Authors:
Hayakawa K, Mishima K, Nozako M, Ogata A, Hazekawa M, Liu AX, Fujioka M, Abe K, Hasebe N, Egashira N, Iwasaki K, Fujiwara M.
Abstract:
Both Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and cannabidiol are
known to have a neuroprotective effect against cerebral ischemia. We
examined whether repeated treatment with both drugs led to tolerance of
their neuroprotective effects in mice subjected to 4h-middle cerebral
artery (MCA) occlusion. The neuroprotective effect of Delta(9)-THC but
not cannabidiol was inhibited by SR141716, cannabinoid CB(1) receptor
antagonist. Fourteen-day repeated treatment with Delta(9)-THC, but not
cannabidiol, led to tolerance of the neuroprotective and hypothermic
effects. In addition, repeated treatment with Delta(9)-THC reversed the
increase in cerebral blood flow (CBF), while cannabidiol did not reverse
that effect. Repeated treatment with Delta(9)-THC caused CB(1) receptor
desensitization and down-regulation in MCA occluded mice. On the
contrary, cannabidiol did not influence these effects. Moreover, the
neuroprotective effect and an increase in CBF induced by repeated
treatment with cannabidiol were in part inhibited by WAY100135,
serotonin 5-HT(1A) receptor antagonist. Cannabidiol exhibited stronger
antioxidative power than Delta(9)-THC in an in vitro study using the
1,1-diphenyl-2-picryhydrazyl (DPPH) radical. Thus, cannabidiol is a
potent antioxidant agent without developing tolerance to its
neuroprotective effect, acting through a CB(1) receptor-independent
mechanism. It is to be hoped that cannabidiol will have a palliative
action and open new therapeutic possibilities for treating
cerebrovascular disorders.