Hayakawa Kazuhide, Mishima Kenichi, Nozako Masanori, Ogata Ayumi, Hazekawa Mai, Liu An-Xin, Fujioka Masayuki, Abe Kohji, Hasebe Nobuyoshi, Egashira Nobuaki, Iwasaki Katsunori, Fujiwara Michihiro
Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Fukuoka City, Fukuoka 814-0180, Japan.
Neuropharmacology. 2007 Mar;52(4):1079-87. doi: 10.1016/j.neuropharm.2006.11.005. Epub 2007 Feb 21.
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.
已知Δ⁹-四氢大麻酚（Δ⁹-THC）和大麻二酚均具有抗脑缺血的神经保护作用。我们研究了对遭受4小时大脑中动脉（MCA）闭塞的小鼠重复给予这两种药物是否会导致其神经保护作用产生耐受性。大麻素CB₁受体拮抗剂SR141716可抑制Δ⁹-THC而非大麻二酚的神经保护作用。连续14天重复给予Δ⁹-THC而非大麻二酚会导致神经保护作用和体温降低作用产生耐受性。此外，重复给予Δ⁹-THC可逆转脑血流量（CBF）的增加，而大麻二酚则无此作用。重复给予Δ⁹-THC会导致MCA闭塞小鼠的CB₁受体脱敏和下调。相反，大麻二酚不影响这些作用。此外，5-羟色胺5-HT₁A受体拮抗剂WAY100135可部分抑制重复给予大麻二酚所诱导的神经保护作用和CBF增加。在使用1,1-二苯基-2-苦基肼基（DPPH）自由基的体外研究中，大麻二酚表现出比Δ⁹-THC更强的抗氧化能力。因此，大麻二酚是一种有效的抗氧化剂，不会对其神经保护作用产生耐受性，通过不依赖CB₁受体的机制发挥作用。希望大麻二酚将具有缓解作用，并为治疗脑血管疾病开辟新的治疗可能性。
