Published Online
on April 21, 2005

A more recent version of this article appeared on May 1, 2005

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Submitted on December 22, 2004
Revised on December 22, 2004
Accepted on February 18, 2005

Cannabidiol Prevents Cerebral Infarction Via a Serotonergic 5-Hydroxytryptamine_1A Receptor-Dependent Mechanism

Kenichi Mishima PhD; Kazuhide Hayakawa; Kohji Abe PhD; Tomoaki Ikeda PhD, MD; Nobuaki Egashira PhD; Katsunori Iwasaki PhD; and Michihiro Fujiwara PhD^*

From the Department of Neuropharmacology (K.M., K.H., N.E., K.I., M.F.), Faculty of Pharmaceutical Sciences, and Advanced Materials Institute (K.I., M.F.), Fukuoka University, Japan; Department of Obstetrics and Gynecology (T.I.), Miyazaki Medical College, University of Miyazaki, Japan; Department of Medical Physics (K.A.), School of Allied Health Sciences, Faculty of Medicine, Osaka University, Japan; and Department of Drug Safety Evaluation (K.A.), Developmental Research Laboratories, Shionogi and Co, Ltd, Osaka, Japan.

^* To whom correspondence should be addressed. E-mail: mfuji{at}fukuoka-u.ac.jp.

Background and Purpose--Cannabidiol has been reported to be a neuroprotectant, but the neuroprotective mechanism of cannabidiol remains unclear. We studied the neuroprotective mechanism of cannabidiol in 4-hour middle cerebral artery (MCA) occlusion mice.

Methods--Male MCA occluded mice were treated with cannabidiol, abnormal cannabidiol, anandamide, methanandamide, cannabidiol plus capsazepine, and cannabidiol plus WAY100135 before and 3 hours after MCA occlusion. The infarct size was determined after 24 hours (2,3,5-triphenyltetrazolium chloride staining). Cerebral blood flow (CBF) was measured at, before and 1, 2, 3, and 4 hours after MCA occlusion.

Results--Cannabidiol significantly reduced the infarct volume induced by MCA occlusion in a bell-shaped curve. Similarly, abnormal cannabidiol but not anandamide or methanandamide reduced the infarct volume. Moreover, the neuroprotective effect of cannabidiol was inhibited by WAY100135, a serotonin 5-hydroxytriptamine_1A (5-HT_1A) receptor antagonist but not capsazepine a vanilloid receptor antagonist. Cannabidiol increased CBF to the cortex, and the CBF was partly inhibited by WAY100135 in mice subjected to MCA occlusion.

Conclusions--Cannabidiol and abnormal cannabidiol reduced the infarct volume. Furthermore, the neuroprotective effect of cannabidiol was inhibited by WAY100135 but not capsazepine, and the CBF increased by cannabidiol was partially reversed by WAY100135. These results suggested that the neuroprotective effect of cannabidiol may be related to the increase in CBF through the serotonergic 5-HT_1A receptor.

Key words: cannabidiol • cerebral infarction • middle cerebral artery • serontonin receptor • 5HT_1A

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