Neuroprotection of Ro25-6981 Against Ischemia/Reperfusion-Induced Brain Injury via Inhibition of Autophagy

Abstract

In this study, we investigated the neuroprotective effect of Ro25-6981 against cerebral ischemia/reperfusion injury. Ro25-6981 alone or in combination with rapamycin was intracerebroventricularly administered to rats which suffered transient forebrain ischemia inducing by 4-vessel occlusion and reperfusion. Nissl staining was used to determine the survival of CA1 pyramidal cells of the hippocampus, while immunohistochemistry was performed to measure neuron-specific enolase (NSE) expression. The expression of autophagy-related proteins, such as microtubule-associated protein l light chain 3 (LC3), Beclin 1, and sequestosome 1 (p62), was assessed by immunoblotting. Nissl staining showed that neuronal damage was reduced in the hippocampal CA1 pyramidal layer in rats that received Ro25-6981. The protective effect of Ro25-6981 was dose-dependent, with a significant effect in the middle-dose range. The expression of NSE increased after Ro25-6981 treatment. Ro25-6981 significantly decreased LC3II (which is membrane bound) and Beclin 1, and increased p62. In addition, Ro25-6981 decreased rapamycin-induced neuronal damage and excessive activation of autophagy after I/R. Taken together, the results suggest that Ro25-6981 could suppress ischemic brain injury by regulating autophagy-related proteins during ischemia/reperfusion.

Pre‐ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress‐dependent autophagy via PERK and IRE1 signalings

“…Currently, the role of autophagy in cerebral ischemic stroke is still inconclusive. Some studies indicate that autophagy is detrimental to neurons during cerebral ischemic injury and inhibiting autophagy can decrease the infarct size and augment neurological scores . However, other studies show that autophagy activation or enhancing mitophagy can protect against IR‐induced injury .…”

“…Some studies indicate that autophagy is detrimental to neurons during cerebral ischemic injury and inhibiting autophagy can decrease the infarct size and augment neurological scores. 38,39 However, other studies show that autophagy activation or enhancing mitophagy can protect against IR-induced injury. 40 The present study added evidence that autophagy was significantly activated and was detrimental to neurons in the acute stage of ischemia injury.…”

Environmental Enrichment Improves Spatial Learning and Memory in Vascular Dementia Rats with Activation of Wnt/β-Catenin Signal Pathway

“…The population of normal neurons in a CA1 subfield were counted at 400× magnification by 2 independent investigators who were blind to the experimental condition in this study. The mean number of neurons was obtained by counting 3 sections per brain and 5 representative fields were randomly selected to count per section (n=4/group) [25]. …”

Sodium hydrosulfide attenuates cerebral ischemia/reperfusion injury by suppressing overactivated autophagy in rats

“…Autophagy is a highly regulated process involving the bulk degradation of cytoplasmic macromolecules and organelles in mammalian cells . Autophagy is involved in many pathophysiological situations, such as inflammation , apoptosis , malignancy , and cerebral ischemia/reperfusion injury .…”

“… also found that ischemic preconditioning enhances autophagy but suppresses autophagic cell death in rat spinal neurons following ischemia/reperfusion, while other reports have found that inhibition of autophagy is protective against ischemia/reperfusion injury. An NMDA glutamate receptor antagonist, Ro25‐6981, suppresses ischemic brain injury by inhibiting autophagy . Inhibition of the mitochondrial calcium uniporter also protects neurocytes against ischemia/reperfusion injury by downregulating excessive mitophagy .…”