Toomey Lillian M, Bartlett Carole A, Majimbi Maimuna, Gopalasingam Gopana, Rodger Jennifer, Fitzgerald Melinda
Experimental and Regenerative Neurosciences, School of Biological Sciences, The University of Western Australia, 35 Stirling Hwy, Perth, WA, 6009, Australia.
Curtin Health Innovation Research Institute, Curtin University, Bentley, Australia.
Exp Brain Res. 2019 Jan;237(1):161-171. doi: 10.1007/s00221-018-5414-0. Epub 2018 Oct 26.
Following neurotrauma, secondary degeneration of neurons and glia adjacent to the injury leads to further functional loss. A combination of ion channel inhibitors (lomerizine + oxATP + YM872) has been shown to be effective at limiting structural and functional loss due to secondary degeneration. Here we assess efficacy of the combination where oxATP is replaced with Brilliant Blue G (BBG), a more clinically applicable P2X receptor inhibitor. Partial optic nerve transection was used to model secondary degeneration in adult female rats. Animals were treated with combinations of lomerizine + YM872 + oxATP or lomerizine + YM872 + BBG, delivered via osmotic mini-pump directly to the injury site. Outcomes assessed were Iba1 + and ED1 + microglia and macrophages, oligodendroglial cell numbers, node/paranode structure and visual function using the optokinetic nystagmus test. The lomerizine + BBG + YM872 combination was at least as effective at the tested concentrations as the lomerizine + oxATP + YM872 combination at preserving node/paranode structure and visual function when delivered locally. However, neither ion channel inhibitor combination significantly improved microglial/macrophage nor oligodendroglial numbers compared to vehicle-treated controls. In conclusion, a locally delivered combination of ion channel inhibitors incorporating lomerizine + BBG + YM872 is at least as effective at limiting secondary degeneration following partial injury to the optic nerve as the combination incorporating oxATP.
神经创伤后，损伤附近的神经元和神经胶质细胞的继发性变性会导致进一步的功能丧失。已证明离子通道抑制剂组合（洛美利嗪+氧化三磷酸腺苷+YM872）在限制继发性变性引起的结构和功能丧失方面是有效的。在此，我们评估用亮蓝G（BBG，一种更具临床适用性的P2X受体抑制剂）替代氧化三磷酸腺苷的组合的疗效。采用部分视神经横断术对成年雌性大鼠的继发性变性进行建模。动物通过渗透微型泵直接将洛美利嗪+YM872+氧化三磷酸腺苷或洛美利嗪+YM872+BBG组合输送到损伤部位进行治疗。使用视动性眼震试验评估的结果包括Iba1+和ED1+小胶质细胞和巨噬细胞、少突胶质细胞数量、结/旁结结构和视觉功能。当局部给药时，在测试浓度下，洛美利嗪+BBG+YM872组合在保留结/旁结结构和视觉功能方面至少与洛美利嗪+氧化三磷酸腺苷+YM872组合一样有效。然而，与载体处理的对照组相比，两种离子通道抑制剂组合均未显著改善小胶质细胞/巨噬细胞数量或少突胶质细胞数量。总之，局部递送的包含洛美利嗪+BBG+YM872的离子通道抑制剂组合在限制视神经部分损伤后的继发性变性方面至少与包含氧化三磷酸腺苷的组合一样有效。
