title: Repeated treatment with cannabidiol but not Delta9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance.
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.
authors.affiliation: Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Fukuoka City, Fukuoka 814-0180, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Kenichi
authors.initials: K
authors.lastname: Mishima
authors.forename: Masanori
authors.initials: M
authors.lastname: Nozako
authors.forename: Ayumi
authors.initials: A
authors.lastname: Ogata
authors.forename: Mai
authors.initials: M
authors.lastname: Hazekawa
authors.forename: An-Xin
authors.initials: AX
authors.lastname: Liu
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujioka
authors.forename: Kohji
authors.initials: K
authors.lastname: Abe
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Hasebe
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Egashira
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iwasaki
authors.forename: Michihiro
authors.initials: M
authors.lastname: Fujiwara
mesh_terms: 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
chemical_list: D018696:Neuroprotective Agents; D010879:Piperazines; D010880:Piperidines; D011720:Pyrazoles; D012702:Serotonin Antagonists; C081293:WAY 100135; D002185:Cannabidiol; D013759:Dronabinol; D000077285:Rimonabant