Savigni Donna L, O'Hare Doig Ryan L, Szymanski Charis R, Bartlett Carole A, Lozić Ivan, Smith Nicole M, Fitzgerald Melinda
Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Animal Biology, The University of Western Australia, Crawley, WA 6009, Australia.
Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia; School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
Neuropharmacology. 2013 Dec;75:380-90. doi: 10.1016/j.neuropharm.2013.07.034. Epub 2013 Aug 16.
Following neurotrauma, cells beyond the initial trauma site undergo secondary degeneration, with excess Ca2+ a likely trigger for loss of neurons, compact myelin and function. Treatment using inhibitors of specific Ca2+ channels has shown promise in preclinical studies, but clinical trials have been disappointing and combinatorial approaches are needed. We assessed efficacy of multiple combinations of three Ca2+ channel inhibitors at reducing secondary degeneration following partial optic nerve transection in rat. We used lomerizine to inhibit voltage gated Ca2+ channels; oxidised adenosine-triphosphate (oxATP) to inhibit purinergic P2X7 receptors and/or 2-[7-(1H-imidazol-1-yl)-6-nitro-2,3-dioxo-1,2,3,4-tetrahydro quinoxalin-1-yl]acetic acid (INQ) to inhibit Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Only the three Ca2+ channel inhibitors delivered in combination significantly preserved visual function, as assessed using the optokinetic nystagmus visual reflex, at 3 months after injury. Preservation of retinal ganglion cells was partial and is unlikely to have accounted for differential effects on function. A range of the Ca2+ channel inhibitor combinations prevented swelling of optic nerve vulnerable to secondary degeneration. Each of the treatments involving lomerizine significantly increased the proportion of axons with normal compact myelin. Nevertheless, limiting decompaction of myelin was not sufficient for preservation of function in our model. Multiple combinations of Ca2+ channel inhibitors reduced formation of atypical node/paranode complexes; outcomes were not associated with preservation of visual function. However, prevention of lengthening of the paranodal gap that was only achieved by treatment with the three Ca2+ channel inhibitors in combination was an important additional effect that likely contributed to the associated preservation of the optokinetic reflex using this combinatorial treatment strategy.
神经创伤后，初始创伤部位以外的细胞会发生继发性变性，过量的Ca2+可能是神经元、紧密髓鞘和功能丧失的触发因素。在临床前研究中，使用特定Ca2+通道抑制剂进行治疗已显示出前景，但临床试验结果令人失望，因此需要采用联合治疗方法。我们评估了三种Ca2+通道抑制剂的多种组合在减少大鼠部分视神经横断后继发性变性方面的疗效。我们使用洛美利嗪抑制电压门控Ca2+通道；氧化三磷酸腺苷（oxATP）抑制嘌呤能P2X7受体和/或2-[7-(1H-咪唑-1-基)-6-硝基-2,3-二氧代-1,2,3,4-四氢喹喔啉-1-基]乙酸（INQ）抑制Ca2+通透的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体。在损伤后3个月，仅联合使用三种Ca2+通道抑制剂能显著保留视觉功能，这是通过视动性眼球震颤视觉反射评估得出的。视网膜神经节细胞的保留是部分性的，不太可能解释对功能的不同影响。一系列Ca2+通道抑制剂组合可防止易发生继发性变性的视神经肿胀。每种涉及洛美利嗪的治疗均显著增加了具有正常紧密髓鞘的轴突比例。然而，在我们的模型中，限制髓鞘脱致密化不足以保留功能。Ca2+通道抑制剂的多种组合减少了非典型结/旁结复合体的形成；结果与视觉功能的保留无关。然而，仅通过联合使用三种Ca2+通道抑制剂治疗才能实现的防止旁结间隙延长是一个重要的额外效果，这可能有助于使用这种联合治疗策略保留视动反射。
