The Institute for Drug Research, Division of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
The Institute for Drug Research, Division of Medicinal Chemistry, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
ACS Chem Neurosci. 2020 Sep 2;11(17):2577-2589. doi: 10.1021/acschemneuro.0c00255. Epub 2020 Aug 3.
Polyneuropathy is a disease involving multiple peripheral nerves injuries. Axon regrowth remains the major prerequisite for plasticity, regeneration, circuit formation, and eventually functional recovery and therefore, regulation of neurite outgrowth might be a candidate for treating polyneuropathies. In a recent study, we synthesized and established the methylene-cycloalkylacetate (MCAs) pharmacophore as a lead for the development of a neurotropic drug (inducing neurite/axonal outgrowth) using the PC12 neuronal model. In the present study we extended the characterizations of the in vitro neurotropic effect of the derivative 3-(3-allyl-2-methylenecyclohexyl) propanoic acid (MCA-13) on dorsal root ganglia and spinal cord neuronal cultures and analyzed its safety properties using blood biochemistry and cell counting, acute toxicity evaluation in mice and different in vitro "off-target" pharmacological evaluations. This MCA derivative deserves further preclinical mechanistic pharmacological characterizations including therapeutic efficacy in in vivo animal models of polyneuropathies, toward development of a clinically relevant neurotropic drug.
多发性神经病是一种涉及多种周围神经损伤的疾病。轴突再生仍然是可塑性、再生、回路形成以及最终功能恢复的主要前提条件，因此，调节神经突生长可能是治疗多发性神经病的候选药物。在最近的一项研究中，我们合成并建立了亚甲基环烷基乙酸（MCAs）药效团，作为开发神经营养药物（诱导神经突/轴突生长）的先导物，使用 PC12 神经元模型。在本研究中，我们扩展了衍生物 3-(3-烯丙基-2-亚甲基环己基)丙酸（MCA-13）对背根神经节和脊髓神经元培养物的体外神经营养作用的特性，并使用血液生化学和细胞计数分析其安全性特性，在小鼠中进行急性毒性评估和不同的体外“非靶点”药理学评估。这种 MCA 衍生物值得进一步进行临床前机制药理学特性研究，包括在多发性神经病的动物模型中的治疗效果，以开发出一种具有临床相关性的神经营养药物。
