Inhibition of Cathepsins B Induces Neuroprotection Against Secondary Degeneration in Ipsilateral Substantia Nigra After Focal Cortical Infarction in Adult Male Rats

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.

Hypoxic Preconditioning Maintains GLT-1 Against Transient Global Cerebral Ischemia Through Upregulating Cx43 and Inhibiting c-Src

“…Triple-fluorescent immunohistochemistry was performed as previously described (Zuo et al, 2018 ). Sections were preincubated with 5% normal serum (containing 0.2% Triton X-100) for 1 h at room temperature, and then incubated overnight at 4°C with mixtures of primary antibodies: goat polyclonal antibody against Cx43 (1:100; Abcam, Cat# ab219493), mouse monoclonal antibody against NeuN (1:1,000; Millipore, Cat# MAB377, RRID: AB_2298772 ), rabbit polyclonal antibody against Iba-1 (1:100, Abcam, Cat# ab108539, RRID: AB_10862652 ).…”

Excitotoxicity: Still Hammering the Ischemic Brain in 2020

“…Remarkably, inhibition of iNOS with aminoguanidine reduced infarct volume after pMCAO in rats when given 24 h later (Iadecola et al, 1995). Cellular release of lysosomal cathepsin B may also contribute to remote cell damage and later secondary degeneration (Zuo et al, 2018).…”

Bone Marrow Stromal Cells Alleviate Secondary Damage in the Substantia Nigra After Focal Cerebral Infarction in Rats

“…Also, the observation in monkeys from Chen et al (2015) revealed an area of high signal in the ipsilateral SN on T2-weighted MRI at 1 week after occlusion in the distal M1 branch of MCA by electrocoagulation. Previously, we have demonstrated that secondary damage occurred in the SN after focal cortical infarction (Zuo et al, 2018). Although some acute phase therapies such as intravenous recombinant tissue plasminogen activator (rt-PA) and endovascular treatment have been shown to improve ischemic stroke outcome, these treatments are only available for a limited number of patients because of the short time window (Campbell et al, 2018; Grossberg et al, 2018).…”

“…Among the survivors about 15–30% left with permanent disability (Go et al, 2014). It has been accepted that cortical cerebral infarction leads to neuropathologic damages not only at primary lesion site, but also in nonischemic remote regions such as hippocampus, thalamus, substantia nigra (SN), distal pyramidal tract, peripheral nerves and muscles (Forno, 1983; Zhang et al, 2012; Dang et al, 2016; Zuo et al, 2016, 2018). This phenomenon is termed as post-stroke secondary degeneration.…”

“…This phenomenon is termed as post-stroke secondary degeneration. 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 (Zuo et al, 2018). Owing to SN has extensive efferent and afferent fibers connecting with globus pallidus, ventrolateral nucleus and motor cortex, SN is a very common brain structure that is subjected to secondary degeneration after distal middle cerebral artery occlusion (dMCAO).…”