Abstract
Stroke is the leading cause of adult disability in the world. In general, recovery from stroke is incomplete. Accumulating evidences have shown that focal cerebral infarction leads to dynamic trans-neuronal degeneration in non-ischemic remote brain regions, with the disruption of connections to synapsed neurons sustaining ischemic insults. Previously, we had reported that the ipsilateral striatum, thalamus degenerated in succession after permanent distal branch of middle cerebral artery occlusion (dMCAO) in Sprague-Dawley (SD) rats and cathepsin (Cath) B was activated before these relay degeneration. Here, we investigate the role of CathB in the secondary degeneration of ipsilateral substantia nigra (SN) after focal cortical infarction. We further examined whether the inhibition of CathB with L-3-trans-(Propyl-carbamoyloxirane-2-carbonyl)-L-isoleucyl-L-proline methyl ester (CA-074Me) would attenuate secondary degeneration through enhancing the cortico-striatum-nigral connections and contribute to the neuroprotective effects. Our results demonstrated that secondary degeneration in the ipsilateral SN occurred and CathB was upregulated in the ipsilateral SN after focal cortical infarction. The inhibition of CathB with CA-074Me reduced the neuronal loss and gliosis in the ipsilateral SN. Using biotinylated dextran amine (BDA) or pseudorabies virus (PRV) 152 as anterograde or retrograde tracer to trace striatum-nigral and cortico-nigral projections pathway, CA-074Me can effectively enhance the cortico-striatum-nigral connections and exert neuroprotection against secondary degeneration in the ipsilateral SN after cortical ischemia. Our study suggests that the lysosomal protease CathB mediates the secondary damage in the ipsilateral SN after dMCAO, thus it can be a promising neuroprotective target for the rehabilitation of stroke patients.
Highlights
Stroke is the leading cause of adult disability in the world
Gross brain morphology confirmed the existence of focal cerebral infarctions in the distal branch of middle cerebral artery occlusion (dMCAO) group, whereas no infarctions were observed in the sham-operated group (Figures 1B,C)
glial fibrillary acidic protein (GFAP)/DAB-staining assay in Figure 1D clearly showed that ischemic foci were confined within the cortex, while secondary degeneration occurred in the ipsilateral substantia nigra (SN) which was remote from the ischemic foci at 2 weeks after dMCAO, suggesting that the focal cortical infarction model was successfully developed
Summary
Stroke is the leading cause of adult disability in the world. In general, recovery from stroke is incomplete. Accumulating evidences have shown that focal cerebral infarction leads to neuropathologic damages at lesion site, and in nonishemic remote brain regions that have synaptic connections with the primary lesion (Uchida et al, 2010; Zhang et al, 2012a; Ohe et al, 2013; Fernández-Andújar et al, 2014; Jones et al, 2015; van Etten et al, 2015) This phenomenon, termed secondary degeneration, has been reported to be associated with sustained dementia, the development of vascular Parkinson’s syndrome and worsen stroke outcomes (Kirton et al, 2007; Domi et al, 2009; DeVetten et al, 2010; Rodriguez-Grande et al, 2013; Baron et al, 2014). Hyperintense regions in the mesencephalic SN were observed in all patients after 7–28 days on diffusion weighted imaging (DWI) or fluid-attenuated inversion recovery (FLAIR) and T2-weighted MRI (T2), indicating that secondary degeneration of the mesencephalic SN occur in human cerebral infarction (Ohe et al, 2013)
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