Inhibition of Cathepsin B Alleviates Secondary Degeneration in Ipsilateral Thalamus After Focal Cerebral Infarction in Adult Rats

Abstract

Secondary degeneration in areas beyond ischemic foci can inhibit poststroke recovery. The cysteine protease Cathepsin B (CathB) regulates cell death and intracellular protein catabolism. To investigate the roles of CathB in the development of secondary degeneration in the ventroposterior nucleus (VPN) of the ipsilateral thalamus after focal cerebral infarction, infarct volumes, immunohistochemistry and immunofluorescence, and Western blotting analyses were conducted in a distal middle cerebral artery occlusion (dMCAO) stroke model in adult rats. We observed marked neuron loss and gliosis in the ipsilateral thalamus after dMCAO, and the expression of CathB and cleaved caspase-3 in the VPN was significantly upregulated; glial cells were the major source of CathB. Although it had no effect on infarct volume, delayed intracerebroventricular treatment with the membrane-permeable CathB inhibitor CA-074Me suppressed the expression of CathB and cleaved caspase-3 in ipsilateral VPN and accordingly alleviated the secondary degeneration. These data indicate that CathB mediates a novel mechanism of secondary degeneration in the VPN of the ipsilateral thalamus after focal cortical infarction and suggest that CathB might be a therapeutic target for the prevention of secondary degeneration in patients after stroke.

Inflammatory Responses in the Secondary Thalamic Injury After Cortical Ischemic Stroke

“…A shRNA-induced knockdown of beclin1, a regulator of autophagy, reduces autophagy, astro/micro-gliosis, and neuronal cell death in the ipsilesional thalamus (100). In another study, cathepsin-B (CathB), a lysosomal marker that increases as a result of autophagosome degradation, has been shown to progressively increase in the thalamus through 28 days after stroke, and its expression corresponds with the increased astroglia/microglia activation and neuronal cell loss (101). Pharmacological inhibition of CathB reduces inflammation and prevents neuronal injury and apoptosis in the ipsilesional thalamus (101), indicating the importance of this gene and the autophagy process in secondary thalamic injury after stroke.…”

“…Some studies have shown that interventions to prevent secondary thalamic injury may be beneficial for recovery of function after stroke. Below is a summary of studies that investigate the role of secondary thalamic injury through manipulating specific molecules involved in inflammatory responses, autophagy, Aβ deposition, and neuronal apoptosis (5,26,50,59,60,(99)(100)(101).…”

“…Interestingly, the observed increase in thalamic neurodegeneration at Day 14 post-stroke is accompanied by a robust surge in microglia activation as well as increased mRNA expression of several pro-inflammatory genes (5). Another intervention to manipulate secondary thalamic injury is to target the autophagic processes (100,101). A shRNA-induced knockdown of beclin1, a regulator of autophagy, reduces autophagy, astro/micro-gliosis, and neuronal cell death in the ipsilesional thalamus (100).…”

“…In another study, cathepsin-B (CathB), a lysosomal marker that increases as a result of autophagosome degradation, has been shown to progressively increase in the thalamus through 28 days after stroke, and its expression corresponds with the increased astroglia/microglia activation and neuronal cell loss (101). Pharmacological inhibition of CathB reduces inflammation and prevents neuronal injury and apoptosis in the ipsilesional thalamus (101), indicating the importance of this gene and the autophagy process in secondary thalamic injury after stroke. Other treatments such as the non-selective calcium channel blocker bepridil (102) and antioxidant ebselen (103) also decrease secondary thalamic injury in different cortical stroke models.…”

Analysis of intestinal microbial communities of cerebral infarction and ischemia patients based on high throughput sequencing technology and glucose and lipid metabolism

“…It is predicted that by 2030, the Chinese population aged ≥60 will be >300 million, and ~2/3 patients with primary cerebral vascular disease will be aged ≥60 years. In recent years, due to personal habits or environmental factors, the age of patients with primary cerebral vascular disease has gradually reduced ( 3 , 4 ). Cerebrovascular disease and CI are currently the leading cause of disability and the second leading cause of mortality in China ( 5 , 6 ).…”