The neuroprotective effect of cannabidiol showed a dose-dependent bell-shaped curve. Abnormal cannabidiol, a cannabidiol analog, produced the same dose-dependent bellshaped curve as cannabidiol, and a higher dose of abnormal cannabidiol did not reduce the infarct volume.
The dose-dependent bell-shaped curve of cannabinoids is not surprising because a similar pattern has been seen for the anti-inflammatory effect of cannabidiol in a murine collagen–induced arthritis model.
Moreover, it has been shown for the reinforcing properties of CP55,940 using an intracere-broventricular self-administration paradigm in rats. Moreover, it has been reported that cannabidiol produced a dose-dependent bell-shaped curve for the electroencephalo-graphic flattening of total power in gerbils subjected to cerebral ischemia.
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Although cannabidiol has been reported to be a full, although weak, agonist of human VR1, in the present study, the neuroprotective effects of cannabidiol were not inhibited by capsazepine, a VR1 antagonist. This does not support the result that the bell-shaped curve obtained by cerebral infarction with increasing doses is related to VR1.
As for the other reason, it has been reported that cannabidiol produces carbon monoxide because phenol hydroxyl groups (Resorcin structure) in cannabidiol participated in the production of carbon monoxide. Moreover, carbon monoxide has been significantly associated with ischemic stroke mortality.
As for the results of these reports, they suggest that at higher doses, cannabidiol may produce a large infarction by MCA occlusion by promoting the production of carbon monoxide, whereas at lower doses, cannabidiol may not be able to prevent the infarct volume induced by the severe condition (ie, a 4-hour MCA occlusion).
In fact, in this study, higher or lower doses of cannabidiol enlarged the infarct volume induced by the 4-hour MCA occlusion. The dose-response curve of cannabidiol should be examined in detail.