Exp. Neurol. [JOURNAL]
Sun
200 papers
Phosphodiesterase 4 as a therapeutic target in Parkinson's disease recent advances.
Zhong J, Xu J, Xue J … +4 more , Qiu Z, Chen B, Yu X, Lin Z
Exp Neurol · 2026 Jun · PMID 41672368 · Publisher ↗
Parkinson's disease (PD), as a common neurodegenerative disorder, is experiencing a continuously increasing incidence worldwide. Patients not only suffer from core motor dysfunction such as tremors, bradykinesia, and mus...
Parkinson's disease (PD), as a common neurodegenerative disorder, is experiencing a continuously increasing incidence worldwide. Patients not only suffer from core motor dysfunction such as tremors, bradykinesia, and muscle rigidity, but also often present with a series of non-motor symptoms including olfactory decline. Phosphodiesterase 4 (PDE4) plays a crucial role in the complex pathological process of PD. As the main hydrolase regulating the intracellular level of cyclic adenosine monophosphate (cAMP), PDE4 is responsible for dynamically regulating this important second messenger molecule with extensive physiological functions. It is worth noting that the dysregulation of the cAMP signaling pathway has been proven to be closely associated with the occurrence and development of neurodegenerative diseases. We will first outline the molecular structural characteristics of PDE4 and its regional and cell-specific distribution in the central nervous system. The focus will be on the multiple and complex roles of PDE4 and the cAMP signal it regulates in the pathogenesis of PD, covering its regulation of networks such as oxidative stress damage, ferroptosis, and endoplasmic reticulum stress (ERS). This paper explores the theoretical basis and latest experimental evidence for the application of PDE4 inhibitors as potential neuroprotective agents or disease-modifying therapies in the treatment of PD. At the same time, it systematically reviews the improvement strategies such as subtype-selective inhibitors, novel drug delivery systems, and structural optimization in response to the key challenges currently faced in the development of PDE4 inhibitors, such as drug selectivity, central permeability, and side effects. Through a systematic analysis of existing research, it deepens the understanding of the regulatory network of PDE4 in PD and provides theoretical basis and forward-looking perspectives for the future development of efficient and safe targeted PDE4 therapeutic drugs and the exploration of new strategies for early prevention and disease process intervention in PD.
DLK inhibition has sex-specific effects on neuroprotection and locomotor recovery after spinal cord injury.
Aldrich JC, Alman SM, Lee SE … +8 more , Scheinfeld AR, Zhang CC, Pike AL, Bremner FC, Calderon O, Goodwani S, Ray WJ, Gaudet AD
Exp Neurol · 2026 May · PMID 41667048 · Full text
Spinal cord injury (SCI) causes devastating functional deficits, in part due to neuroinflammation, oxidative stress, and excitotoxicity that drive death of lesion-adjacent viable neurons. Dual leucine zipper kinase (DLK)...
Spinal cord injury (SCI) causes devastating functional deficits, in part due to neuroinflammation, oxidative stress, and excitotoxicity that drive death of lesion-adjacent viable neurons. Dual leucine zipper kinase (DLK) is a neuron-enriched kinase that responds to cellular stress by activating the c-Jun N-terminal kinase (JNK) pathway, driving both stress-responsive gene expression and neuronal apoptosis. We hypothesized that SCI would robustly activate DLK signaling and that acute pharmacological inhibition of DLK would suppress JNK pathway activation, thereby enhancing neuroprotection and locomotor recovery in our mouse model of moderate contusion SCI. Using western blotting, we observed that SCI induced strong and sustained activation of the JNK pathway in the injured spinal cord starting at 4 h post-injury through 7 days. Complementary analysis of single-nucleus RNA-seq revealed that DLK expression is highly enriched in neurons across all injury phases. Following SCI, neurons exhibited robust, time-dependent upregulation of multiple DLK-responsive transcripts, consistent with sustained pathway activation during the acute and subacute periods. Systemic treatment with the selective DLK inhibitor IACS-52825 effectively suppressed intraspinal JUN activation in a dose-dependent manner. However, unexpectedly, treatment delayed functional recovery and expanded lesion volume by 71% in male mice with no significant effect in females. These findings highlight the complex roles of DLK signaling after SCI, revealing a need to understand the sex-specific molecular mechanisms that modulate injury outcomes. Future studies should further optimize timing, location, and cellular targeting of DLK therapeutic strategies to improve neuroprotection and neurologic recovery after SCI.
Dendritic spine dysgenesis in spinal cord injury: A structural contributor to pain and spasticity.
Kauer SD, Effraim PR, Bangalore L … +2 more , Waxman SG, Tan AM
Exp Neurol · 2026 May · PMID 41654287 · Publisher ↗
Pain and spasticity are common consequences of spinal cord injury (SCI) that profoundly diminish quality of life. Although pain arises from sensory pathways and spasticity from motor pathways, both reflect post-injury me...
Pain and spasticity are common consequences of spinal cord injury (SCI) that profoundly diminish quality of life. Although pain arises from sensory pathways and spasticity from motor pathways, both reflect post-injury mechanisms that renders spinal circuits hyperexcitable. Dendritic spines-specialized protrusions on neuronal dendrites that mediate excitatory synaptic transmission-undergo striking structural remodeling after SCI. Abnormal spine morphology has been documented in both the superficial and deeper laminae of the dorsal horn, correlating with pain, and on motor neurons in the lumbar spinal cord after, correlating with spasticity. These abnormalities include: (i) increased spine density, (ii) redistribution of spines closer to the soma, and (iii) enlargement of spine heads. A growing body of evidence implicates dysregulation of the Rac1-PAK1 signaling pathway in driving these changes, and pharmacologic inhibition of this pathway can reverse these dendritic spine dysgeneses and attenuate circuit hyperexcitability in preclinical models. This review examines dendritic spine pathology as a shared mechanistic substrate linking pain and spasticity after SCI and highlights dendritic spines and their regulatory pathways a promising therapeutic target for intervention.
Neuropathic pain after spinal cord injury: Mechanisms, animal models and pain assessments.
Tao Z, Zhou X, Jin L … +5 more , Xu N, Cao Y, Wu Z, Jiang C, Chen Z
Exp Neurol · 2026 May · PMID 41651207 · Publisher ↗
Neuropathic pain after spinal cord injury (SCI-NP) often has lifelong and significant negative effects. Therefore, understanding its underlying mechanisms is a current research priority. SCI-NP involves central sensitiza...
Neuropathic pain after spinal cord injury (SCI-NP) often has lifelong and significant negative effects. Therefore, understanding its underlying mechanisms is a current research priority. SCI-NP involves central sensitization, neuroinflammation and functional remodeling in the brain, hyperexcitability of primary sensory neurons, and peripheral-central interactions. The mechanism of SCI-NP at the spinal cord level is an important one to study. Glial cell activation and proinflammatory pathways in the spinal cord are the key drivers that lead to central sensitization at the spinal cord level, and they constitute the main mechanisms of current research. However, the mechanism of SCI-NP remains unclear, mainly because of the lack of standardized and uniform animal models in preclinical studies. Animal models provide a basis for the mechanistic study of SCI-NP, but the stability and repeatability of these models pose problems. Behavioral evaluation of animal models of SCI-NP has focused on mechanical and heat-induced pain thresholds, but this phenotype is different from the clinical diagnostic criteria of SCI-NP in patients, which includes at least four positive signs according to the DN4 scale. Electrophysiological recordings, especially from spinal dorsal horn neurons and dorsal root ganglia neurons, provide important support for SCI-NP research. In summary, the development of SCI-NP involves a complex pathological process, and its mechanisms remain incompletely understood. Existing models and detection methods require refinement. This review focuses on the research progress in this field and looks forward to future research directions.
Monocyte-derived macrophages promote retinal damage after ischemic stroke via IL-1β-dependent mechanism.
Lin HB, Zhang JY, Li M … +6 more , Pang XX, Shi ZR, Li K, Cao XL, Li F, Zhang HF
Exp Neurol · 2026 May · PMID 41621472 · Publisher ↗
Vision impairment following ischemic stroke is a prevalent complication that significantly compromises patients' quality of life. Inflammatory responses critically contribute to retinal dysfunction in this condition. Ret...
Vision impairment following ischemic stroke is a prevalent complication that significantly compromises patients' quality of life. Inflammatory responses critically contribute to retinal dysfunction in this condition. Retinal myeloid cells contributed to the retinal inflammatory response, which presented heterogeneity after retinal injury. In this study, we employed the classical middle cerebral artery occlusion (MCAO) mouse model to simulate ischemic stroke. We demonstrated that stroke-induced retinal damage manifests as diminished photoreceptor responses and increased retinal cell apoptosis by using electroretinogram, TdT-mediated dUTP Nick-End Labeling and hematoxylin-eosin staining. Furthermore, we observed myeloid cell infiltration into the retina post-stroke and retinal inflammatory activation after stroke via immunofluorescence staining, retinal bulk RNA sequencing and luminex assay. Through retinal single-cell RNA sequencing, Cx3cr1Ccr2 reporter mice and CCL2 neutralizing antibodies interventions, we observed that infiltrating monocyte-derived macrophages expand and exhibit a predominantly pro-inflammatory phenotype in the retina following stroke. Subsequent experiments utilizing IL-1β neutralizing antibodies and Nlrp3-deficient mice established that IL-1β derived from monocyte-derived macrophages promotes ischemic stroke-induced retinal damage. Collectively, our findings demonstrate that monocyte-derived macrophages drive retinal pathology after ischemic stroke via IL-1β-dependent mechanisms.
The crosstalk between chaperone-mediated autophagy and apoptosis via ATM/p53-mitochondria-dependent signaling contributed to ischemia-induced cerebral injuries.
Hu Q, Wang Y, Fan J … +3 more , Hou X, Zhou Y, Yin Y
Exp Neurol · 2026 May · PMID 41620198 · Publisher ↗
Stroke is the second leading cause of death and a leading cause of disability worldwide. Neuronal loss is a significant factor in determining the outcome of ischemic stroke. However, there is no effective treatment for n...
Stroke is the second leading cause of death and a leading cause of disability worldwide. Neuronal loss is a significant factor in determining the outcome of ischemic stroke. However, there is no effective treatment for neuronal loss caused by stroke. This study found that acute ischemia upregulated chaperone-mediated autophagy (CMA) levels in both in vivo and in vitro models. Further, it was observed that inhibition of CMA with pharmacological intervention or LAMP2A knockdown (KD) ameliorated neuronal loss induced by acute ischemia. In addition, inhibition of CMA before or upon acute ischemia can significantly reduce the infarct size and restore neurological function, indicating that a CMA-targeted strategy may facilitate the outcomes of acute ischemic stroke. Notably, pharmacological intervention for CMA under normoxia conditions did not significantly affect neuronal survival. Meanwhile, intervention to CMA upregulation upon the acute ischemia may prevent the decreased CMA in the recovery stage of cerebral ischemia. Moreover, since mitochondrial dysfunction plays a vital role in the initiation and activation of apoptosis, the role of CMA in neuronal mitochondrial function was observed with MitoSOX and TMRM staining. It was found that CMA upregulation contributed to oxygen-glucose deprivation (OGD)-induced mitochondrial injuries. Based on the reported association between ataxia telangiectasia mutated (ATM)-mitochondria signaling and p53 in the occurrence of apoptosis, the activation of p53 was evidenced as the downstream event of the ATM-mitochondria signaling and played a vital role in apoptosis upon OGD. Our current study indicates that there is crosstalk between autophagy and apoptosis. These findings highlight the critical role of CMA in the outcomes of ischemic stroke and implicate its potential application in stroke therapy.
Long-term continuous theta burst stimulation ameliorates L-DOPA-induced dyskinesia in Parkinsonian rats through modulation of the cerebello-thalamo-striatal circuit.
Wang L, Wang Y, Yang S … +7 more , Bai Y, Wu X, Sun Q, Hui Y, Li L, Qiao H, Zhang Q
Exp Neurol · 2026 May · PMID 41620197 · Publisher ↗
Levodopa-induced dyskinesia (LID) is a debilitating complication of Parkinson's disease therapy. Emerging evidence suggests that the cerebellum is involved via cerebello -thalamo-striatal pathways.We first performed dual...
Levodopa-induced dyskinesia (LID) is a debilitating complication of Parkinson's disease therapy. Emerging evidence suggests that the cerebellum is involved via cerebello -thalamo-striatal pathways.We first performed dual viral tracing to confirm cerebello-thalamo-striatal connectivity in a unilateral 6- hydroxydopamine rat model of LID. We then compared the efficacy of two cerebellar continuous theta burst stimulation (cTBS) protocols: a 2block protocol (14 days) and an intensified 3block protocol (10 days). Behavioral outcomes were assessed using the abnormal involuntary movement scale (AIMs). Local field potentials were recorded from the cerebellar dentate nucleus (DN) to characterize oscillatory variations. Striatal FosB expression was quantified as the molecular endpoint. Viral tracing confirmed the anatomical connectivity from the DN to the dorsolateral striatum via the parafascicular thalamus. Both the two protocols alleviated orolingual dyskinesia, with the 3block cTBS protocol demonstrated superior therapeutic efficacy (p < 0.001). Electrophysiological analysis revealed that LID was associated with reduced δ-band power and enhanced low-γ power in DN. Notably, cTBS normalized these aberrant oscillatory patterns by increasing δ power and decreasing pathological low-γ activity. The magnitude of δ power was negatively correlated with orolingual AIMs scores (r = -0.467, p = 0.021), whereas low-γ power was positively correlated with total dyskinesia severity (r = 0.551, p = 0.005) and orolingual AIMs scores (r = 0.581, p = 0.003). At the molecular level, cTBS normalized pathologically elevated striatal FosB expression in LID rats (p < 0.001). Collectively, these findings suggest that long-term cerebellar cTBS selectively ameliorates orolingual dyskinesia by modulating the cerebello-thalamo-striatal circuit.
B7-H3 upregulation in ischemic stroke: friend or foe?
Challa SR, Baker IM, Fornal CA … +7 more , Mada SR, Khan N, Jackson SN, Saldes E, Klopfenstein JD, Asuthkar S, Veeravalli KK
Exp Neurol · 2026 May · PMID 41620196 · Full text
B7-H3 (CD276) is an immune checkpoint co-signaling molecule expressed on immune and non-immune cells. It is best known for suppressing T-cell responses but can also promote inflammation depending on the microenvironment....
B7-H3 (CD276) is an immune checkpoint co-signaling molecule expressed on immune and non-immune cells. It is best known for suppressing T-cell responses but can also promote inflammation depending on the microenvironment. In neuroinflammatory models such as experimental autoimmune encephalomyelitis, B7-H3 expression increases concomitantly with the inflammatory response, and its inhibition is associated with reduced disease progression. Although its role in ischemic stroke remains unclear, we hypothesized that cerebral ischemia/reperfusion (I/R) would upregulate B7-H3 expression in the ischemic brain and that increased B7-H3 expression would positively correlate with pro-inflammatory cytokine expression. Young and aged male and female rodents, including normotensive and spontaneously hypertensive rats to model comorbid hypertension, underwent transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Brain tissue was collected on post-MCAO days 1, 3, 5, or 7. B7-H3 mRNA was analyzed by real-time PCR, whereas protein expression was assessed by Western blotting and immunohistochemistry at selected time points. B7-H3 expression was significantly upregulated in the ischemic brain across sexes, age groups, and species. The extent of B7-H3 degradation was influenced by species, sex, age, and time after cerebral I/R. Upregulation of B7-H3 was observed at both the mRNA and protein levels and was localized primarily to the somatosensory cortex and caudate putamen in the ipsilateral (ischemic) hemisphere, the main regions affected in this MCAO model. Elevated B7-H3 expression in the ischemic brain positively correlated with the pro-inflammatory mediator TNFα. In rats, the temporal profile of B7-H3 expression paralleled the early inflammatory phase associated with secondary tissue damage after ischemic stroke. These findings identify B7-H3 as an ischemia-induced immune checkpoint molecule in the brain that may modulate post-stroke immune responses and support further investigation into its beneficial versus detrimental roles in neuroinflammation and its potential as a therapeutic target following cerebral I/R.
Initiation site of experimentally-evoked spreading depolarizations influence tissue outcomes in a murine stroke model.
Bennett MC, Morton RA, Carlson AP … +1 more , Shuttleworth CW
Exp Neurol · 2026 May · PMID 41611073 · Full text
Spreading depolarization waves (SDs) are implicated in secondary expansion of brain injuries and are the target for initial clinical intervention trials. However, the assumption that SD directly causes neuronal injury ha...
Spreading depolarization waves (SDs) are implicated in secondary expansion of brain injuries and are the target for initial clinical intervention trials. However, the assumption that SD directly causes neuronal injury has been challenged by recent findings with experimentally-induced SD in stroke models. The current study addressed this controversy by examining whether stroke consequences are confounded by the precise location of experimental SD initiation. Focal ischemic lesions were generated by transient distal middle cerebral artery occlusion in male mice. Clusters of SDs (6 at 10-min intervals) were induced by either focal KCl application or optogenetic stimulation during occlusion. SDs were initiated either in regions close to the infarct core (penumbral-SD; <50% perfusion) or in less compromised tissue in the same hemisphere (remote-SD; >70% perfusion). Despite the fact that all SDs fully invaded stroke expansion areas, the location of experimental SD induction had significant effects on stroke outcomes measured 48 h after reperfusion. Penumbral-SDs resulted in larger infarct expansion than seen in control stroke mice lacking experimentally-imposed SD. Conversely, remote-SDs led to significantly smaller infarcts than stroke alone. Laser speckle contrast imaging of blood flow in injury expansion areas showed enhanced hypoperfusion responses after penumbral-SDs and larger hyperemic responses after remote-SDs, suggesting that differential vascular responses could contribute to stroke outcomes. Overall, this study helps to reconcile different prior reports by showing that experimentally-induced SDs can either exacerbate or reduce stroke-induced injury depending on the SD initiation site and further strengthens evidence for injurious roles of SDs initiating in vulnerable brain tissue.
Activation of oligodendrocyte precursor cells triggers cognitive dysfunction and synaptic defects in SAE.
Wu Y, Yang Z, Liu H … +5 more , Li J, Liu R, Li Y, Chen Y, Su B
Exp Neurol · 2026 May · PMID 41611072 · Publisher ↗
Sepsis-associated encephalopathy (SAE) is defined as a diffuse neurological dysfunction that occurs secondary to sepsis, in the absence of direct central nervous system infection, and is associated with high rates of inc...
Sepsis-associated encephalopathy (SAE) is defined as a diffuse neurological dysfunction that occurs secondary to sepsis, in the absence of direct central nervous system infection, and is associated with high rates of incidence, mortality, and disability. Despite its clinical significance, the neuropathological mechanisms underlying SAE are not yet fully understood, making its pathogenesis a focal point of ongoing research. Oligodendrocyte precursor cells (OPCs), which are the most proliferative cell type within the central nervous system, primarily contribute to the generation of mature oligodendrocytes and are integral to myelination and the maintenance of myelin. Nevertheless, the role and pathological changes of OPCs during the acute phase of SAE remain inadequately characterized. This study illustrates that OPCs in the hippocampal CA1 region may undergo immune activation under SAE conditions, characterized by significantly elevated inflammatory transcription and phagocytic capacity. Additionally, activated OPCs in SAE mice may contribute to the synaptic pruning of neurons. By generating PDGFRa-Cre/ERT transgenic mice and conducting stereotactic injections of pAAV-EGFP-flex-DTA virus into the hippocampal CA1 region to selectively ablate OPCs, we observed a significant enhancement in cognitive function in SAE mice. This improvement is likely due to the alleviation of synaptic structural and functional impairments in neurons. Our findings indicate that OPCs play a critical role in the pathogenesis of SAE, highlighting their potential as a novel therapeutic target for this condition.
Integrated miRNA-proteomic profiling identifies chronic vesicle-trafficking and proteostasis disruptions after mild traumatic brain injury.
Yadikar H, Ansari MA
Exp Neurol · 2026 May · PMID 41605412 · Publisher ↗
BACKGROUND: Mild traumatic brain injury (mTBI) often produces persistent deficits, yet the molecular mechanisms driving chronic pathology remain undefined. OBJECTIVE: We aimed to identify mechanistic drivers of long-term...
BACKGROUND: Mild traumatic brain injury (mTBI) often produces persistent deficits, yet the molecular mechanisms driving chronic pathology remain undefined. OBJECTIVE: We aimed to identify mechanistic drivers of long-term dysfunction after mTBI by integrating proteomics, transcriptomics, and behavioral outcomes. METHODS: Adult rats were subjected to a modified Marmarou weight-drop mTBI model (diffuse closed-head injury) or a sham procedure. Cortical tissue was analyzed at 21 days post-injury (chronic phase) by quantitative proteomics and small RNA sequencing, while neurological and motor functions were tracked longitudinally (subacute to chronic phases). Key molecular changes were validated via Western blotting and RT-qPCR. RESULTS: mTBI induced widespread and persistent alterations in cortical protein expression, particularly affecting vesicle-trafficking and proteostasis-related pathways. Several proteins-including Rab11b, Dnm2, TIA1, Snx30, Sbf1, and Vma21-exhibited robust decreases across both proteomic and immunoblot analyses, indicating reproducible impairment of endosomal recycling and stress-response mechanisms. Cavin-2 and COMMD2 showed significant fold changes at the proteomic level but were not entirely validated and therefore remain preliminary observations. Differentially expressed miRNAs exhibited coordinated regulatory patterns, and integrated miRNA-protein signatures achieved high discriminatory performance (AUC > 0.95) in separating injured from control animals. CONCLUSIONS: These findings demonstrate that even an mTBI causes enduring disruptions in protein homeostasis, vesicle trafficking, and post-transcriptional regulation, which correlate with chronic behavioral deficits. The injury-responsive networks identified provide a systems-level foundation for future mechanistic studies and highlight promising candidate biomarkers to improve mTBI diagnosis and monitoring.
Low-frequency TMS ameliorates neonatal hypoxia-ischemia injury by normalizing glutamatergic transmission in penumbra.
Goussakov I, Synowiec S, Drobyshevsky A
Exp Neurol · 2026 May · PMID 41592691 · Full text
Perinatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of morbidity and mortality in term neonates. The current standard of care, therapeutic hypothermia, provides only partial neuroprotection. This study inv...
Perinatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of morbidity and mortality in term neonates. The current standard of care, therapeutic hypothermia, provides only partial neuroprotection. This study investigates the potential of low-frequency transcranial magnetic stimulation (LF-TMS) as a novel non-pharmacological adjunct therapy by targeting a key pathological mechanism of HIE: a persistent, pathological increase in glutamatergic synaptic transmission, or hypoxic long-term potentiation. Using a neonatal mouse model of hypoxia-ischemia, we administered a single session of LF-TMS 30 min after the hypoxic event. We then evaluated its effects on synaptic function via slice electrophysiology and on brain injury volume using serial MRI. Our results show that hypoxia-ischemia induced significant and lasting synaptic potentiation in the perilesional region of the somatosensory cortex. LF-TMS treatment successfully reduced this elevated glutamatergic response to control levels, suggesting a therapeutic mechanism similar to long-term depression and/or depotentiation by downregulating AMPA receptors. LF-TMS provided significant neuroprotection, as demonstrated by reductions in volumes of the ischemic core and penumbra 48 h after the injury. LF-TMS did not alter excitability in sham-treated mice, confirming its safety as a targeted intervention for pathological conditions without affecting normal brain function. This study supports that LF-TMS is a promising neuroprotective strategy that mitigates brain injury in a neonatal hypoxia-ischemia model.
Ectopically overexpressed glycine transporter 2 contributes to epileptogenesis in DEPDC5-related epilepsy.
Yang T, Banerjee R, Scheper M … +4 more , Jiang M, Dai S, Aronica E, Wang Y
Exp Neurol · 2026 May · PMID 41587632 · Publisher ↗
Loss-of-function mutations in DEPDC5 (DEP domain-containing protein 5), a critical negative regulator of mTORC1 (mechanistic Target of Rapamycin Complex 1), are often identified in patients with refractory epilepsy. To u...
Loss-of-function mutations in DEPDC5 (DEP domain-containing protein 5), a critical negative regulator of mTORC1 (mechanistic Target of Rapamycin Complex 1), are often identified in patients with refractory epilepsy. To understand its underlying pathogenesis and develop novel therapeutics, we used a highly clinically relevant rat model of DEPDC5-related epilepsy and resected human patient tissues to profile the molecular architecture in the dysplastic cortex. We report here that Slc6a5 (solute carrier family 6 member 5 gene), a marker gene for glycinergic inhibitory neurons, is ectopically overexpressed in mutant excitatory neurons in both experimental animal and human tissues. Using CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) in utero electroporation (IUE) to simultaneously knock out Depdc5 and Slc6a5 in forebrain excitatory neurons reduces seizure frequency and duration. These data suggest that SLC6A5 plays an important role in the epileptogenesis of DEPDC5-related epilepsy, although the underlying mechanisms remain unclear.
Mismatch between oxygen delivery and consumption in the cerebral watershed during subacute global hypoperfusion.
Li B, Cao H, Takase H … +8 more , Allu SR, Wu Y, Fu B, Vinogradov SA, Lo EH, Arai K, Ayata C, Sakadžić S
Exp Neurol · 2026 May · PMID 41581692 · Publisher ↗
Hemodynamically significant carotid artery stenosis is a common clinical condition that can lead to chronic cerebral hypoperfusion. Despite the well-recognized pivotal role of pial collaterals in maintaining cerebral per...
Hemodynamically significant carotid artery stenosis is a common clinical condition that can lead to chronic cerebral hypoperfusion. Despite the well-recognized pivotal role of pial collaterals in maintaining cerebral perfusion during focal arterial occlusions, regulation of microvascular blood flow and oxygenation in the cerebral watershed "pial-collateral territory" during chronic hypoperfusion remains unexplored. To answer this question, we applied 2-photon microscopy and Doppler optical coherence tomography to assess the changes in cerebral blood flow, capillary red-blood-cell (RBC) flux, and intravascular oxygen partial pressure (PO), seven days after bilateral common-carotid artery stenosis (BCAS). The measurements were performed in the middle-cerebral-artery (MCA) territory and the watershed between the MCA and anterior-cerebral-artery territories in the awake, head-restrained C57BL/6 mice, through a glass-sealed cranial window. The results showed that BCAS induced a significant decrease in microvascular perfusion in the watershed area compared to the MCA territory, with the largest RBC flux reduction observed in the subcortical white matter. The watershed area exhibited a larger drop between arterial and venous PO and the calculated oxygen saturation, indicating a significant increase in oxygen extraction fraction following BCAS. Structural analysis of the microvasculature showed significant BCAS-induced dilation of pial collaterals, suggesting a potential compensatory mechanism to improve blood flow in the hypoperfused watershed. However, microvascular morphology did not change in either region, implying an absence of structural remodeling at this early stage. Collectively, these findings point to an oxygen supply-consumption mismatch and heightened vulnerability in the watershed areas, particularly affecting the subcortical white matter, during flow-limiting cervical artery stenosis.
Exosomes-mediated delivery of miR-27a-3p antagomir alleviates white matter injury by regulating PPARγ/PRDX1/JNK pathway after subarachnoid hemorrhage in rats.
Zhang Z, Liang F, Wen D … +11 more , Chen H, Gu N, Li Z, Wang L, Wang Y, Pan Q, Zhu Y, Xu D, Sun X, Cheng C, Yan J
Exp Neurol · 2026 May · PMID 41581691 · Publisher ↗
White matter injury (WMI) is a critical factor contributing to poor neurological outcomes following subarachnoid hemorrhage (SAH). MicroRNAs (miRNAs) are key regulators of WMI-related pathology and can be delivered via e...
White matter injury (WMI) is a critical factor contributing to poor neurological outcomes following subarachnoid hemorrhage (SAH). MicroRNAs (miRNAs) are key regulators of WMI-related pathology and can be delivered via exosomes, yet their mechanisms and therapeutic potential remain largely unexplored. In this study, miRNA sequencing revealed a significant upregulation of miR-27a-3p in peripheral blood exosomes after SAH, which was further confirmed in white matter tissue. BV2 cell-derived exosomes loaded with miR-27a-3p antagomir were administered intranasally and effectively targeted oligodendrocytes. Treatment with these exosomes alleviated WMI by reducing oligodendrocyte apoptosis and promoting the proliferation and differentiation of oligodendrocyte precursor cells, leading to improved neurological and electrophysiological recovery. Mechanistically, miR-27a-3p inhibited PPARγ, resulting in downregulation of PRDX1 and activation of the JNK pathway, which triggered oligodendrocyte apoptosis. These findings demonstrate that exosome-mediated delivery of miR-27a-3p antagomir mitigates SAH-induced WMI through modulation of the PPARγ/PRDX1/JNK axis, providing a promising noninvasive therapeutic approach for enhancing white matter repair and functional recovery after SAH.
Molecular and biochemical insights into dysregulation of glycosphingolipid metabolism in a mouse model of lysosomal free sialic acid storage disorder.
Sabir MS, Hossain MS, Pollard L … +5 more , Leoyklang P, Huizing M, Gahl WA, Platt FM, Malicdan MCV
Exp Neurol · 2026 May · PMID 41580110 · Publisher ↗
Free sialic acid storage disorder (FSASD) is caused by pathogenic biallelic variants in SLC17A5, which encodes the lysosomal sialic acid exporter, sialin. FSASD is characterized by the accumulation of lysosomal free sial...
Free sialic acid storage disorder (FSASD) is caused by pathogenic biallelic variants in SLC17A5, which encodes the lysosomal sialic acid exporter, sialin. FSASD is characterized by the accumulation of lysosomal free sialic acid, leading to either a severe, childhood-lethal form or a more slowly progressive neurodegenerative disorder associated with the p.Arg39Cys (p.R39C) variant, i.e., Salla disease. While dysregulated glycosphingolipid (GSL) metabolism has been observed in cellular models of FSASD, this study provides the first in vivo biochemical dissection of GSL metabolism in a knock-in mouse model harboring the Slc17a5 p.R39C variant. We employed an integrated multi-modal approach, including sialic acid quantification, exploratory untargeted lipidomics, HPLC-based GSL profiling, bulk transcriptomics, and 4-MU-based lysosomal enzyme activity assays in brain and peripheral tissues (liver and kidney). Exploratory untargeted lipidomic screening revealed region-dependent lipid alterations, with more pronounced changes in the cerebellum than in the forebrain. Pathway-level analyses indicated enrichment of lipid classes related to sphingolipid and GSL metabolism. Targeted biochemical analyses demonstrated that several GSL species accumulate predominantly in the brain, with minimal changes in peripheral tissues, whereas glucosylceramide levels were significantly reduced in all brain regions analyzed. Transcriptomic profiling identified dysregulation of several genes involved in GSL and sialic acid metabolism. Enzyme activity assays corroborated the transcriptomic findings, demonstrating increased activity of several lysosomal glycohydrolases, including neuraminidase 1/3/4 and β-hexosaminidase. Collectively, these findings highlight dysregulated GSL metabolism as a prominent biochemical consequence of sialin deficiency in vivo and highlight its putative role in FSASD neuropathology.
Microglial P2RY12 mediates migration to and protection of cerebral microvasculature after ischemia-reperfusion via Caveolin-1.
Wang Y, Li X, Li W … +3 more , Wang C, Xu G, Yu S
Exp Neurol · 2026 May · PMID 41577116 · Publisher ↗
Disruption of blood-brain barrier (BBB) integrity after cerebral ischemia-reperfusion (I/R) injury contributes to neuroinflammation and neuronal damage. Microglia plays a significant role in the repair processes of the B...
Disruption of blood-brain barrier (BBB) integrity after cerebral ischemia-reperfusion (I/R) injury contributes to neuroinflammation and neuronal damage. Microglia plays a significant role in the repair processes of the BBB, and the G protein-coupled receptor P2RY12 is involved in microglial chemotactic migration. However, its precise function and associated downstream mechanisms are unclear. Caveolin-1 (Cav-1), a membrane scaffold protein, plays a key role in signal transduction and cellular motility. This study employed in vivo and in vitro experimental models to explore the functional role of the P2RY12-Cav-1 interaction after ischemic stroke. Blocking P2RY12 with PSB0739 worsened neurological deficits and BBB disruption. In contrast, the P2RY12 agonist 2MeSADP attenuated I/R injury, promoted Bv2 cell migration. Disrupting lipid rafts with methyl-β-cyclodextrin (MβCD) abolished these benefits. Co-immunoprecipitation verified P2RY12 interacts with the scaffolding domain of Cav-1. These findings reveal a possible mechanism by which the P2RY12-Cav-1 signaling axis regulates microglial chemotaxis for microvascular protection, offering a potential therapeutic target for the treatment of ischemic stroke.
Palmitoylethanolamide ameliorates postoperative cognitive dysfunction via microglial PPARα-mediated anti-inflammatory and neuroprotective mechanisms.
Zhang X, Wu W, Zheng Z … +3 more , Liu G, Li D, Li L
Exp Neurol · 2026 May · PMID 41577115 · Publisher ↗
BACKGROUND: Postoperative cognitive dysfunction (POCD) is a frequent neurological complication characterized by memory and learning impairments in the elderly, while effective pharmacological interventions remain limited...
BACKGROUND: Postoperative cognitive dysfunction (POCD) is a frequent neurological complication characterized by memory and learning impairments in the elderly, while effective pharmacological interventions remain limited. Palmitoylethanolamide (PEA), an endogenous lipid mediator with anti-inflammatory and neuroprotective properties, has emerged as a potential therapeutic candidate. METHODS: An aged mouse model of POCD was used to evaluate the effects of PEA. Cognitive performance was assessed by the open field test, novel object recognition, and Barnes maze. Neuroinflammation, microglial activation, neuronal integrity, and synaptic plasticity-related proteins were assessed using immunostaining and molecular analyses both in vivo and in vitro. To determine the role of peroxisome proliferator-activated receptor-α (PPARα), stereotaxic delivery of shPPARα virus to prefrontal cortex (PFC) microglia was performed. RESULTS: PEA treatment significantly improved both short- and long-term memory in aged POCD mice. Mechanistically, PEA attenuated microglial activation, shifted microglial activation toward the anti-inflammatory phenotype, preserved neuronal survival, and upregulated synaptic plasticity-associated proteins. Importantly, PEA restored PPARα activity, and knockdown of PPARα abolished these protective effects both in vivo and in vitro, confirming its essential role. CONCLUSIONS: PEA alleviates cognitive deficits in aged POCD mice by enhancing PPARα signaling, reducing neuroinflammation, and promoting neuronal protection. These findings support PEA as a promising therapeutic strategy for the treatment of aged POCD.
Unveiling distinct neuroimmune responses in mouse models of cervical spinal cord injury: Hemisection versus hemicontusion.
Chen W, Adam L, Michel-Flutot P … +3 more , Mansart A, Vinit S, Vivodtzev I
Exp Neurol · 2026 May · PMID 41577114 · Publisher ↗
Traumatic cervical spinal cord injury (cSCI) causes severe neurological deficits and long-term disability. Preclinical models such as cervical vertebrate level 2 (C2) hemisection (C2HS), which disrupts communication betw...
Traumatic cervical spinal cord injury (cSCI) causes severe neurological deficits and long-term disability. Preclinical models such as cervical vertebrate level 2 (C2) hemisection (C2HS), which disrupts communication between respiratory centers and the phrenic motoneurons pool, have been used for decades to study respiratory dysfunction and neuroinflammation after cSCI. Recently, contusive injuries such as cervical vertebrate level 3 hemicontusion (C3HC) have been increasingly employed, as they induce phrenic motoneuron damage and offer a more clinically relevant model of SCI. However, these two different models may engage distinct pathophysiological cascades, raising concerns about the generalizability of findings across injury paradigms. In this study, we compared neuroimmune responses following C2HS or C3HC in mice. Animals underwent either lesion, and spinal cord segments (C1-C8) were collected seven days post-injury for immuno-histological analyses around the lesion level and flow cytometry analyses at the lesion level. We observed that C2HS preserved more neurons accompanied by an upregulation of CD86 and F4/80 in macroglia, markers of activated macrophages, suggesting a response oriented toward phagocytic and reparative functions. This phenotype was associated with limited pro-inflammatory cell infiltration and normalized level of systemic IL-6 level. Conversely, C3HC induced more extensive tissue damage, heightened microglial activation, a trend toward increased astrocytic reactivity, and significantly elevated CSPG levels on the contralateral side. Moreover, a persistent NK cell, neutrophil, and CD43 infiltrating cells, along with sustained elevation of circulating IL-6 These findings demonstrate distinct neuroinflammatory signatures and repairing mechanisms between models. This study underscores, for the first time, how injury type shapes neuroimmune mechanisms, reinforcing the need for lesion-specific therapeutic strategies in cervical spinal cord injury.
Role of glycolysis-mediated histone lactylation in microglial activation and progression of neurodegenerative diseases.
Wang S, Wang J, Hu Z … +2 more , Wu L, Huang L
Exp Neurol · 2026 May · PMID 41577113 · Publisher ↗
Microglia-mediated neuroinflammation is a key driver of neurodegenerative disease progression, yet the metabolic mechanisms underlying microglial dysfunction remain poorly understood. Recent studies highlight glycolytic...
Microglia-mediated neuroinflammation is a key driver of neurodegenerative disease progression, yet the metabolic mechanisms underlying microglial dysfunction remain poorly understood. Recent studies highlight glycolytic reprogramming in activated microglia, which generates lactate that, in turn, promotes histone lactylation, an epigenetic modification that significantly alters gene expression. This glycolysis-histone lactylation axis has been implicated in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders, where its dysregulation exacerbates chronic neuroinflammation and neuronal damage. Despite this, the precise molecular mechanisms linking microglial metabolic shifts to epigenetic remodeling and disease pathogenesis are not fully defined. This review consolidates current knowledge on how the glycolysis-histone lactylation pathway influences microglial phenotypes and function in neurodegenerative contexts. We explore the molecular machinery driving lactate-mediated histone modifications, their transcriptional consequences, and their pathological impact on disease progression. Importantly, we discuss emerging therapeutic strategies targeting this metabolic-epigenetic axis, including glycolysis inhibitors and lactylation modulators, as promising precision medicine approaches for neurodegenerative diseases. By elucidating these mechanisms, this review provides a framework for developing metabolism-based interventions aimed at restoring microglial homeostasis and slowing neurodegeneration.
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