Imbalance in redox homeostasis is a major cause of age-related cognitive impairment. The endocannabinoid system (ECS) is a key player in regulating synaptic transmission, plasticity and memory. Increasing evidence indicates an important interplay between the two systems. However, how excessive oxidative stress could alter ECS and that, in turn, impairs its modulatory role in synaptic plasticity and cognitive function remains elusive. In the present study, we examined this causal link in D-galactose-induced oxidative rats. First, the reactive oxygen species generating enzymes, especially nitric oxide synthase (NOS), indeed show an elevated expression in D-galactose-treated rats, and this was correlated to an impaired hippocampal long-term potentiation (LTP) and spatial memory loss in animal behavioral tests. Second, the cannabinoid receptor type I (CB1)-mediated signaling is known to regulate synaptic plasticity. We show that a decrease in CB1 and increase in degradation enzymes for CB1 ligand endocannabinoid anandamide all occurred to D-galactose-treated rats. Surprisingly, application of low-dose anandamide, known to reduce LTP under physiological condition, now acted to enhance LTP in D-galactose-treated rats, most likely resulted from the inhibition of GABAergic synapses. Furthermore, this reversal behavior of CB1-signaling could be fully simulated by a NOS inhibitor, diphenyleneiodonium. These observations suggest that interaction between redox dysfunction and ECS should contribute significantly to the impaired synaptic plasticity and memory loss in D-galactose-treated rats. Therefore, therapies focusing on the balance of these two systems may shed lights on the treatment of age-related cognitive impairment in the future.

氧化还原稳态的失衡是与年龄有关的认知障碍的主要原因。内源性大麻素系统（ECS）是调节突触传递，可塑性和记忆的关键参与者。越来越多的证据表明这两个系统之间存在重要的相互作用。但是，过度的氧化应激如何改变ECS，进而削弱其在突触可塑性和认知功能中的调节作用，仍然难以捉摸。在本研究中，我们研究了这种因果关系d-半乳糖诱导的氧化大鼠。首先，产生活性氧的酶，尤其是一氧化氮合酶（NOS），确实在AFP中表达升高d-半乳糖治疗的大鼠，这与动物行为测试中受损的海马长时程增强（LTP）和空间记忆丧失有关。其次，已知大麻素I型（CB1）介导的信号传导可调节突触可塑性。我们表明，CB1的减少和CB1配体内源性大麻素anandamide降解酶的增加都发生了d-半乳糖治疗的大鼠。出人意料的是，已知在生理条件下可降低LTP的低剂量Anandamide的应用现在可以增强LTP的LTP。d-半乳糖处理的大鼠，最有可能是由抑制GABA能突触引起的。此外，CB1信号的这种逆转行为可以由NOS抑制剂二苯二碘鎓完全模拟。这些观察结果表明，氧化还原功能障碍和ECS之间的相互作用应显着促进受损的突触可塑性和记忆丧失。d-半乳糖治疗的大鼠。因此，将来着重于这两个系统的平衡的疗法可能会为与年龄相关的认知障碍的治疗提供启示。