The Cannabinoid Receptor Agonist WIN55,212-2 Ameliorates Hippocampal Neuronal Damage After Chronic Cerebral Hypoperfusion Possibly Through Inhibiting Oxidative Stress and ASK1-p38 Signaling

Chronic cerebral hypoperfusion (CCH) is a major contributor to cognitive decline and degenerative processes leading to Alzheimer's disease, vascular dementia, and aging. However, the delicate mechanism of CCH-induced neuronal damage, and therefore proper treatment, remains unclear. WIN55,212-2 (WIN) is a nonselective cannabinoid receptor agonist that has been shown to have effects on hippocampal neuron survival. In this study, we investigated the potential roles of WIN, as well as its underlying mechanism in a rat CCH model of bilateral common carotid artery occlusion. Hippocampal morphological changes and mitochondrial ultrastructure were detected using hematoxylin and eosin staining and electron microscopy, respectively. Various biomarkers, such as reactive oxidative species (ROS), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were used to assess the level of oxidative stress in the hippocampus. Furthermore, the expression levels of neuronal nuclei (NeuN), apoptosis signal-regulating kinase 1 (ASK1)-p38 signaling proteins, cleaved Caspase-9 and -3, and cytochrome-c (Cyt-C) were accessed by western blotting. CCH decreased the levels of NeuN, Cyt-C (mitochondrial), SOD, and CAT, and increased the levels of MDA, phosphorylated ASK1 and phosphorylated p38, cleaved Caspase-9 and -3, and Cyt-C (cytoplasm), which were reversed by WIN treatment. Chronic treatment with WIN also improved CCH-induced neuronal degeneration and mitochondrial fragmentation. These findings indicated that WIN may be a potential therapeutic agent for ischemic neuronal damage, involving a mechanism associated with the suppression of oxidative stress and ASK1-p38 signaling.