Abstract
3-n-Butylphthalide (NBP) may be beneficial for the treatment of ischemic stroke with multiple actions on different pathophysiological processes. In the present study, we investigated the effect of NBP isomers on learning and memory impairment induced by chronic cerebral hypoperfusion in rats. Male Wistar rats were orally administered 10 and 30 mg/kg l-, d-, or dl-NBP daily for 23 days after bilateral permanent occlusion of the common carotid arteries. Rats receiving 10 mg/kg l-NBP performed significantly better in tests for spatial learning and memory, and they had attenuated cerebral pathology, including neuronal damage, white matter rarefaction, and glial activation compared with controls. Furthermore, 10 mg/kg l-NBP-treated rats had significantly higher choline acetyltransferase activity, decreased cortical lipid peroxide, and reduced hippocampal superoxide dismutase activity, compared with vehicle controls. However, d- and dl-NBP did not show significant beneficial effects. The present findings demonstrate that the beneficial effects of l-NBP on hypoperfusion-induced cognitive deficits may be due to preventing neuropathological alterations, inhibiting oxidative damage and increasing acetylcholine synthesis. Our results strongly suggest that l-NBP has therapeutic potential for the treatment of dementia caused by decreased cerebral blood flow.
Footnotes
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This work was supported by National 973 Fundamental Project of China Grant 2004CB518906; Program for Changjiang Scholars and Innovative Research Team in University Grant IRT0514; and Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine (Peking Union Medical College), Ministry of Education.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.118760.
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ABBREVIATIONS: VaD, vascular dementia; AD, Alzheimer's disease; BCCAO, bilateral permanent occlusion of the common carotid arteries; AChE, acetylcholinesterase; Ach, acetylcholine; WM, white matter; NBP, 3-n-butylphthalide; SOD, superoxide dismutase; CAT, catalase; GSH-Px, glutathione peroxidase; MDA, malondialdehyde; GFAP, glial fibrillary acidic protein; ChAT, choline acetyltransferase; PBS, phosphate-buffered saline; ANOVA, analysis of variance; Hippo, hippocampus.
- Received December 31, 2006.
- Accepted March 19, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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