Repeated treatment with cannabidiol but not Delta9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance.
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.
Hayakawa
Kazuhide
K
Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Fukuoka City, Fukuoka 814-0180, Japan.
Mishima
Kenichi
K
Nozako
Masanori
M
Ogata
Ayumi
A
Hazekawa
Mai
M
Liu
An-Xin
AX
Fujioka
Masayuki
M
Abe
Kohji
K
Hasebe
Nobuyoshi
N
Egashira
Nobuaki
N
Iwasaki
Katsunori
K
Fujiwara
Michihiro
M
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002185:Cannabidiol / Q000627:therapeutic use*; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004361:Drug Tolerance / Q000502:physiology*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D000077285:Rimonabant; D012702:Serotonin Antagonists / Q000494:pharmacology; D013997:Time Factors
D018696:Neuroprotective Agents; D010879:Piperazines; D010880:Piperidines; D011720:Pyrazoles; D012702:Serotonin Antagonists; C081293:WAY 100135; D002185:Cannabidiol; D013759:Dronabinol; D000077285:Rimonabant