Icariside II Affects Hippocampal Neuron Axon Regeneration and Improves Learning and Memory in a Chronic Cerebral Hypoperfusion Rat Model

Chronic cerebral hypoperfusion (CCH) is a basic pathological process that is comorbid with brain diseases, such as vascular Parkinsonism and Alzheimer's disease. Icariside II (ICS II), which is one of the main metabolites of icariin, has anti-inflammatory and antioxidant effects and protects against ischemic brain injury. This study aims to investigate the neuroprotective effects of ICS II on neuronal axon regeneration-related factors in a CCH rat model. Sprague-Dawley (SD) rats were divided into the following four groups: sham group, model group and 4 and 8 mg/kg/day ICS II administration groups. Learning and spatial memory functions were tested using a Morris water maze. Pathological changes were observed in the rat hippocampal tissue by hematoxylin and eosin (H&E) staining. Neuronal axon regeneration-related proteins (GAP-43, MAP-2 and Nogo-A) were observed by immunohistochemical staining and detected by the average optical density method. The results showed that 8 mg/kg/day of ICS II can effectively reduce the escape latency and prolong the target quadrant residence time at 12 weeks and that ICS II can improve the histopathological changes in the CA1 area of the rat hippocampus. Moreover, ICS II administration at 8 mg/kg/day significantly increased GAP-43 and MAP-2 expression and reduced Nogo-A expression in the CA1 area of the rat hippocampus at 12 weeks; however, significant differences were not observed at 4 and 8 weeks. Hence, ICS II at a dosage of 8 mg/kg/day could promote learning and memory abilities and improve histopathological changes in the rat hippocampus in a CCH rat model. These results may be related to the promotion of neuronal axon regeneration in the CA1 area of the hippocampus under increases in hippocampal GAP-43 and MAP-2 protein expression and decreased Nogo-A protein expression.