Repeated treatment with cannabidiol but not Δ⁹-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance

Both Δ⁹-tetrahydrocannabinol (Δ⁹-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 4 h-middle cerebral artery (MCA) occlusion. The neuroprotective effect of Δ⁹-THC but not cannabidiol was inhibited by SR141716, cannabinoid CB₁ receptor antagonist. Fourteen-day repeated treatment with Δ⁹-THC, but not cannabidiol, led to tolerance of the neuroprotective and hypothermic effects. In addition, repeated treatment with Δ⁹-THC reversed the increase in cerebral blood flow (CBF), while cannabidiol did not reverse that effect. Repeated treatment with Δ⁹-THC caused CB₁ 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 Δ⁹-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 CB₁ receptor-independent mechanism. It is to be hoped that cannabidiol will have a palliative action and open new therapeutic possibilities for treating cerebrovascular disorders.