Neurology Division, Louis Stokes Cleveland Dept. of Veterans Affairs Medical Center, Cleveland, Ohio, United States of America.
PLoS One. 2013;8(2):e57895. doi: 10.1371/journal.pone.0057895. Epub 2013 Feb 25.
The potassium channel antagonist 4-aminopyridine (4-AP) improves a variety of motor abnormalities associated with disorders of the cerebellum. The most rigorous quantitative data relate to 4-AP's ability to improve eye movement deficits in humans referable to dysfunction of the cerebellar flocculus. Largely based on work in the ataxic mouse mutant tottering (which carries a mutation of the Cacna1a gene of the P/Q voltage-activated calcium channel), 4-AP is hypothesized to function by enhancing excitability or rhythmicity of floccular Purkinje cells. We tested this hypothesis by determining whether systemic or intrafloccular administration of 4-AP would ameliorate the eye movement deficits in tottering that are attributable to flocculus dysfunction, including the reductions in amplitude of the yaw-axis vestibulo-ocular reflex (VOR) and vision-enhanced vestibulo-ocular reflex (VVOR), and the optokinetic reflex (OKR) about yaw and roll axes. Because tottering's deficits increase with age, both young and elderly mutants were tested to detect any age-dependent 4-AP effects. 4-AP failed to improve VOR, VVOR, and OKR gains during sinusoidal stimuli, although it may have reduced the tendency of the mutants' responses to VOR and VVOR to decline over the course of a one-hour recording session. For constant-velocity optokinetic stimuli, 4-AP generated some enhancement of yaw OKR and upward-directed roll OKR, but the effects were also seen in normal C57BL/6 controls, and thus do not represent a specific reversal of the electrophysiological consequences of the tottering mutation. Data support a possible extra-floccular locus for the effects of 4-AP on habituation and roll OKR. Unilateral intrafloccular 4-AP injections did not affect ocular motility, except to generate mild eye elevations, consistent with reduced floccular output. Because 4-AP did not produce the effects expected if it normalized outputs of floccular Purkinje cells, there is a need for further studies to elucidate the drug's mechanism of action on cerebellar motor dysfunction.
钾通道拮抗剂 4-氨基吡啶（4-AP）可改善与小脑功能障碍相关的多种运动异常。最严格的定量数据与 4-AP 改善与小脑绒球功能障碍相关的人类眼球运动缺陷的能力有关。在共济失调小鼠突变体 tottering（携带 P/Q 电压激活钙通道的 Cacna1a 基因突变）的研究基础上，4-AP 被假设通过增强绒球浦肯野细胞的兴奋性或节律性起作用。我们通过确定全身性或绒球内给予 4-AP 是否会改善 tottering 的眼球运动缺陷来测试该假设，这些缺陷归因于绒球功能障碍，包括 yaw 轴前庭眼反射（VOR）和视觉增强前庭眼反射（VVOR）的振幅降低，以及 yaw 和 roll 轴的视动反射（OKR）。由于 tottering 的缺陷随年龄增长而增加，因此测试了年轻和老年突变体以检测任何年龄相关的 4-AP 作用。4-AP 未能改善正弦刺激期间的 VOR、VVOR 和 OKR 增益，尽管它可能降低了突变体对 VOR 和 VVOR 的反应在一个小时的记录过程中下降的趋势。对于恒速视动刺激，4-AP 产生了 yaw OKR 和向上定向的 roll OKR 的一些增强，但在正常 C57BL/6 对照中也观察到了这些作用，因此不能代表 tottering 突变的电生理后果的特异性逆转。数据支持 4-AP 对习惯化和 roll OKR 的影响可能存在于绒球外的位置。单侧绒球内 4-AP 注射不会影响眼球运动，除了产生轻微的眼球抬高，这与绒球输出减少一致。由于 4-AP 没有产生如果它使绒球浦肯野细胞的输出正常化所预期的效果，因此需要进一步的研究来阐明药物对小脑运动功能障碍的作用机制。
