Exp. Neurol. [JOURNAL]
Sun
200 papers
Imbalance of nociceptive homeostasis drives spinal cord injury pain.
Kim J, Lee J, Kwon J … +2 more , Kwon M, Gwak Y
Exp Neurol · 2026 Aug · PMID 41999832 · Publisher ↗
Somatosensory synaptic transmission is an adapting phenomenon according to changes of synaptic environments composed of neurons and glial cells. Synaptic architecture in the spinal dorsal horn well recognizes and identif...
Somatosensory synaptic transmission is an adapting phenomenon according to changes of synaptic environments composed of neurons and glial cells. Synaptic architecture in the spinal dorsal horn well recognizes and identifies sensory modalities, such as nociceptive and non-nociceptive, however, sensory neurons do not identify only single modality, therefore, synaptic transmission is dynamic and phasic events. More importantly, maladaptive synaptic plasticity developed chronically and critically drives the new setup of synaptic environments that results in enhanced or decreased synaptic transmission, which is called loss of synaptic homeostasis or newly developed synaptic homeostasis. Overall, the synaptic homeostasis critically controls distinct painful and non-painful sensory signals from peripheral to the higher nervous system via the discrimination of sensory modality. After neurotrauma, such as spinal cord injury, new set of synaptic environments reveal the tendency of excitatory signaling rather than inhibitory and directly correlated with neuropathic pain-like behaviors (hypersensitivity) with enhanced neuronal activity (hyperexcitability) in the spinal dorsal horn neurons. A newly developed imbalance of excitatory and inhibitory persists rather than returning to normal and contributing to the development of sensorimotor, cognition, motivation, and chronic pain. Taken together, understanding the imbalance between excitatory and inhibitory in synaptic transmission is essential to develop the therapeutic strategy for SCI pathophysiology. In this review, we address the basic mechanism to how SCI leads to the imbalance of excitatory and inhibitory followed by development of new synaptic environments in the injured spinal dorsal horn that results in chronic neuronal hyperexcitability and neuropathic pain.
5,6,7-Trimethoxyflavone protects from ischemic brain injury by attenuating BBB leakage.
Zang X, Sun L, Zhou C … +8 more , Zhang Z, Ji S, Tang H, Xia S, Bao X, Gao S, Dai Y, Xu Y
Exp Neurol · 2026 Aug · PMID 41999831 · Publisher ↗
Ischemic stroke results from occlusion of a cerebral artery. According to current treatment guidelines, thrombolytic therapy and thrombectomy can effectively restore blood flow and salvage surviving neurons. However, isc...
Ischemic stroke results from occlusion of a cerebral artery. According to current treatment guidelines, thrombolytic therapy and thrombectomy can effectively restore blood flow and salvage surviving neurons. However, ischemia-reperfusion injury post-stroke can lead to sustained neural dysfunction and blood-brain barrier (BBB) disruption, initiating an inflammatory cascade. 5,6,7-Trimethoxyflavone (TMF), a newly identified flavonoid with anti-inflammatory properties, has not been fully explored in the context of ischemic diseases or hypoxia-induced injury. In this study, TMF or a vehicle was intravenously administered to adult male C57BL/6 J mice subjected to 60-min middle cerebral artery occlusion (MCAO), followed by intraperitoneal injections 4.5 h after reperfusion and daily for an additional two days. Bulk RNA sequencing was conducted to investigate the molecular mechanisms of TMF in ischemic brain injury. Infarct size, BBB integrity, cerebral endothelial cell structure, and neurobehavioral outcomes were assessed to evaluate the effects of TMF treatment. TMF treatment significantly reduced neuronal death, preserved vascular integrity, decreased immune cell infiltration, inhibited the immune response, and alleviated post-stroke neurological deficits. Mechanistically, TMF mitigated BBB-associated protein loss, disrupted cytokine interactions linked to damage, and exhibited notable anti-inflammatory effects.
SPP1-mediated microglial synaptic engulfment modulates the glial-vascular unit: Mechanistic insights into electroacupuncture for ischemic stroke.
Xu C, Li X, Zhao R … +4 more , Dong J, Wang X, Xia W, Han Y
Exp Neurol · 2026 Aug · PMID 41999830 · Publisher ↗
BACKGROUND: This study aimed to investigate the protective effect of electroacupuncture (EA) on the glial-vascular unit (GVU) in ischemic stroke (IS) by regulating microglial synaptic phagocytosis through secreted phosph...
BACKGROUND: This study aimed to investigate the protective effect of electroacupuncture (EA) on the glial-vascular unit (GVU) in ischemic stroke (IS) by regulating microglial synaptic phagocytosis through secreted phosphoprotein 1 (SPP1). METHODS: This study involved basic and clinical aspects. Clinically, our research used EA and non-EA groups to investigate the effect of EA on the functional improvement of patients with IS. Basic research involved a mouse model and the following experimental groupings: middle cerebral artery occlusion reperfusion (MCAO/R) NC group, MCAO/R shSpp1 group, MCAO/R EA group, and MCAO/R shSpp1 EA group. In the MCAO/R shSpp1 and MCAO/R shSpp1 EA groups, AAV-shSpp1 was injected stereotactically into the ipsilateral temporoparietal cortex (3 μL per mouse). Thirty days later, a mouse model of MCAO/R was constructed for the four groups, including the MCAO/R NC group, and the MCAO/R EA group. After 24 h, the MCAO/R EA group and the MCAO/R shSpp1 EA group underwent EA treatment for two weeks. Following behavioral tests, Super-Resolution Vascular Imaging, and Laser Speckle Contrast Imaging, brain tissues were collected for immunofluorescence, TUNEL staining, transmission electron microscopy (TEM), Quantitative Real-Time PCR (RT-qPCR) and western blotting analysis. RESULTS: Analysis revealed that EA and Spp1 knockdown restored synaptic structure and synaptic protein expression levels, reduced microglial phagocytic events, improved blood-brain barrier integrity, reduced infarct volume, and improved behavioral performance (P<0.5). When EA was combined with Spp1 knockdown, there was no further improvement in any parameter, thus identifying a ceiling effect and suggesting that SPP1 represented the terminal rate-limiting node in the EA protective chain. CONCLUSION: The downregulation of SPP1 replicated the multicellular protective phenotype of EA, establishing SSP1 as a necessary downstream molecule for EA-induced effects and providing a theoretical and experimental basis for the modernization of acupuncture and a multimodal stroke rehabilitation strategy centered on SPP1 that is both interventional and monitorable.
mtHsp70 overexpression enhances neuroprotection through ATF5-dependent UPRmt signaling after traumatic brain injury.
Zhang Y, Jin Y, Han R … +4 more , Shen Y, Wang Z, Sun X, Liu J
Exp Neurol · 2026 Aug · PMID 41999829 · Publisher ↗
Traumatic brain injury (TBI) induces secondary neuronal damage, in which mitochondrial dysfunction plays a central role. Mitochondrial heat shock protein 70 (mtHsp70) is a key mitochondrial chaperone involved in protein...
Traumatic brain injury (TBI) induces secondary neuronal damage, in which mitochondrial dysfunction plays a central role. Mitochondrial heat shock protein 70 (mtHsp70) is a key mitochondrial chaperone involved in protein folding and proteostasis, yet its role in TBI pathology remains unclear. In the present study, we investigated the neuroprotective function of mtHsp70 and its underlying mechanisms using a controlled cortical impact (CCI) mouse model. We found that CCI selectively reduced mtHsp70 levels within mitochondria, accompanied by its cytoplasmic accumulation, while total cellular mtHsp70 expression remained unchanged. Stereotactic AAV-mediated overexpression of mtHsp70 in the cortex significantly reduced neuronal apoptosis, improved motor and cognitive behavioral outcomes, and increased neuronal survival following CCI. In vitro, mtHsp70 overexpression in HT22 cells attenuated H₂O₂-induced neuronal injury, improved mitochondrial respiration (OCR), and reduced mitochondrial protein aggregation. Mechanistically, mtHsp70 overexpression increased the expression of mitochondrial unfolded protein response (UPRmt)-related proteins, including HSP60 and Lonp1, and restored mitochondrial membrane potential. Importantly, ATF5 knockdown attenuated mtHsp70-induced upregulation of UPRmt-associated proteins and diminished mitochondrial respiratory improvement, suggesting that mtHsp70-mediated protection is dependent on ATF5-associated UPRmt signaling. Together, these findings indicate that mitochondrial mtHsp70 deficiency contributes to neuronal injury after CCI, whereas restoration of mtHsp70 improves mitochondrial proteostasis and neuronal survival. Targeting the mtHsp70-UPRmt pathway may represent a potential therapeutic strategy for TBI.
High-intensity interval training and moderate-intensity continuous training improve hippocampal synaptic plasticity in Alzheimer's disease via differential lactylation.
Chen L, Ye Y, Guo X … +12 more , Li R, Xia S, Chen F, Wang S, Cao Y, Hu Z, Qiu Y, Wang L, Chi D, Yang M, Tao J, Liu W
Exp Neurol · 2026 Aug · PMID 41999828 · Publisher ↗
While both high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) are known to benefit physical health, their comparative effects on cognitive function in Alzheimer's disease (AD) remai...
While both high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) are known to benefit physical health, their comparative effects on cognitive function in Alzheimer's disease (AD) remain unclear. Here, using equal number 3.5 months old male (28 ± 2 g) and female (24.0 ± 1.1 g) 5 × FAD transgenic mice, we demonstrate that HIIT and MICT improve AD pathology and cognitive performance, as evidenced by reduced amyloid-β deposition and enhanced hippocampal synaptic plasticity. Both exercise modalities significantly elevated lactate levels in the blood and hippocampus of AD mice. The functional consequences of this increase, however, were not linear. We found that while low lactate (2 mM) universally enhanced excitatory postsynaptic potentials in the hippocampus, high lactate (7 mM) was inhibitory, with no significant effects observed at intermediate concentrations (4 and 6 mM), an effect independent of genotype. To mechanistically link lactate dynamics to functional benefits, we performed lactylation-based proteomics. This revealed that HIIT and MICT differentially modulated protein lactylation-both reduced lactylation of glutamatergic synaptic proteins, but HIIT specifically upregulated lactylation of necroptosis-related proteins (CypA/Cyp40), while MICT downregulated proteasome-related proteins (Psmc1/Psmα7). Our findings suggest that exercise-induced lactate dynamically regulates brain function via protein lactylation, offering a novel therapeutic avenue for AD.
Neuropathological hallmarks during the chronic phase of ischemic stroke in mice and humans.
Khan R, Guzman G, Do T … +10 more , Devlin P, Ahn J, Tan C, Venna VR, Marrelli SP, Koochak H, Di Gesù CM, Flores A, McCullough LD, Ritzel RM
Exp Neurol · 2026 Aug · PMID 41999827 · Publisher ↗
BACKGROUND: Advances in acute stroke care, including endovascular thrombectomy and improved neurocritical management, have increased survival after ischemic stroke. However, stroke remains a leading cause of long-term di...
BACKGROUND: Advances in acute stroke care, including endovascular thrombectomy and improved neurocritical management, have increased survival after ischemic stroke. However, stroke remains a leading cause of long-term disability, with many survivors experiencing persistent neurological and cognitive impairments. The chronic neurological consequences of stroke, particularly its potential to accelerate brain aging, remain poorly understood. METHODS: We examined chronic neurobehavioral changes at 2 and 6 months after middle cerebral artery occlusion in male C57Bl/6 mice. Behavioral assessments included the open field test (OFT), novel object recognition test (NORT), fear conditioning (FC), nesting activity, and tail suspension testing. Transcriptomic profiling was performed using RNA isolated from the ipsilateral hemisphere and flow cytometric analysis was utilized to assess microglial/macrophage phenotypes, and senescent-like phenotypes (SA-βGal and lipofuscin) in stroke mice. Neuropathological evaluation of human brain samples from patients with chronic stroke was performed by immunohistochemistry (IHC) to quantify demyelination (MBP), neuronal apoptosis (TUNEL), and Aβ42. RESULTS: Experimental stroke led to consistent cognitive dysfunction and motor decline up to 6 months after ischemic injury. Histological and flow cytometric analyses revealed a significant increase in hippocampal gliosis, white matter degradation, senescent cell accumulation, and dysregulated microglial function. Histological analysis of postmortem human brains showed marked microgliosis, elevated senescent cell burden and increased amyloid deposition. Transcriptomic analysis demonstrated persistent upregulation of apoptosis-related pathways, microglial activation signatures, and complement cascade components. CONCLUSION: Our findings demonstrate that ischemic stroke induces enduring neurodegenerative-like changes, a maladaptive and non-resolving myeloid/microglial response, and cognitive impairment. These findings support the concept that stroke accelerates brain aging ("inflamm-aging"), characterized by premature cellular senescence, altered microglial states, and ongoing neurodegeneration. Targeting senescence and chronic inflammation may represent promising therapeutic strategies to preserve long-term cognitive health after stroke.
The cannabidiol (CBD): Tetrahydrocanabinol (THC) concentration ratio is critical for neuroprotection and recovery following traumatic brain injury.
Friedman LK, Zeman RJ, Peng H
Exp Neurol · 2026 Aug · PMID 41997410 · Publisher ↗
An optimal ratio of cannabidiol (CBD) to tetrahydrocanabinol (THC) was hypothesized to protect against neuropathological consequences following traumatic brain injury (TBI). Varied CBD:THC extract concentrations were com...
An optimal ratio of cannabidiol (CBD) to tetrahydrocanabinol (THC) was hypothesized to protect against neuropathological consequences following traumatic brain injury (TBI). Varied CBD:THC extract concentrations were compared with hemp CBD lacking THC (CBD). Neurons, glia, and parvalbumin interneurons (PV-INs) were evaluated. Weight loss was observed following high doses of THC dominant cannabis, THC. Neuroscores and vestibulomotor performance were optimally restored with CBD:THC. However, THC dominant treatments resulted in early onset to spontaneous seizures post-TBI. The alternating T-maze showed the CBD group had the highest spontaneous alternation rates whereas TBI + vehicle, CBD, CBD, and THC groups had the lowest. The novel object recognition memory task showed CBD treated animals had the best performance, while TBI or THC treated groups had the worst. The forced swim test (FST) revealed immobility time was highest after TBI and lowest after THC or THC treatment post-TBI. The elevated plus maze (EPM) revealed the CBD group spent the most time in closed arms. Both tests indicate that reduced anxiety was THC dependent. In the absence of TBI, THC treatment resulted in the highest mobility. All combinations resulted in reduced injury post-TBI but CBD and THC afforded the most protection and THC the least. Reduced GFAP labeling was highest with CBD dominant cannabis supporting its neuroprotective role against inflammation. Rescue of diminished bilateral PV-INs was observed within the hippocampus and medial prefrontal cortex (mPFC) with CBD dominant treatment (CBD, CBD) supporting their anticonvulsant effect. Loss of PV-INs with THC dominant treatment supports their proconvulsant effect. Thus, CBD and THC have different beneficial therapeutic effects indicating an optimal concentration ratio is critical for neuropathological therapeutics. SIGNIFICANCE STATEMENT: There is currently no optimal treatment that can prevent behavioral and cellular pathology as well as onset of spontaneous seizures associated with traumatic brain injury (TBI). We hypothesized that an optimal ratio of CBD:THC is required to protect against neuropathological consequences following TBI. Six extracts with varied CBD:THC ratio concentrations were compared with hemp CBD lacking THC. CBD dominant cannabis with critical THC dosing afforded the most neuroprotection and behavioral recovery, whereas THC dominant cannabis stimulated spontaneous seizure onset. CBD and THC had different beneficial therapeutic effects indicating an optimal concentration ratio is critical for neuropathological therapeutics. Absorbable medical carriers will offer delivery treatment options to optimize both short- and long-term drug efficacy relating to neuropathological disorders.
TRPC6-TXNIP-NLRP3 signaling axis is involved in type 2 diabetes-associated cognitive dysfunction and the intervention of ginsenoside Rg1.
Fu Y, Zhu X, Liang H … +7 more , Fan L, Shi Q, Zhang H, Sun X, Wang G, Deng Y, Li W
Exp Neurol · 2026 Aug · PMID 41990909 · Publisher ↗
Type 2 diabetes-associated cognitive dysfunction (TDACD) poses a significant global public health challenge. However, the core molecular mechanisms underlying its pathogenesis remain incompletely understood, and the deve...
Type 2 diabetes-associated cognitive dysfunction (TDACD) poses a significant global public health challenge. However, the core molecular mechanisms underlying its pathogenesis remain incompletely understood, and the development of effective therapeutic interventions continues to face considerable obstacles. Here, we identify the role of the TRPC6-TXNIP-NLRP3 signaling axis in TDACD and to investigate the protective effects and mechanisms of ginsenoside Rg1 against TDACD. T2DM mice exhibited aberrant TRPC6 activation and calcium dyshomeostasis. CHREBP increased nuclear accumulation, and TXNIP upregulate. Ultimately, triggering neuroinflammatory responses and mitochondrial apoptotic. These changes were characterized by upregulation of NLRP3 inflammasome components, increased caspase-3 activity, and cytochrome c release. However, both TRPC6 knockout and Rg1 administration can improve cognitive dysfunction and neuronal damage. In vitro experiments showed that the TRPC6 inhibitor BI749327 can effectively inhibit TRPC6-TXNIP activation, inhibit NLRP3 inflammasome assembly, and reduce neuronal damage and apoptosis, while maintaining intracellular Ca homeostasis and mitochondrial membrane potential. In conclusion, TRPC6-induced calcium overload and the TXNIP-NLRP3 signaling pathway are involved in the development of TDACD. Moreover, the neuroprotective effects of Rg1 against TDACD are associated with inhibition of the TRPC6-TXNIP-NLRP3 signaling axis.
Deep cerebellar stimulation restores chronic motor deficits and loss of GABAergic neurons following sensorimotor cortex surgical brain injury in female rats.
Kim M, Chan HH, Fisher B … +7 more , Bangalore N, Shamah M, Shimeall S, Mandava N, Hogue O, Machado AG, Baker KB
Exp Neurol · 2026 Aug · PMID 41990908 · Publisher ↗
BACKGROUND: Acquired brain injury, whether the result of trauma, stroke, or iatrogenic complications, may cause persistent motor and cognitive deficits with limited effective treatments. Recent studies suggest that deep...
BACKGROUND: Acquired brain injury, whether the result of trauma, stroke, or iatrogenic complications, may cause persistent motor and cognitive deficits with limited effective treatments. Recent studies suggest that deep brain stimulation (DBS) of the lateral cerebellar nucleus (LCN) promotes long-term motor recovery after ischemic stroke and traumatic brain injury. Here, we examined the effect of LCN-DBS on motor recovery, and associated mechanisms, in an aspiration lesion model of surgical brain injury (SBI) in female rats. METHODS: Ten female Long-Evans rats underwent unilateral, catheter-assisted aspiration lesioning of sensorimotor cortex and DBS electrode implantation in the contralesional LCN. Three weeks post-SBI, rats were pseudo-randomly assigned to one of two experimental groups: SBI-sham DBS control (STIM-) and stimulation group (STIM+). The STIM+ group received 30 Hz LCN-DBS for six weeks. Motor performance was assessed pre- and post-SBI, as well as weekly during DBS, using the pasta matrix task, cylinder test, and horizontal ladder rung walking task. An additional five animals served as naïve controls for immunohistochemistry. RESULTS: Three weeks post-SBI, all lesioned animals demonstrated significant motor deficits. After six weeks of LCN-DBS, the STIM+ group demonstrated significant motor improvement compared to STIM- animals. IHC analysis revealed that STIM+ animals exhibited increased GAD67- and PV-positive GABAergic neurons compared to STIM- animals. CONCLUSION: LCN-DBS promotes motor recovery following SBI, potentially by modulating GABAergic neurotransmission in perilesional cortex. These findings further support LCN-DBS as a promising therapeutic intervention for motor rehabilitation following SBI, particularly in female subjects who are underrepresented in neuroscience research.
Altered perivascular diffusion and elevated circulating cell-derived microparticles among individuals with enlarged perivascular spaces in subclinical cerebral small vessel disease.
Hein ZM, Che Mohd Nassir CMN
Exp Neurol · 2026 Aug · PMID 41990907 · Publisher ↗
Enlarged perivascular spaces (ePVS) are increasingly recognized as early markers of cerebral small vessel disease (CSVD), yet their underlying pathophysiology, particularly the role of perivascular fluid dynamics and cir...
Enlarged perivascular spaces (ePVS) are increasingly recognized as early markers of cerebral small vessel disease (CSVD), yet their underlying pathophysiology, particularly the role of perivascular fluid dynamics and circulating vascular biomarkers, remains incompletely understood. This study investigated the relationships between ePVS, glymphatic-related diffusion metrics, circulating microparticles (MPs), and cognitive performance in asymptomatic adults with low-to-moderate cardio-cerebrovascular risk (stratified using QRISK3). Sixty participants underwent 3 T MRI, including diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS), neuropsychological assessment, and quantification of circulating MPs and their subtypes. ePVS were graded using STRIVE-2 criteria. Multivariable regression, mediation analysis with bootstrap resampling, and receiver operating characteristic (ROC) analyses were performed to evaluate associations and diagnostic performance. ePVS were present in 43.3% of participants, all restricted to Grade 1 severity. Individuals with ePVS exhibited significantly lower DTI-ALPS index values and higher QRISK3 scores. Leukocytes and platelet-derived MPs (CD62L+ and CD62P, respectively) and total MPs were elevated in the ePVS group. However, only CD62P MPs were correlated with reduced DTI-ALPS. In multivariable models, ePVS burden and processing speed were independently associated with DTI-ALPS, while CD62P MPs exerted an indirect effect on ePVS via DTI-ALPS, supporting a full mediation pathway. Diagnostic modelling demonstrated excellent discrimination for ePVS using DTI-ALPS alone (AUC >0.92), outperforming demographic variables, QRISK3, and MPs. Together, these findings suggest that platelet-related microvascular activation may be linked to early perivascular dysfunction through alterations in perivascular fluid dynamics, preceding overt white matter injury or cognitive impairment. While DTI-ALPS does not directly measure glymphatic function, it may represent a sensitive imaging correlate of early perivascular pathology relevant to CSVD risk stratification.
Transcranial magneto-acoustical stimulation regulates motor cortex-subthalamic nucleus neural activity to improve motor disorders in a Parkinson's disease mouse model.
Zhang S, An Y, Xu Y … +6 more , Mi J, Lu X, Liu J, Wang Y, Sun J, Xu G
Exp Neurol · 2026 Aug · PMID 41980634 · Publisher ↗
Parkinson's disease (PD) is marked by progressive dopaminergic neurodegeneration and motor circuit dysfunction. Transcranial magneto-acoustical stimulation (TMAS) is a novel non-invasive neuromodulation technique that co...
Parkinson's disease (PD) is marked by progressive dopaminergic neurodegeneration and motor circuit dysfunction. Transcranial magneto-acoustical stimulation (TMAS) is a novel non-invasive neuromodulation technique that combines a static magnetic field with low-intensity focused ultrasound. In this study, we investigated the therapeutic potential of TMAS in a PD mouse model by targeting the primary motor cortex (M1). Using dual-channel fiber photometry and behavioral assessments, we found that TMAS significantly enhanced calcium activity in M1 and suppressed abnormal hyperactivity in the subthalamic nucleus (STh), thereby restoring cortical-subcortical functional balance. TMAS also improved interregional neural synchrony and motor performance in pole, wire hang, and open field tests. Anterograde viral tracing confirmed direct anatomical projections from M1 to STh, supporting circuit-level modulation. Histological analysis showed no structural damage after TMAS, and c-Fos expression increased in M1, indicating cortical activation. Furthermore, TMAS increased TH-positive cell counts, mean optical density, and stained area in the substantia nigra pars compacta (SNc), suggesting an enhancement of TH expression in surviving dopaminergic neurons. These findings suggest that TMAS may represent a safe and effective strategy for restoring motor function in PD, offering promising prospects for non-invasive neuromodulation therapy.
Models of neuroprotection in Parkinson's disease: Exploring cellular, molecular, and microenvironmental targets.
Álvarez-Luquín DD, González-Fernández RR, Ichikawa-Escamilla E … +7 more , Torres-Velasco ME, Martínez-Martínez E, Arce-Sillas A, Juárez-Vaquera VH, Miranda-Narvaez CL, Hernández M, Adalid-Peralta L
Exp Neurol · 2026 Aug · PMID 41967563 · Publisher ↗
Parkinson's disease (PD), the second most common neurodegenerative disorder in the world, is characterized by the chronic and progressive death of dopaminergic neurons. Several intraneuronal mechanisms, as well as microe...
Parkinson's disease (PD), the second most common neurodegenerative disorder in the world, is characterized by the chronic and progressive death of dopaminergic neurons. Several intraneuronal mechanisms, as well as microenvironmental factors, are involved in neurodegeneration. Currently, the care for PD patients is focused on controlling motor symptoms. Designing interventions that help stop neurodegeneration remains a major challenge in PD management. This review analyzes various neuroprotective approaches that could promote neuronal survival. We explore innovative strategies, such as gene therapy, the use of exosomes, microbiome modulation, and vagus nerve stimulation. The study emphasizes that these interventions could prevent cellular damage and potentially restore neuronal function. Furthermore, the study emphasizes the importance of understanding the underlying molecular mechanisms in order to develop combined therapies. The research considers critical factors, such as suppressing neuroinflammation and the role of sex hormones in neuron survival. Thus, this review focuses on the molecular mechanisms of neuroprotective strategies under investigation to aid in developing new therapeutic interventions.
High Theta (4-10 Hz) power as a biomarker of inhibition during epileptogenesis in an animal model of mesial temporal lobe epilepsy.
Lévesque M, Li FR, Wang S … +1 more , Avoli M
Exp Neurol · 2026 Aug · PMID 41967562 · Publisher ↗
Theta oscillations (4-10 Hz) are a prominent electrophysiological feature of the hippocampus and are highly dependent on the activity of interneurons and GABAergic signaling. In mesial temporal lobe epilepsy (MTLE), thet...
Theta oscillations (4-10 Hz) are a prominent electrophysiological feature of the hippocampus and are highly dependent on the activity of interneurons and GABAergic signaling. In mesial temporal lobe epilepsy (MTLE), theta oscillations are disrupted in the hippocampus and extra-hippocampal structures. We studied here the time-sensitive changes of hippocampal theta oscillations during epileptogenesis and whether the ictogenic effects induced by the optogenetic stimulation of hippocampal CaMKII-positive principal cells are mirrored by changes in theta oscillations. CaMKII-ChR2 mice (n = 11) were treated with kainic acid (15 mg/kg, i.p.) and recorded from one day before status epilepticus (SE) to 25 days after. In a subgroup of mice (n = 6), optogenetic stimulation (1 Hz, 180 s ON, 220 s OFF) of CaMKII-positive principal cells was performed for 15 days starting 3 h after SE. In non-stimulated, control mice (n = 5), we found that the power of theta oscillations significantly increased during the latent phase and was then followed by a gradual decrease that marked the transition between the latent and chronic epileptic phases. In stimulated animals (n = 6), power of theta oscillations followed a similar time-sensitive pattern. Our findings suggest that time-sensitive changes in theta power are reliable biomarkers of inhibitory interneuron GABAergic function during epileptogenesis.
TRPV4 exacerbates neurological deficits after traumatic brain injury through the Ca-ROS-pyroptosis signaling axis.
Zhang P, Xing Z, Gao Z … +6 more , Bao S, Chen Z, Lin X, Ni H, Zhuge Q, He Z
Exp Neurol · 2026 Aug · PMID 41966245 · Publisher ↗
OBJECTIVE: Calcium (Ca) overload is a critical driver of secondary injury following traumatic brain injury (TBI). The transient receptor potential vanilloid 4 (TRPV4), a Ca-permeable cation channel pivotal in calcium sig...
OBJECTIVE: Calcium (Ca) overload is a critical driver of secondary injury following traumatic brain injury (TBI). The transient receptor potential vanilloid 4 (TRPV4), a Ca-permeable cation channel pivotal in calcium signaling, may contribute to post-traumatic Ca dysregulation and neuronal damage. This study aimed to elucidate the role of TRPV4 in TBI pathogenesis and its potential mechanism. METHODS: To explore this, we established an in vivo TBI model using controlled cortical impact (CCI) and an in vitro model by mechanically scratching HT22 neuronal cells. TRPV4 expression was modulated through lentivirus infection and adeno-associated virus injection. Subsequently, a series of in vivo and in vitro experiments were conducted to evaluate TRPV4's effect. RESULTS: The expression of TRPV4 was significantly upregulated in neurons following TBI. TRPV4 overexpression markedly increased lesion volume, neurological deficits, and neuronal loss, whereas TRPV4 knockdown mitigated these effects. Furthermore, TRPV4 activation disrupted mitochondrial dynamics and function, promoting neuronal pyroptosis. Mechanistically, TRPV4-mediated Ca influx amplified reactive oxygen species (ROS) production and NF-κB phosphorylation, exacerbating mitochondrial damage and activating pyroptotic signaling pathways. CONCLUSIONS: In conclusion, our findings demonstrate that elevated neuronal TRPV4 expression aggravates secondary brain injury following TBI through the TRPV4-Ca-ROS-pyroptosis signaling axis. These insights underscore TRPV4 as a promising therapeutic target for mitigating TBI-related damage.
Retraction Notice to "Bone marrow stromal cells-derived exosomes reduce neurological damage in traumatic brain injury through the miR-124-3p/p38 MAPK/GLT-1 axis" [Experimental Neurology 365 (2023) 114408].
Zhuang Z, Liu M, Dai Z … +5 more , Luo J, Zhang B, Yu H, Xue J, Xu H
Exp Neurol · 2026 Jul · PMID 41945041 · Publisher ↗
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A refined chronic MPTP/probenecid model of Parkinson's disease in mature adult mice.
Shen Z, Garland B, Mellick GD … +1 more , Ma L
Exp Neurol · 2026 Aug · PMID 41941954 · Publisher ↗
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons, leading to decreased dopamine levels and motor deficits. The neurotoxin 1-methyl-4-phenyl-1,...
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons, leading to decreased dopamine levels and motor deficits. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is frequently used to induce dopaminergic neuron death in mouse models to mimic PD pathology. However, many acute/subacute protocols cause relatively rapid, sometimes partially reversible nigrostriatal injury, rather than slow, progressive neurodegeneration observed in idiopathic PD. While chronic MPTP regimens can better mimic disease progression, the high systemic toxicity of MPTP raises concerns about survival, particularly in mature or aged mice. In this study, we developed a refined chronic low-dose MPTP/probenecid regimen in mature adult C57BL/6 J mice comprising ten injections over five weeks. An initial challenge dose (25 mg/kg) excluded hypersensitive animals (four mice), allowing a subsequent reduced-dose maintenance regimen (20 mg/kg) to achieve 100% survival. Longitudinal assessment revealed a gradual phenotypic decline in treated animals. At two months post-treatment, MPTP/p mice exhibited fragmented locomotor activity, increased grooming, and impaired short-term spatial memory, which progressed to reduced motor endurance and postural instability by four months. Neuropathological evaluation confirmed significant loss of tyrosine hydroxylase-positive neurons and phosphorylated α-synuclein aggregation in the substantia nigra. Collectively, this optimized chronic MPTP/p protocol recapitulates the gradual emergence of motor, cognitive, and neuropathological hallmarks of PD, while maintaining animal survival rate necessary for longitudinal investigation. This model therefore offers a robust platform for therapeutic testing and is particularly well-suited for integration with gene knockout models to elucidate molecular mechanisms underlying PD.
Age- and sex-dependent differences in white matter pathology in the chronic phase of diffuse traumatic brain injury in the mouse.
Michalettos G, Ruscher K, Marklund N
Exp Neurol · 2026 Aug · PMID 41941953 · Publisher ↗
Traumatic brain injury (TBI) is commonly associated with white matter injury, leading to persistent symptoms and long-term disability. While advanced age is linked to worse outcome post-TBI, the influence of sex remains...
Traumatic brain injury (TBI) is commonly associated with white matter injury, leading to persistent symptoms and long-term disability. While advanced age is linked to worse outcome post-TBI, the influence of sex remains highly controversial. The present study aimed to identify age- and sex-dependent differences in white matter pathology during the chronic phase of TBI using the central (midline) fluid percussion injury (cFPI) model. Young (8-12 weeks) and aged (55-78 weeks) male and female mice were subjected to cFPI and end-point analyses were performed at 30 days post-injury (dpi). Histological and immunohistochemical assessments, combined with Western Blot analyses, were employed to evaluate white matter structure and changes in white matter related proteins, respectively. Furthermore, we conducted 5-ethynyl-2-deoxyuridine (EdU) labeling injections during the first week post-injury to assess whether post-injury oligodendrogenesis is related to white matter alterations at 30 dpi. Following TBI, male mice sustained higher ventricular expansion and external capsule atrophy compared to females. These changes were observed in the absence of TBI-induced cortical atrophy at 30 dpi. Regardless of age, male mice exhibited a more pronounced inflammatory response compared to females, characterized by a greater Ionized calcium-binding adaptor molecule 1 (Iba1) coverage and a higher number of Iba1+/EdU+ cells within their white matter tracts. A reduction in myelin basic protein (MBP) levels was evident in both male and female young mice but not in aged groups. When compared to young male mice, young female mice exhibited a distinct neurofilament heavy chain (NF-H) protein phosphorylation pattern, a difference absent in aged mice. Notably, while male mice showed a robust increase in newly generated mature oligodendrocytes within their white matter tracts, TBI did not induce comparable oligodendrogenesis in females. This study highlights sex- and age-related differences in white matter pathophysiology that may explain sex differences in outcomes following TBI.
Selective spinal interneuron activation enhances the hypercapnic ventilatory response in chronic spinal cord injury.
Brezinski AN, Konkel KS, Hodges MR … +2 more , Kurpad S, Satkunendrarajah K
Exp Neurol · 2026 Aug · PMID 41933716 · Publisher ↗
The ability to sense and regulate breathing in response to changes in carbon dioxide (CO₂) levels is vital for maintaining respiratory and systemic homeostasis. Impaired CO chemosensitivity is a common feature of several...
The ability to sense and regulate breathing in response to changes in carbon dioxide (CO₂) levels is vital for maintaining respiratory and systemic homeostasis. Impaired CO chemosensitivity is a common feature of several debilitating conditions, including chronic obstructive pulmonary disease (COPD), central hypoventilation syndromes, and cervical spinal cord injury (cSCI) and contributes to significant respiratory complications such as reduced ventilatory drive, poor gas exchange, and diminished adaptability to metabolic demands. Chronic cSCI disrupts descending respiratory pathways, leading to impaired ventilatory function and, consequently disrupted CO regulation leading to reliance on mechanical ventilation. Currently there are few effective treatments for spinal cord injury induced respiratory dysfunction, particularly in the chronic phase of injury where additional recovery is difficult to elicit. In this study, we investigated whether stimulation of excitatory spinal interneurons (eINs) could enhance respiratory responses to hypercapnia in health and during chronic cSCI. Mid-cervical eINs located in the intermediate lamina were chemogenetically activated via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), and breathing was assessed during CO challenges in awake, unrestrained animals using whole-body plethysmography. Acute stimulation of cervical eINs increased breathing in response to acute respiratory challenges in animals at 8-and 12-weeks post-traumatic cSCI and in uninjured animals. Importantly, this respiratory enhancement occurred without observable affects in non-respiratory motor functions, such as forelimb grip strength, suggesting that the effects of eIN activation were specific to respiratory circuits. Together these findings identify cervical eINs as a promising neuromodulatory target and a promising therapeutic avenue for improving ventilatory function in chronic SCI. More broadly, this approach may offer therapeutic potential for other respiratory conditions characterized by diminished chemosensitivity and ventilatory control, providing a foundation for future translational strategies in respiratory neurorehabilitation.
Altered glucose metabolic pattern in basal ganglia: F-FDG PET/CT semi-quantitative analysis of metabolic signatures in neonatal bilirubin encephalopathy.
Lei J, Yu J, Zheng X … +6 more , Lai X, Chen J, Yang M, Yu M, Wang Y, Tan N
Exp Neurol · 2026 Jul · PMID 41933715 · Publisher ↗
Neonatal bilirubin encephalopathy arises from unconjugated bilirubin deposition in the brain. Conventional tests are limited: serum bilirubin does not reflect intracerebral load, and MRI T1 changes are late and confounde...
Neonatal bilirubin encephalopathy arises from unconjugated bilirubin deposition in the brain. Conventional tests are limited: serum bilirubin does not reflect intracerebral load, and MRI T1 changes are late and confounded by myelination. We evaluated whether F-FDG PET detects early metabolic abnormalities and monitor progression. Twelve Sprague-Dawley rat were randomly assigned to bilirubin-exposed or control groups. The bilirubin-exposed group received intraperitoneal bilirubin from postnatal day 3. F-FDG PET/CT was performed on days 7 and 21, and regional standardized uptake values and cerebellum-normalized SUV ratios were quantified. Serum bilirubin, histology, immunohistochemistry and qRT-PCR were assessed in parallel. The model showed elevated serum bilirubin (p < 0.001) and neuronal injury. On day 7, PET revealed regional hypermetabolism in hippocampus and thalamus (p < 0.01), coinciding with increased IL-6 (cortex, thalamus) and TNF-α (thalamus). By day 21, widespread hypometabolism involved cortex, basal ganglia, hippocampus, thalamus, and brainstem (p < 0.001), with only residual thalamic IL-6. GFAP indicated persistent astrocytic activation, whereas MAP2 and NeuN were largely preserved. The SUV ratio analysis showed a pattern consistent with the SUV-based findings.F-FDG PET detected age-dependent metabolic alterations in bilirubin encephalopathy and may be useful for early detection and longitudinal monitoring.
AngII promotes hippocampal neuron ferroptosis via inhibiting the PPARγ/ACSL3 axis leading to hypertension-related cognitive impairment.
Wu Z, Huo X, Huang Y … +4 more , Gong T, Zhao P, Zhu Y, Zeng Q
Exp Neurol · 2026 Jul · PMID 41933714 · Publisher ↗
Although hypertension (HYP) consistently predicts cognitive decline, the precise pathogenic cascade within the brain remains elusive. Here we interrogated whether the PPARγ/ACSL3 axis governs HYP-elicited hippocampal fer...
Although hypertension (HYP) consistently predicts cognitive decline, the precise pathogenic cascade within the brain remains elusive. Here we interrogated whether the PPARγ/ACSL3 axis governs HYP-elicited hippocampal ferroptosis and consequent cognitive dysfunction. This study aimed to explore the role of the PPARγ/ACSL3 axis in HYP-induced neuronal ferroptosis and cognitive impairment. In the HYP rat model, behavioral tests (Morris water maze and Y-maze tests) demonstrated that rats in the hypertensive group had a significant decline in learning and memory. Mechanistically, the AngII-AT1R axis was found to be activated in the hippocampus, accompanied by typical ultrastructural features of ferroptosis, increased iron accumulation, elevated oxidative stress, and downregulation of PPARγ, ACSL3, and key ferroptosis defense proteins (GPX4, XCT, and FPN1). In vitro, ACSL3 overexpression alleviated AngII-induced neuronal ferroptosis. Furthermore, the PPARγ agonist rosiglitazone attenuated lipid peroxidation and iron overload by transcriptionally upregulating ACSL3, a direct regulatory relationship confirmed by dual-luciferase reporter assay. In conclusion, under hypertensive conditions, BRAS activation inhibits the PPARγ/ACSL3 axis via the AngII-AT1R pathway, aggravates lipid peroxidation and ferroptosis in hippocampal neurons, and ultimately contributes to cognitive decline. This study provides new experimental evidence for the mechanism research and therapeutic target exploration of HYP-related cognitive impairment.
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