · Publisher ↗
Post-traumatic epilepsy (PTE) is a chronic and debilitating seizure disorder that arises following traumatic brain injury (TBI) and is characterized by persistent neuroinflammation, epigenetic dysregulation, long-term ne...
Post-traumatic epilepsy (PTE) is a chronic and debilitating seizure disorder that arises following traumatic brain injury (TBI) and is characterized by persistent neuroinflammation, epigenetic dysregulation, long-term neurological deficits, and recurrent seizures. Despite its clinical significance, there are currently no effective therapies that halt epileptogenesis and improve functional outcomes after TBI. Targeting epigenetic mechanisms, particularly histone deacetylation, represents a promising therapeutic strategy. Histone deacetylase (HDAC) inhibitors, such as sodium butyrate (SB), modulate gene expression by preserving histone acetylation in neurons and glial cells, thereby influencing gene networks and pathways involved in epileptogenesis. Using a controlled cortical impact model in adult male mice, we evaluated the effects of SB (600 mg/kg for 21 days post-injury) on neuroinflammation, epilepsy development, and long-term behavioral outcomes. Seizure progression and epileptogenic biomarkers were assessed by continuous 24/7 video-EEG monitoring for 4 months and the seizure threshold was assessed by 6-Hz test for 4 months post-injury. SB treatment effectively normalized TBI-induced HDAC hyperactivity, significantly reduced both acute and chronic neuroinflammation, reduced inhibitory interneuron loss, enhanced hippocampal neurogenesis, reduced mossy fiber sprouting and markedly alleviated cognitive and affective neuropsychiatric impairments. Although SB did not alter the overall incidence of PTE, it significantly increased seizure threshold, reduced seizure frequency, and attenuated key epileptogenic biomarkers, indicating a meaningful modification of disease progression. These results support that SB, by targeting injury-induced HDAC hyperactivation during the latent period, interrupts maladaptive epigenetic and neuroinflammatory cascades, thereby reducing progression to chronic epilepsy and neurological dysfunction. Collectively, these findings demonstrate HDAC inhibition as a viable neuroprotective and disease-modifying strategy, offering a promising therapeutic avenue to mitigate epilepsy burden and improve neurological recovery following TBI.
Subplate neurons: potential targets for dysfunction after hypoxic-ischemic brain injury.
Wang Y, Cui H
Exp Neurol · 2026 May · PMID 42214745 · Publisher ↗
Hypoxic-ischemic brain injury (HIBI) is a leading cause of long-term neurological disability in children, often resulting in motor deficits, cognitive impairments, and behavioral abnormalities. Effective curative interve...
Hypoxic-ischemic brain injury (HIBI) is a leading cause of long-term neurological disability in children, often resulting in motor deficits, cognitive impairments, and behavioral abnormalities. Effective curative interventions for hypoxic-ischemic brain injury (HIBI) and its sequelae remain very limited. Recent research suggests that some disabilities are closely linked to the developmental disruption of neural circuits, characterized by aberrant thalamocortical projections, reduced network oscillatory activity, and loss of functional connectivity across brain regions. In this context, subplate neurons (SPNs), a transient but crucial population of "hub" cells during development, play a central role in coordinating neuronal migration and establishing early synaptic networks. Critically, SPNs are highly vulnerable to hypoxic-ischemic (HI) insult. Damage to SPNs not only disrupts the structural integrity of subcortical circuits but also leads to a loss of synchrony in functional networks, positioning them as a key mechanism in HIBI-related neurological dysfunction. This review focuses on the vulnerability of subplate neurons following hypoxia-ischemia and their impact on neural circuitry. Furthermore, we explore potential neuroprotective strategies targeting SPNs, offering new therapeutic perspectives and opportunities for repair to improve outcomes in HIBI.
Human brain slice culture model of STXBP1 encephalopathy reveals disruption of neuronal network activity and changes in gene expression.
McLeod F, Dimtsi A, Savage MA … +4 more , Tan YC, Hedley A, Trevelyan AJ, Clowry GJ
Exp Neurol · 2026 May · PMID 42214744 · Publisher ↗
STXBP1 haploinsufficiency, a major genetic cause of developmental and epileptic encephalopathies, exhibits variability in clinical severity and remains poorly understood mechanistically. Although STXBP1 encodes a core pr...
STXBP1 haploinsufficiency, a major genetic cause of developmental and epileptic encephalopathies, exhibits variability in clinical severity and remains poorly understood mechanistically. Although STXBP1 encodes a core presynaptic protein essential for SNARE-mediated neurotransmitter release, evidence from rodent models and patient-derived neurons indicates that its deficiency produces far broader molecular and cellular disruptions across multiple neurodevelopmental processes. Understanding how these widespread perturbations contribute to STXBP1 encephalopathy requires integrative approaches that extend beyond single-phenotype assays. Here, we used foetal human organotypic cortical cultures that preserve tissue architecture including the transient subplate, a critical hub in early cortical network development. Human cultures (15-18 post-conception weeks) retaining intact subplate, cortical plate, and progenitor zone organisation, were subjected to shRNA-mediated STXBP1 knockdown. We combined live calcium imaging, targeted transcriptomics, protein expression validation, and neurite-growth assays to assess functional and structural outcomes. STXBP1 knockdown disrupted spontaneous subplate neuronal network activity observed by calcium imaging at 14 days in vitro, reducing signal amplitude and synchronicity, indicating impaired early circuit function. Transcriptomic profiling revealed dysregulation of gene expression involved in synaptogenesis, ion transport, and extracellular matrix organisation. Protein-level analyses confirmed alterations in key synaptic components. At the cellular level, neurons exhibited shortened neurites and accumulation of the axon-guidance receptor EPHA4 at growth cones, suggesting defects in early connectivity. These findings expand the mechanistic framework of STXBP1 encephalopathy beyond synaptic dysfunction to encompass coordinated molecular, structural and network-level pathology during a critical window of cortical development, highlighting convergent pathways that may inform early therapeutic strategies.
Evaluation of the neuroprotective effects of ergosterol in a streptozotocin-induced Alzheimer's disease rat model: Insights into anti-inflammatory and antioxidant mechanisms.
Kulkarni R, Kumari S, Sharma P … +3 more , Dhapola R, Medhi B, HariKrishnaReddy D
Exp Neurol · 2026 May · PMID 42208720 · Publisher ↗
Oxidative stress and neuroinflammatory processes constitute pivotal pathogenic mechanisms in the progression of Alzheimer's disease (AD), an age-associated neurodegenerative disorder, as well as in other neurodegenerativ...
Oxidative stress and neuroinflammatory processes constitute pivotal pathogenic mechanisms in the progression of Alzheimer's disease (AD), an age-associated neurodegenerative disorder, as well as in other neurodegenerative conditions. This study is the first to integrate in-silico TLR4-targeted molecular docking of ergosterol with comprehensive in-vivo validation, thereby providing mechanistic insight into its potential role as a neuroprotective agent. The present experimental work aimed to explore the effects of ergosterol (25, 50, and 100 mg/kg body weight) and its combination with the standard drug donepezil, as an antioxidant and anti-inflammatory agent, in a streptozotocin (STZ) induced AD rat model. In silico docking studies were first performed, in which ergosterol and donepezil were docked to the TLR4 receptor (PDB ID: 2Z62). The docking scores of ergosterol and donepezil were - 3.318 and - 3.934, respectively, with MMGBSA ΔG bind scores of -36.9 and - 39.19, ergosterol demonstrated neuroprotective potential with supportive computational evidence suggesting possible TLR4 interaction. RMSD values for both ergosterol-TLR4 and donepezil-TLR4 complexes indicated stable binding interactions. In the in-vivo STZ model, ergosterol administration significantly improved memory and learning impairments, as assessed by the Morris water maze, Novel Object Recognition Test, and Elevated Plus Maze Test. It also reversed changes in glutathione and malondialdehyde levels and showed protective effects in the hippocampus. Moreover, ergosterol ameliorated neuroinflammation by reducing glial cell activation. These findings provide experimental evidence that ergosterol prevents memory loss, learning impairments, oxidative stress, and neuroinflammation in ICV-STZ rats. In conclusion, ergosterol, either alone or in combination with donepezil, may constitute a promising therapeutic strategy against AD through its dual action on oxidative stress and neuroinflammation.
Modulation of CREB signaling contributes to anxiety-like phenotypes in a kindling model of adult zebrafish.
Kumari S, Wlodkowic D, Singh D
Exp Neurol · 2026 May · PMID 42208719 · Publisher ↗
Epilepsy is a chronic neurological condition that is often accompanied by psychiatric comorbidities, including anxiety and social dysfunction. Several animal models of epilepsy exist but they are costly, laborious, and e...
Epilepsy is a chronic neurological condition that is often accompanied by psychiatric comorbidities, including anxiety and social dysfunction. Several animal models of epilepsy exist but they are costly, laborious, and ethically constrained. In this regard, zebrafish (Danio rerio) offer a promising alternative animal model. However, most epilepsy studies have focused on acute seizure models, and long-term paradigms addressing neurobehavioral comorbidities are still lacking in zebrafish. We earlier developed a chronic pentylenetetrazole (PTZ)-induced kindling model in adult zebrafish that showed cognitive deficits. In the present study, we extended the work by investigating psychiatric comorbidities and associated molecular alterations in the previously developed model. Adult zebrafish were repeatedly exposed to 1.25 mM concentration of PTZ until kindling followed by assessment of anxiety and social function deficits. In results, kindled fish showed altered exploration, increased dark preference, and reduced social engagement, indicative of heightened anxiety-like behavior and social deficits. At the molecular level, increased slc25a5 and reduced ppp3r1a, bdnf, vdac3, and prohibitin, as well as significant increase in phosphorylated CREB was observed. The results suggested impaired mitochondrial function and dysregulated synaptic plasticity contributing to the observed behavioral alterations. The current findings support the utility of the chronic PTZ zebrafish model for studying epilepsy-associated psychiatric comorbidities and suggest its potential as a cost-effective platform for mechanistic studies and preclinical therapeutic screening.
Corrigendum to "Aspirin mitigates sepsis-associated encephalopathy by modulating ICAM-1 and MMP-9 signaling: Evidence from clinical cohorts and mechanistic experiments" [Experimental Neurology 403 (2026) 115813].
Cui Y, Lu S, Lv K … +7 more , Zhang H, Pang M, Wang H, Tian X, Chen H, Qiu J, Wang H
Exp Neurol · 2026 Sep · PMID 42203555 · Publisher ↗
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Corrigendum to "Caffeine inhibits hypoxia-induced nuclear accumulation in HIF-1α and promotes neonatal neuronal survival" [Experimental Neurology, 317 (2019) 66-77].
Li HL, Zaghloul N, Ahmed I … +4 more , Omelchenko A, Firestein BL, Huang H, Collins L
Exp Neurol · 2026 Sep · PMID 42191516 · Publisher ↗
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Unwanted axon growth: PTEN and the suppression of axon plasticity in adult nerves.
Eaton S, Komirishetty P, Larouche M … +4 more , Areti A, Ong H, Martinez J, Zochodne DW
Exp Neurol · 2026 May · PMID 42190953 · Publisher ↗
In adults, peripheral nerves comprise bundles of disseminated motor, sensory and autonomic axons that are considered stable neuroanatomical units. The only exceptions to this established wiring are very distal terminal b...
In adults, peripheral nerves comprise bundles of disseminated motor, sensory and autonomic axons that are considered stable neuroanatomical units. The only exceptions to this established wiring are very distal terminal branches in target organs, such as skin. Here we provide a remarkable deviation from this state of affairs in the peripheral nerves of mice with a conditional knockout of sensory neuron PTEN (phosphatase and tensin homolog deleted on chromosome ten). PTEN is normally expressed in adult sensory neurons, particularly small IB4 nonpeptidergic subtypes and its knockdown after injury or during experimental diabetes improves axon regrowth. We studied Advillin Cre;PTEN null mice lacking PTEN in their sensory neurons. Harvested and cultured DRG neurons displayed enhanced neurite outgrowth in vitro. In vivo, these mice were healthy and had a normal sensory behavioural phenotype. However, the nerves of mice lacking sensory neuron PTEN were highly abnormal, with augmented clusters of small myelinated and unmyelinated axons populating endoneurial fascicles of their peripheral nerve trunks. The axon clusters did not disrupt normal fascicular anatomy but invested the epidermis with greater axon numbers. Within endoneurial fascicles, supernumerary axons formed regenerative units and expressed selected growth-related markers, unlike normal adult axons. This was not accompanied by rises in dorsal root ganglia (DRG) neuron numbers, indicating enhanced distal sprouting from parent neurons. Additionally, sprouting axons were electrophysiologically intact, generating rises in the amplitudes of sensory nerve action potentials. Despite this extensive activity resembling active regeneration of intact nerves, regeneration indices after superimposed injury were only modestly enhanced or unchanged. This unusual behaviour of adult sensory axons lacking a single growth-suppressive molecule may identify insights into what molecular constraints the nervous system normally utilizes to suppress inappropriate plasticity.
Targeting neuronal HK2 alleviates glutamate neurotoxicity and MCAO-induced ischemic brain injury.
Chen C, Wu J, Zhu Z … +11 more , Ding Y, Mai F, Hong S, Luo H, Li Y, Chen Y, Lu B, Yan G, Huang Y, Zhou Y, Yin W
Exp Neurol · 2026 May · PMID 42177970 · Publisher ↗
Acute ischemic stroke (AIS) persists as a major cause of death and long-term disability globally. The restricted efficacy of current neuroprotective treatments highlights the importance of identifying novel mechanisms of...
Acute ischemic stroke (AIS) persists as a major cause of death and long-term disability globally. The restricted efficacy of current neuroprotective treatments highlights the importance of identifying novel mechanisms of neuronal injury and therapeutic targets. Hexokinase 2 (HK2) has been shown to promote microglial Interleukin-1β (IL-1β) transcription and astrocytic exosome biogenesis after stroke. However, the role of HK2 in neuronal injury is largely unknown. Here, we found that excitatory glutamate selectively upregulates neuronal HK2 through both transcriptional and ubiquitin-proteasomal pathways. Inhibition of HK2 significantly reduces glutamate-induced neuronal injury. Additionally, knockdown of neuronal HK2 by adeno-associated viruses (AAVs) remarkably improved neurological function and alleviated brain injury following middle cerebral artery occlusion (MCAO) in mice. Further study revealed that suppressing HK2 notably decreases the formation of neuronal autophagosomes in vitro and in vivo. Moreover, HK2 directly interacts with Parkin, a key protein involved in mitophagy. Blocking the interaction between HK2 and Parkin effectively prevents glutamate-induced mitophagy. In conclusion, our findings suggest that neuronal HK2 exerts damaging effects in AIS via its non-metabolic function of promoting mitophagy. Therefore, these results suggest that inhibition of HK2 represents a promising therapeutic approach for neuroprotection.
Transcranial direct current stimulation promotes functional recovery in rats with traumatic brain injury by inhibiting SLC7A11-mediated Disulfidptosis and Neuroinflammation.
You H, Zou Q, Zhu T … +5 more , Li S, Hou Y, Liu C, Yin Y, Sun W
Exp Neurol · 2026 Sep · PMID 42176875 · Publisher ↗
BACKGROUND: Traumatic brain injury (TBI) lacks effective pharmaceutical treatments. While transcranial direct current stimulation (tDCS) shows promise in neurorehabilitation, its potential to mitigate disulfidptosis, a n...
BACKGROUND: Traumatic brain injury (TBI) lacks effective pharmaceutical treatments. While transcranial direct current stimulation (tDCS) shows promise in neurorehabilitation, its potential to mitigate disulfidptosis, a novel cell death mechanism driven by disulfide stress, remains unexplored. OBJECTIVE: This study aimed to investigate whether tDCS facilitates neurofunctional recovery in TBI by modulating SLC7A11-associated disulfidptosis. METHODS: A rat model of TBI was established using controlled cortical impact. Integrated transcriptomic and untargeted metabolomic analyses were performed to identify metabolic and transcriptomic alterations after TBI. Temporal changes in SLC7A11 and NQO1 protein expression were assessed by Western blotting, while NADPH levels, SOD activity, and the NADP/NADPH ratio were measured using biochemical assays on days 1, 3, 7, 14, 21, and 28 post-surgery. Following TBI, rats in the therapeutic efficacy experiment underwent an 8-week anodal tDCS intervention. In the SLC7A11-overexpression experiment, behavioral and molecular assessments were performed after 4 weeks of tDCS treatment. Neurological function was monitored using rotarod, open field, and Y-maze tests at weeks 1, 2, 4, 6, and 8 after intervention. Histopathological damage and apoptosis were assessed by HE staining, Nissl staining, transmission electron microscopy, and TUNEL staining. In addition, neuronal survival, SLC7A11 expression, NQO1 protein expression, oxidative stress, apoptotic markers, and cytoskeletal alterations were evaluated using immunostaining, Western blotting, biochemical assays, and ELISA. To validate the role of SLC7A11, an SLC7A11-overexpressing adenovirus was injected intracerebrally one week before TBI induction, followed by tDCS treatment. Behavioral performance, pathological injury, apoptosis, F-actin expression, IBA1 immunoreactivity, and serum levels of IL-1β, IL-6, and TNF-α were then assessed. RESULTS: Multi-omics analysis revealed significant upregulation of SLC7A11 and enrichment of disulfidptosis-associated metabolic pathways in TBI tissues. Temporally, TBI induced sustained SLC7A11 upregulation, reduced NQO1 expression, decreased NADPH and SOD levels, and increased NADP/NADPH ratios. tDCS intervention significantly ameliorated neurobehavioral deficits, reduced hippocampal and cortical tissue damage, and suppressed oxidative stress and apoptosis. Notably, tDCS preserved NeuN-positive neurons, downregulated SLC7A11, partially restored NQO1 expression, and improved NAD(P)H-associated redox homeostasis. No significant F-actin alteration was detected at the examined time point. Furthermore, SLC7A11 overexpression attenuated the neuroprotective effects of tDCS, impairing behavioral recovery and enhancing neuronal injury, apoptotic signaling, and neuroinflammatory responses. CONCLUSION: tDCS promotes functional recovery in rats with TBI, at least in part, by attenuating SLC7A11-mediated disulfidptosis and neuroinflammation, highlighting a potential therapeutic mechanism for brain injury rehabilitation.
Sex differences in persistent decline in neurological function after modeling repetitive sport-related mild head injuries in young mice.
Schreihofer D, Abad-Jacobi C, Duggal A … +11 more , Kuo A, Vann P, Ahmed A, Metzger D, Oppong-Gyebi A, Mensah-Kane P, Trinh OTP, Zhou Z, Taylor M, Colon-Perez L, Sumien N
Exp Neurol · 2026 Sep · PMID 42176874 · Publisher ↗
Repetitive mild traumatic brain injury (rmTBI) may lead to neurological deficits long after the last injury. However, few studies have examined the persistence of deficits in both sexes. Although women tend to have poore...
Repetitive mild traumatic brain injury (rmTBI) may lead to neurological deficits long after the last injury. However, few studies have examined the persistence of deficits in both sexes. Although women tend to have poorer outcomes than men after concussion, little is known about the cumulative effects of rmTBI during chronic recovery periods. We hypothesized that female mice would display more severe and longer lasting neurological deficits than males following 25 rmTBI over 30 days. Anesthetized mice were subjected to rmTBI using a weight drop model over a trapdoor to provide impact and rotational acceleration. rmTBI was performed 5 days a week for 5 weeks. Mice were assessed starting 5 and 15 weeks following the final injury. A separate pilot study followed male mice for 12 months. Both sexes showed motor deficits 5- and 15-weeks following injury, but only male mice developed affective and cognitive deficits by 15 weeks post injury. These deficits became more pronounced 12 months after injury, supporting a persistent decline long after rmTBI. Sex differences were not readily explained by changes in inflammation in the brain (GFAP, Iba1) that were transient in both sexes and resolved by 15 weeks except for in the optic tract. Diffusion tensor imaging analysis suggests that rmTBI induces disruptions in brain microstructure in several white matter tracts and thalamus that persist for at least 6 months. In contrast to findings in human TBI, female mice appeared to experience better outcomes from rmTBI than males, but the underlying mechanisms remain to be elucidated.
A GPCR atlas across human microglial states in Alzheimer's disease: Insights from snRNA-seq and hiPSC models.
Zhang B, Ran Z, Li XY … +3 more , Wei ZH, Wang DM, Lu MH
Exp Neurol · 2026 Sep · PMID 42173233 · Publisher ↗
Microglia are the resident immune cells of the central nervous system, and their state heterogeneity is closely associated with the pathological progression of Alzheimer's disease (AD). Single-nucleus RNA sequencing (snR...
Microglia are the resident immune cells of the central nervous system, and their state heterogeneity is closely associated with the pathological progression of Alzheimer's disease (AD). Single-nucleus RNA sequencing (snRNA-seq) studies have identified multiple transcriptional states of microglia in human AD brain. However, the characteristics and potential functions of G protein-coupled receptors (GPCRs) across different states remain poorly systematized. This review systematically searched and reviewed snRNA-seq studies based on human brain tissue published between 2020 and 2025. By re-analyzing GPCR expression across these datasets, we focuses on characterizing the differential expression characteristics and potential functions of GPCRs in five key AD-related microglial states: disease-associated microglia, tau-associated microglia, inflammation-associated microglia, proliferation-associated microglia, and interferon-associated microglia. Furthermore, we cross-reference these findings with single-cell sequencing data from human induced pluripotent stem cell (hiPSC)-derived microglia to prioritize a conserved set of GPCRs of high interest. In summary, by integrating transcriptomic evidence from both post-mortem human brain and hiPSC models, this review not only refines the understanding of microglial heterogeneity in AD but also provides a set of candidate GPCR targets for subsequent validation and drug discovery efforts against AD.
Potentiation of GPR68 alleviates post-ischemia BBB dysfunction and brain edema in mice.
Sun W, Fu W, Zhou Y … +2 more , Tiwari V, Zha XM
Exp Neurol · 2026 Sep · PMID 42173232 · Publisher ↗
Ischemia-reperfusion can increase blood-brain barrier (BBB) permeability and extravasation of peripheral molecules. Further damage to BBB results in blood vessel rupture and hemorrhagic transformation (HT). Associated wi...
Ischemia-reperfusion can increase blood-brain barrier (BBB) permeability and extravasation of peripheral molecules. Further damage to BBB results in blood vessel rupture and hemorrhagic transformation (HT). Associated with these processes, brain edema is common. In previous studies, we and others have shown that Ogerin, a small molecule positive modulator of the acid-sensitive GPR68- reduces ischemic brain injury. Here, we asked whether Ogerin attenuates post-ischemia BBB leakage, HT, or edema. To determine HT and edema, we first analyzed the 2,3,5-triphenyltetrazolium chloride (TTC) images from a previous study. In male mice, Ogerin administration reduced both HT severity and brain edema. Ogerin had no significant effect in GPR68-/- mice. Ipsilateral brain tissue exhibited increased mouse IgG and reduced ZO-1 and NeuN, and Ogerin showed a trend of increasing Claudin-5 clustering at cerebral microvessels. In female animals, Ogerin significantly reduced post-stroke edema while showed a trend of reducing HT severity. Combining TTC staining and a sensitive and quantitative fluorescent approach to detect Evans Blue, we examined BBB permeability and brain injury at 72 h. Ogerin reduced brain infarct, edema, and Evans Blue extravasation on day 3 after reperfusion. These results suggest that GPR68 activation may protect against post-tMCAO BBB hyperpermeability, alleviate HT, and reduce brain edema. These findings, together with the earlier observations on brain injury, suggest that pharmacological potentiation of GPR68 is a promising therapeutic intervention for improving post-ischemia outcomes.
Plasma transfusion therapy enhances recovery from traumatic brain injury.
Chang WC, Chen WC, Wu KY … +6 more , Deng SM, Chiang MH, Lee JC, Wei KC, Chen YT, Huang GJ
Exp Neurol · 2026 Sep · PMID 42173231 · Publisher ↗
Traumatic brain injury (TBI) is a leading cause of disability and death worldwide. Despite its significant impact, effective treatments for TBI remain limited, and the resulting damage is largely irreversible. Recently,...
Traumatic brain injury (TBI) is a leading cause of disability and death worldwide. Despite its significant impact, effective treatments for TBI remain limited, and the resulting damage is largely irreversible. Recently, plasma or whole blood transfusion has been demonstrated to enhance neurogenesis, improve cognitive outcomes, and even promote the recovery from ischemic brain injury in mice. Based on these findings, this study aims to investigate whether plasma transfusion also offers benefits in the recovery process following TBI. Our results demonstrate that intravenous plasma transfusion in TBI mice significantly improves sensorimotor functions, reduces perilesional cell death, and preserves axonal projections. Global LC-MS/MS proteomics of the injured cortex further revealed ferroptosis signaling as the most significantly altered pathway, according to Ingenuity Pathway Analysis. Furthermore, different sources of plasma exert varying therapeutic effects, with young plasma, rather than aged or TBI-derived plasma, leading to the most remarkable behavioral improvement. Comparative proteomics analysis of young, aged, and TBI plasma identified thirteen candidate proteins that may be involved in these therapeutic effects. Overall, these findings indicate that plasma transfusion, especially from young healthy donors, improves functional outcomes and alleviates structural brain damage, offering a potential therapeutic strategy for TBI.
A multi-omics atlas reveals spatially resolved sphingolipid metabolic reprogramming after spinal cord injury.
Jiang Z, Wang L, Liu W … +9 more , Huang H, Guo Y, Wang Z, Ouyang J, Huang H, Shen T, Jiang X, Yin W, Ren C
Exp Neurol · 2026 Sep · PMID 42167519 · Publisher ↗
Secondary injury cascades following spinal cord injury (SCI) are closely associated with local metabolic dysregulation and persistent neuroinflammation. However, the spatiotemporal patterns of alterations centered on sph...
Secondary injury cascades following spinal cord injury (SCI) are closely associated with local metabolic dysregulation and persistent neuroinflammation. However, the spatiotemporal patterns of alterations centered on sphingolipid metabolism within the injury microenvironment, as well as their specific regulatory mechanisms in relation to neuroimmune inflammation, remain poorly understood at a systematic level. In this study, we integrated high-throughput lipidomics, spatial transcriptomics, and single-cell RNA sequencing (scRNA-seq) of multiple SCI models, to systematically construct a multidimensional spatiotemporal atlas of sphingolipid metabolism following injury. Lipidomics analysis revealed remodeling of sphingolipid metabolism, characterized by the progressive accumulation of neurotoxic sphingolipid metabolites and the depletion of myelin-associated lipids. Spatial transcriptomics demonstrated that regions of sphingolipid metabolism were strikingly confined to the 'inflammatory infiltration core' and the 'scar interface'. At the single-cell level, microglia were identified as the central cellular mediators of this metabolic reprogramming. Notably, we discovered a distinct microglial subpopulation characterized by high expression of the peroxisomal enzyme Hsd17b4 and the disease-associated marker Spp1, termed the 'high-sphingolipid metabolism' subtype. Pseudotime trajectory analysis indicated that sustained elevation of sphingolipid metabolic activity constitutes a potential determinant that prevents microglia from returning to homeostasis and drives their maladaptive polarization toward a chronic pathological phenotype. Immunofluorescence staining confirmed the specific enrichment of Hsd17b4/Spp1 microglia within the injury core. Our findings demonstrate that sphingolipid metabolism reprogramming in microglia represents a key mechanistic step in the propagation of secondary injury following SCI. These results provide novel theoretical foundations and potential therapeutic targets for modulating the immuno-metabolic microenvironment to promote functional recovery after spinal cord injury.
FTO-mediated m6A demethylation of BCLW mRNA attenuates neuronal ferroptosis after intracerebral hemorrhage.
Ding H, Chen G, Tang J … +7 more , Zhang J, Li H, Liu Y, Li X, Bai L, Lu J, Li H
Exp Neurol · 2026 Sep · PMID 42167518 · Publisher ↗
Intracerebral hemorrhage (ICH) is a devastating stroke subtype associated with high mortality and disability rates, driven by both primary and secondary brain injury, including ferroptosis-an iron-dependent form of regul...
Intracerebral hemorrhage (ICH) is a devastating stroke subtype associated with high mortality and disability rates, driven by both primary and secondary brain injury, including ferroptosis-an iron-dependent form of regulated cell death characterized by lipid peroxidation. Emerging evidence suggests that N6-methyladenosine (m6A) mRNA methylation, a key epigenetic regulator of gene expression, may influence neuronal survival after ICH; however, its role in ferroptosis remains unclear. Here, we demonstrate that ICH induces m6A hypermethylation in striatal neurons, coinciding with downregulation of the m6A demethylase fat mass and obesity-associated protein (FTO). Neuron-specific overexpression of FTO restores m6A homeostasis, attenuates ferroptosis, and preserves mitochondrial integrity. Mechanistically, FTO is associated with B-cell lymphoma-w (BCLW) mRNA, a pro-survival member of the BCL2 family, and reduces its m6A methylation thereby enhancing its translation. Exogenous recombinant BCLW protein exerts neuroprotective effects comparable to those of FTO overexpression, suppressing lipid peroxidation and iron accumulation. Our findings identify the FTO-m6A-BCLW axis as a critical epigenetic regulator of neuronal ferroptosis post-ICH, providing potential therapeutic targets to mitigate secondary brain injury in hemorrhagic stroke.
Attenuation of postoperative cognitive dysfunction by Mongolian medical warm acupuncture associates with suppressed neuroinflammation and preserved synaptic structural plasticity.
Meng M, Wang B, Bai X … +6 more , Baoyin S, An Y, Sheng H, Bao S, Wang T, Wu L
Exp Neurol · 2026 Sep · PMID 42162855 · Publisher ↗
Postoperative cognitive dysfunction (POCD) is a common complication following surgery, characterized by hippocampus-dependent cognitive impairment as its core clinical feature. Mongolian Medical Warm Acupuncture (MMWA),...
Postoperative cognitive dysfunction (POCD) is a common complication following surgery, characterized by hippocampus-dependent cognitive impairment as its core clinical feature. Mongolian Medical Warm Acupuncture (MMWA), a traditional therapeutic modality in Mongolian medicine, has been shown to both inhibit neuroinflammation and positively regulate neuronal migration and synaptic plasticity in various brain injury models. However, systematic evidence remains lacking as to whether these multifaceted effects are coordinated via a core upstream signaling node. MMWA was found to improve behavioral performance (including learning, memory, and spatial recognition) in POCD mice, to attenuate hippocampal neuronal damage, and to suppress pro-inflammatory cytokine levels, thereby mitigating neuroinflammation and delaying disease progression. Through analyses at the protein and transcript levels, combined with immunohistochemical staining and Golgi staining, it was revealed that MMWA restored aberrant synaptic architecture, a finding that coincided with alterations in the synaptic transmission-related protein TENM3 and associated neurotransmitter profiles. To further characterize the signaling events accompanying these phenotypic improvements, the dynamic changes of components within the PI3K/AKT and MAPK/ERK pathways (as identified by proteomic profiling) were examined. Following MMWA treatment, the phosphorylation levels of PI3K and AKT were significantly elevated, whereas the phosphorylation level of MEK was significantly reduced. In conclusion, the present study demonstrates that MMWA attenuates postoperative cognitive decline via suppressing neuroinflammation, restraining microglial activation, and preserving synaptic structural plasticity. These protective effects are accompanied by an upregulation of TENM3 and concurrent alterations in inflammation-associated signaling molecules. These findings identify TENM3 as a previously unrecognized molecular correlate underlying the neuroprotective response to MMWA in the context of POCD.
Spinal cord injury as a window into hippocampal dysfunction: Linking inflammation, neurogenesis, and network oscillations to cognitive decline.
Abroumand Gholami A, Khachatryan LG, Gulnoza R … +5 more , Mortazavi F, Nilufar N, Tahmasebi F, Babaloo H, Davlatov S
Exp Neurol · 2026 Sep · PMID 42150700 · Publisher ↗
The hippocampus, essential for learning, memory, and affective regulation, is increasingly recognized as vulnerable to systemic and remote insults. Spinal cord injury (SCI), traditionally viewed as a motor-sensory disord...
The hippocampus, essential for learning, memory, and affective regulation, is increasingly recognized as vulnerable to systemic and remote insults. Spinal cord injury (SCI), traditionally viewed as a motor-sensory disorder, can trigger widespread neurobiological changes that extend beyond the lesion site and affect distant brain regions, particularly the hippocampus. SCI-induced systemic inflammation, oxidative stress, HPA axis dysregulation, autonomic dysfunction, chronic pain, and disrupted neuroimmune signaling collectively contribute to hippocampal pathology. Preclinical studies reveal a biphasic glial response characterized by early astrocytic and microglial activation followed by chronic pro-inflammatory polarization, sustained cytokine release, and loss of inhibitory checkpoints. Convergent mechanisms, including ER stress, chemokine signaling, cell-cycle re-entry, and α-synuclein accumulation, exacerbate neuronal loss and impair adult neurogenesis. Structural and functional consequences include persistent silent glutamatergic synapses enriched in NR2B-containing NMDA receptors, dendritic atrophy, mitochondrial dysfunction, and reductions in theta and gamma oscillations, all of which are associated with impaired synaptic plasticity and apoptosis. Behaviorally, experimental models consistently demonstrate spatial and recognition memory deficits, together with depression- and anxiety-like phenotypes. Translation to humans remains variable. While structural MRI studies often fail to demonstrate overt hippocampal atrophy, proton MR spectroscopy has revealed reduced hippocampal Glx levels associated with impaired memory performance. Together, these findings position SCI-induced hippocampal dysfunction as a multidimensional process involving neuroinflammation, oxidative stress, impaired neurogenesis, synaptic remodeling, and network disruption. These alterations may substantially contribute to the cognitive, emotional, and memory-related sequelae observed after SCI and identify the hippocampus as an important but often overlooked therapeutic target.
Primary and immortalized microglia exhibit divergent responses to hemoglobin.
Umpornpun KP, Oldham BB, Vekaria HJ … +6 more , Zamorano M, Merchant M, Johnson G, Wang GY, Eskandari R, Miller BA
Exp Neurol · 2026 Sep · PMID 42142646 · Publisher ↗
Microglia are the resident innate immune cells of the central nervous system and play critical roles in normal development and pathology. In hemorrhagic stroke, including neonatal intraventricular hemorrhage (IVH), micro...
Microglia are the resident innate immune cells of the central nervous system and play critical roles in normal development and pathology. In hemorrhagic stroke, including neonatal intraventricular hemorrhage (IVH), microglia are thought to orchestrate the brain's immune response to blood breakdown products such as hemoglobin (Hgb) (Erdei et al., 2020). To better understand the pathology of neuroinflammatory diseases such as IVH, in vitro models, using primary microglia and immortalized microglia such as BV-2 cells, are widely used. However, fundamental differences between these cell types remain poorly characterized. Here, we compare inflammatory, cytotoxic, and metabolic responses of primary rat microglia and BV-2 cells in response to Hgb that is released after IVH. Metabolic profiling demonstrated higher basal metabolic activity and non-mitochondrial respiration indicative of reactive oxygen species production in primary microglia, with adaptive metabolic switching in response to Hgb exposure. In contrast, BV-2 cells exhibited high energy demand and limited metabolic shifts in response to Hgb. Primary microglia exhibited robust tumor necrosis factor alpha (TNF-α) release at low Hgb concentrations, consistent with our prior studies. In contrast, BV-2 cells required higher Hgb concentrations to elicit measurable TNF-α release. Cytotoxicity assessments revealed elevated baseline lactate dehydrogenase (LDH) release in BV-2 cells, whereas higher doses of Hgb were needed to elevate LDH levels in primary microglia. Together, these findings demonstrate critical immunometabolic distinctions between primary and immortalized microglial cells and establish that BV-2 cells do not reliably recapitulate primary microglial responses to blood breakdown products. Researchers using in vitro microglial preparations to study brain hemorrhage must carefully consider these differences when designing experiments, as reliance on BV-2 cells alone risks misrepresenting the neuroinflammatory response to IVH.
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