Cerebral white matter lesions (WMLs) are frequently observed in vascular dementia and Alzheimer's disease and are believed to be responsible for cognitive dysfunction. The cerebral WMLs are most likely caused by chronic cerebral hypoperfusion and can be experimentally induced by permanent bilateral common carotid artery occlusion (BCCAO) in rats. Previous studies found the involvement of oxidative stress and astrocytic activation in the cerebral WMLs of BCCAO rats. Gypenoside (GP), a pure component extracted from the Gyrostemma pentaphyllum Makino, a widely reputed medicinal plants in China, has been reported to have some neuroprotective effects via anti-oxidative stress and anti-inflammatory mechanisms. In the present study, we investigated the protective effect of GP against cerebral WMLs and the underlying mechanisms for its inhibition of cognitive decline in BCCAO rats. Adult male Sprague-Dawley rats were orally administered daily doses of 200 and 400mg/kg GP for 33 days after BCCAO, and spatial learning and memory were assessed using the Morris water maze. Following behavioral testing, oxygen free radical levels and antioxidative capability were measured biochemically. The levels of lipid peroxidation and oxidative DNA damage were also assessed by immunohistochemical staining for 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine, respectively. Activated astrocytes were also assessed by immunohistochemical staining and Western blotting with GFAP antibodies. The morphological changes were stained with Klüver-Barrera. Rats receiving 400mg/kg GP per day performed significantly better in tests for spatial learning and memory than saline-treated rats. GP 400mg/kg per day were found to markedly scavenge oxygen free radicals, enhance antioxidant abilities, decrease lipid peroxide production and oxidative DNA damage, and inhibit the astrocytic activation in corpus callosum and optic tract in BCCAO rats. However, GP 200mg/kg per day had no significant effects. GP may have therapeutic potential for treating dementia induced by chronic cerebral hypoperfusion and further evaluation is warranted.
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