The Adelson Center for the Biology of Addictive Diseases and The Mauerberger Chair in Neuropharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Br J Pharmacol. 2011 Aug;163(7):1391-401. doi: 10.1111/j.1476-5381.2011.01280.x.
Extensive in vitro and in vivo studies have shown that cannabinoid drugs have neuroprotective properties and suggested that the endocannabinoid system may be involved in endogenous neuroprotective mechanisms. On the other hand, neurotoxic effects of cannabinoids in vitro and in vivo were also described. Several possible explanations for these dual, opposite effects of cannabinoids on cellular fate were suggested, and it is conceivable that various factors may determine the final outcome of the cannabinoid effect in vivo. In the current review, we focus on one of the possible reasons for the dual neuroprotective/neurotoxic effects of cannabinoids in vivo, namely, the opposite effects of low versus high doses of cannabinoids. While many studies reported neuroprotective effects of the conventional doses of cannabinoids in various experimental models for acute brain injuries, we have shown that a single administration of an extremely low dose of Δ(9) -tetrahydrocannabinol (THC) (3-4 orders of magnitude lower than the conventional doses) to mice induced long-lasting mild cognitive deficits that affected various aspects of memory and learning. These findings led to the idea that this low dose of THC, which induces minor damage to the brain, may activate preconditioning and/or postconditioning mechanisms and thus will protect the brain from more severe insults. Indeed, our recent findings support this assumption and show that a pre- or a postconditioning treatment with extremely low doses of THC, several days before or after brain injury, provides effective long-term cognitive neuroprotection. The future therapeutical potential of these findings is discussed.
大量的体外和体内研究表明，大麻素类药物具有神经保护特性，并提示内源性大麻素系统可能参与内源性神经保护机制。另一方面，也描述了大麻素在体外和体内的神经毒性作用。对于大麻素对细胞命运的这种双重相反作用，提出了几种可能的解释，并且可以想象，各种因素可能决定大麻素在体内的最终作用结果。在当前的综述中，我们重点讨论了大麻素在体内产生双重神经保护/神经毒性作用的一种可能原因，即低剂量与高剂量大麻素的相反作用。虽然许多研究报告了大麻素在各种急性脑损伤的实验模型中的神经保护作用，但我们已经表明，单次给予极低剂量的 Δ(9)-四氢大麻酚（THC）（比常规剂量低 3-4 个数量级）可诱导小鼠产生持久的轻度认知缺陷，从而影响记忆和学习的各个方面。这些发现导致了这样一种想法，即这种低剂量的 THC 会对大脑造成轻微损伤，可能会激活预处理和/或后处理机制，从而保护大脑免受更严重的损伤。事实上，我们最近的研究结果支持了这一假设，并表明在脑损伤前或后几天用极低剂量的 THC 进行预处理或后处理，可以提供有效的长期认知神经保护。讨论了这些发现的未来治疗潜力。
