Journal Article

Protection against Experimental Stroke by Ganglioside GM1 Is Associated with the Inhibition of Autophagy

Li, Li, Lu, Jianfei, Tian, Jinghua, Zhou, Changman, Wang, Tianlong, Long, Mitchell King-Wei, Chen, Yong

2016

Overview

Ganglioside GM1, which is particularly abundant in the central nervous system (CNS), is closely associated with the protection against several CNS disorders. However, controversial findings have been reported on the role of GM1 following ischemic stroke. In the present study, using a rat middle cerebral artery occlusion (MCAO) model, we investigated whether GM1 can protect against ischemic brain injury and whether it targets the autophagy pathway. GM1 was delivered to Sprague-Dawley male rats at 3 doses (25 mg/kg, 50 mg/kg, 100 mg/kg) by intraperitoneal injection soon after reperfusion and then once daily for 2 days. The same volume of saline was given as a control. Tat-Beclin-1, a specific autophagy inducer, was administered by intraperitoneal injection at 24 and 48 hours post-MCAO. Infarction volume, mortality and neurological function were assessed at 72 hours after ischemic insult. Immunofluorescence and Western blotting were performed to determine the expression of autophagy-related proteins P62, LC3 and Beclin-1 in the penumbra area. No significant changes in mortality and physiological variables (heart rate, blood glucose levels and arterial blood gases) were observed between the different groups. However, MCAO resulted in enhanced conversion of LC3-I into LC3-II, P62 degradation, high levels of Beclin-1, a large area infarction (26.3±3.6%) and serious neurobehavioral deficits. GM1 (50 mg/kg) treatment significantly reduced the autophagy activation, neurobehavioral dysfunctions, and infarction volume (from 26.3% to 19.5%) without causing significant adverse side effects. However, this biological function could be abolished by Tat-Beclin-1. GM1 demonstrated safe and robust neuroprotective effects that are associated with the inhibition of autophagy following experimental stroke.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alzheimer's disease / Anesthesiology / Animals / Apoptosis / Apoptosis Regulatory Proteins - genetics / Apoptosis Regulatory Proteins - metabolism / Autophagy / Autophagy - drug effects / Beclin-1 / Biological effects / Blood / Brain / Brain - blood supply / Brain - drug effects / Brain - metabolism / Brain - pathology / Brain injury / Brain Ischemia - drug therapy / Brain Ischemia - genetics / Brain Ischemia - metabolism / Brain Ischemia - pathology / Cell death / Central nervous system / Cerebral blood flow / Cerebral infarction / Disease Models, Animal / Drug Administration Schedule / G(M1) Ganglioside - antagonists & inhibitors / G(M1) Ganglioside - pharmacology / Ganglioside GM1 / Gases / Gene Expression Regulation / Gene Products, tat - genetics / Gene Products, tat - metabolism / Guillain-Barre syndrome / Head injuries / Heart rate / Heat-Shock Proteins - genetics / Heat-Shock Proteins - metabolism / Histology / Hospitals / Hypoxia / Immunofluorescence / Infarction / Infarction, Middle Cerebral Artery - drug therapy / Infarction, Middle Cerebral Artery - genetics / Infarction, Middle Cerebral Artery - metabolism / Infarction, Middle Cerebral Artery - pathology / Inhibition / Injection / Injections, Intraperitoneal / Ischemia / Laboratory animals / Male / Microtubule-Associated Proteins - genetics / Microtubule-Associated Proteins - metabolism / Mortality / Neuroprotection / Neuroprotective Agents - antagonists & inhibitors / Neuroprotective Agents - pharmacology / Occlusion / Phagocytosis / Proteins / Rats / Rats, Sprague-Dawley / Recombinant Fusion Proteins - genetics / Recombinant Fusion Proteins - metabolism / Recombinant Fusion Proteins - pharmacology / Reperfusion / Rodents / Sequestosome-1 Protein / Side effects / Signal Transduction / Stroke / Stroke - drug therapy / Stroke - genetics / Stroke - metabolism / Stroke - pathology / Surgery / Survival Analysis / Western blotting