mPGES-1 is found to be up-regulated in the dopaminergic neurons of the substantia nigra pars compacta (SNpc) of postmortem brain tissue from Parkinson’s disease (PD) patients and neurotoxin 6-hydroxydopamine (6-OHDA)-induced PD mice. Since the genetic deletion of mPGES-1 abolished 6-OHDA-induced PGE₂ production and 6-OHDA-induced dopaminergic neurodegeneration in vitro and in vivo models, mPGES-1 enzyme has the potential to be an important target for PD therapy. In the present work, we investigated whether a small organic molecule as mPGES-1 inhibitor could exhibit the neuroprotective effects against 6-OHDA-induced neurotoxicity in in vitro and in vivo models. For this research goal, a new series of arylsulfonyl hydrazide derivatives was prepared and investigated whether these compounds may protect neurons against 6-OHDA-induced neurotoxicity in both in vitro and in vivo studies. Among them, compound 7s (MPO-0144) as a mPGES-1 inhibitor (PGE₂ IC₅₀ = 41.77 nM; mPGES-1 IC₅₀ = 1.16 nM) exhibited a potent neuroprotection (ED₅₀ = 3.0 nM) against 6-OHDA-induced in PC12 cells without its own neurotoxicity (IC₅₀ = >10 μM). In a 6-OHDA-induced mouse model of PD, administration of compound 7s (1 mg/kg/day, for 7 days, i.p.) ameliorated motor impairments and dopaminergic neuronal damage. These significant biological effects of compound 7s provided the first pharmacological evidence that mPGES-1 inhibitor could be a promising therapeutic agent for PD patients.

发现 mPGES-1 在帕金森病 (PD) 患者和神经毒素 6-羟基多巴胺 (6-OHDA) 诱导的 PD 小鼠死后脑组织的黑质致密部 (SNpc) 的多巴胺能神经元中上调。由于 mPGES-1 的基因缺失在体外和体内模型中消除了 6-OHDA 诱导的 PGE ₂产生和 6-OHDA 诱导的多巴胺能神经变性，因此 mPGES-1 酶有可能成为 PD 治疗的重要靶标。在目前的工作中，我们研究了作为 mPGES-1 抑制剂的有机小分子是否可以在体外和体内表现出针对 6-OHDA 诱导的神经毒性的神经保护作用。楷模。为此研究目标，制备了一系列新的芳基磺酰肼衍生物，并在体外和体内研究中研究了这些化合物是否可以保护神经元免受 6-OHDA 诱导的神经毒性。其中，化合物7s ( MPO-0144 ) 作为 mPGES-1 抑制剂 (PGE ₂ IC ₅₀  = 41.77 nM; mPGES-1 IC ₅₀ = 1.16 nM  ) 对 6-OHDA- 表现出有效的神经保护作用 (ED ₅₀ = 3.0 nM)在 PC12 细胞中诱导而没有自身的神经毒性 (IC ₅₀  = >10 μM)。在 6-OHDA 诱导的 PD 小鼠模型中，给予化合物7s（1 mg/kg/天，持续 7 天，ip) 改善运动障碍和多巴胺能神经元损伤。化合物7s的这些显着生物学作用提供了第一个药理学证据，证明 mPGES-1 抑制剂可能是 PD 患者的一种有前途的治疗剂。