Department of Pathology and Cell Biology, Université de Montréal, Montreal, Quebec, Canada.
Cell Death Dis. 2010;1(2):e27. doi: 10.1038/cddis.2009.23.
Glaucoma is the leading cause of irreversible blindness worldwide. Loss of vision due to glaucoma is caused by the selective death of retinal ganglion cells (RGCs). Treatments for glaucoma, limited to drugs or surgery to lower intraocular pressure (IOP), are insufficient. Therefore, a pressing medical need exists for more effective therapies to prevent vision loss in glaucoma patients. In this in vivo study, we demonstrate that systemic administration of galantamine, an acetylcholinesterase inhibitor, promotes protection of RGC soma and axons in a rat glaucoma model. Functional deficits caused by high IOP, assessed by recording visual evoked potentials from the superior colliculus, were improved by galantamine. These effects were not related to a reduction in IOP because galantamine did not change the pressure in glaucomatous eyes and it promoted neuronal survival after optic nerve axotomy, a pressure-independent model of RGC death. Importantly, we demonstrate that galantamine-induced ganglion cell survival occurred by activation of types M1 and M4 muscarinic acetylcholine receptors, while nicotinic receptors were not involved. These data provide the first evidence of the clinical potential of galantamine as neuroprotectant for glaucoma and other optic neuropathies, and identify muscarinic receptors as potential therapeutic targets for preventing vision loss in these blinding diseases.
青光眼是全球范围内导致不可逆性失明的主要原因。青光眼导致的视力丧失是由视网膜神经节细胞（RGC）的选择性死亡引起的。目前，青光眼的治疗方法仅限于降低眼内压（IOP）的药物或手术，这些方法还不够有效。因此，迫切需要更有效的治疗方法来防止青光眼患者的视力丧失。在这项体内研究中，我们证明了全身性给予乙酰胆碱酯酶抑制剂加兰他敏可促进大鼠青光眼模型中 RGC 体和轴突的保护。通过从上丘记录视觉诱发电位来评估由高眼压引起的功能缺陷，加兰他敏可改善这些功能缺陷。这些作用与眼压降低无关，因为加兰他敏不会改变青光眼眼中的压力，而且它在视神经切断后促进神经元存活，视神经切断是一种与压力无关的 RGC 死亡模型。重要的是，我们证明了加兰他敏诱导的神经节细胞存活是通过激活 M1 和 M4 型毒蕈碱乙酰胆碱受体实现的，而烟碱受体则不参与其中。这些数据首次提供了加兰他敏作为治疗青光眼和其他视神经病变的神经保护剂的临床潜力的证据，并确定毒蕈碱受体可能是预防这些致盲性疾病视力丧失的潜在治疗靶点。
