Experimental Neurology最新文献

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 (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.

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, Cx3cr1^GFPCcr2^RFP 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.

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.

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.

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.