Department of Clinical Neurobiology, Peninsula College of Medicine and Dentistry, University of Plymouth, Plymouth, UK.
Neuropathol Appl Neurobiol. 2012 Oct;38(6):535-47. doi: 10.1111/j.1365-2990.2011.01248.x.
Δ⁹-tetrahydrocannabinol (Δ⁹-THC) is neuroprotective in models of Parkinson's disease (PD). Although CB1 receptors are increased within the basal ganglia of PD patients and animal models, current evidence suggests a role for CB1 receptor-independent mechanisms. Here, we utilized a human neuronal cell culture PD model to further investigate the protective properties of Δ⁹-THC.
Differentiated SH-SY5Y neuroblastoma cells were exposed to PD-relevant toxins: 1-methyl-4-phenylpyridinium (MPP+), lactacystin and paraquat. Changes in CB1 receptor level were determined by quantitative polymerase chain reaction and Western blotting. Cannabinoids and modulatory compounds were co-administered with toxins for 48 h and the effects on cell death, viability, apoptosis and oxidative stress assessed.
We found CB1 receptor up-regulation in response to MPP+, lactacystin and paraquat and a protective effect of Δ⁹-THC against all three toxins. This neuroprotective effect was not reproduced by the CB1 receptor agonist WIN55,212-2 or blocked by the CB1 antagonist AM251. Furthermore, the antioxidants α-tocopherol and butylhydroxytoluene as well as the antioxidant cannabinoids, nabilone and cannabidiol were unable to elicit the same neuroprotection as Δ⁹-THC. However, the peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist T0070907 dose-dependently blocked the neuroprotective, antioxidant and anti-apoptotic effects of Δ⁹-THC, while the PPARγ agonist pioglitazone resulted in protection from MPP+-induced neurotoxicity. Furthermore, Δ⁹-THC increased PPARγ expression in MPP+-treated SH-SY5Y cells, another indicator of PPARγ activation.
We have demonstrated up-regulation of the CB1 receptor in direct response to neuronal injury in a human PD cell culture model, and a direct neuronal protective effect of Δ⁹-THC that may be mediated through PPARγ activation.
Δ⁹-四氢大麻酚（Δ⁹-THC）在帕金森病（PD）模型中具有神经保护作用。尽管 PD 患者和动物模型的基底神经节中 CB1 受体增加，但目前的证据表明存在 CB1 受体非依赖性机制。在这里，我们利用人类神经元细胞培养 PD 模型来进一步研究 Δ⁹-THC 的保护特性。
分化的 SH-SY5Y 神经母细胞瘤细胞暴露于与 PD 相关的毒素：1-甲基-4-苯基吡啶（MPP+）、乳酰半胱氨酸和百草枯。通过定量聚合酶链反应和 Western blot 测定 CB1 受体水平的变化。将大麻素和调节化合物与毒素共同给药 48 小时，并评估对细胞死亡、活力、细胞凋亡和氧化应激的影响。
我们发现 CB1 受体在 MPP+、乳酰半胱氨酸和百草枯的作用下上调，Δ⁹-THC 对这三种毒素均具有保护作用。这种神经保护作用不能被 CB1 受体激动剂 WIN55,212-2 复制，也不能被 CB1 拮抗剂 AM251 阻断。此外，抗氧化剂 α-生育酚和丁羟甲苯以及抗氧化大麻素纳比隆和大麻二酚也不能产生与 Δ⁹-THC 相同的神经保护作用。然而，过氧化物酶体增殖物激活受体-γ（PPARγ）拮抗剂 T0070907 剂量依赖性地阻断了 Δ⁹-THC 的神经保护、抗氧化和抗细胞凋亡作用，而 PPARγ 激动剂吡格列酮则导致 MPP+诱导的神经毒性得到保护。此外，Δ⁹-THC 增加了 MPP+处理的 SH-SY5Y 细胞中 PPARγ 的表达，这是 PPARγ 激活的另一个指标。
我们已经证明，在人类 PD 细胞培养模型中，CB1 受体在神经元损伤的直接反应中上调，并且 Δ⁹-THC 具有直接的神经元保护作用，这可能是通过 PPARγ 激活介导的。
