Novel Application Of Common Pharmacological Agents Nimodipine And Botulinum Toxin A On Traumatic Nerve Regeneration Following Microsurgical Repair: A Pilot Study
Scott K. Odorico, BS, Nikita Shulzhenko, MD, Weifeng Zeng, MD, Aaron Dingle, PhD, David Francis, MD, Samuel Poore, MD, PhD.
University of Wisconsin-Madison, Madison, WI, USA.
Purpose: Peripheral nerve damage is a frequent problem in civilian and military populations; an estimated 2.8-5% of trauma admissions contain a peripheral nerve injury. Currently, end-to-end, tension-free microsurgical nerve repair (neurorrhaphy) is the gold standard treatment. However, neurorrhaphy is not neuroprotective and does not address the complex molecular environment of a regenerating nerve required for complete functional restoration. Anecdotal clinical evidence indicates that widely used pharmacological agents botulinum toxin A (BTX, a neurotoxic protein) and nimodipine (NDP, a L-type calcium channel blocker) may improve functional recovery of injured nerves, but the mechanisms remain unknown. This research investigates BTX and NDP, independently and in combination, for their novel capacity to improve neural regeneration and functional recovery following neurorrhaphy.
Methods: 32 Lewis rats underwent surgical tibial nerve transection and neurorrhaphy. Post-op pharmaceutical treatment groups included: 1) Sham surgery (n=4); 2) Sham surgery+BTX (n=4); 3) NDP+saline injection (control for BTX, N=6); 4) BTX+NDP (n=6); 5) Saline+placebo pill (control for NDP, n=6); 6) BTX+placebo pill (n=6). Outcomes were assessed using behavioral (rotarod, horizontal ladder walk), electrophysiological (nerve conduction velocity [NCV], compound nerve action potential [CNAP], duration of response), and stereological means (myelinated axon count estimation, epineurial cross sectional area). Statistical significance was determined by one-way ANOVA.
Results: The NDP+saline group outperformed other treatment groups in the ladder walk, resulting in the fewest deep slips (15.07% vs 30.77% in BTX+NDP, p=0.117), fewest misses (3.54% vs 4.21% in BTX+NDP, p=0.809), and most correct steps (70.53% vs 55.58% in BTX+NDP, p=0.143). Rotarod testing resulted in no clear differences between treatment groups with all groups performing worse than sham controls. There was an observed sex bias between groups in which females tended to outperform males within groups in both behavioral modalities. Electrophysiological testing portrayed similar outcomes to ladder walk testing in which NDP+saline resulted in the fastest NCV (0.81m/s vs 0.59m/s in BTX+NDP, p=0.126), and shortest duration of response (22.68Ás vs 65.96Ás in BTX+NDP, p=0.171) among the treatment groups. Our unbiased stereological analyses resulted in the BTX+NDP group having the highest myelinated axon count (9,249.54 vs 7,334.94 in NDP+saline, p=0.036), but when epineurial area is controlled for, this difference diminishes (0.005/um2 vs 0.0043/um2 in NDP+saline, p=0.201). When separated by sex, males tended to have higher axon counts than females (8,615.03 vs 6,052.84 in NDP+saline, p=0.036).
Conclusions: This pilot study represents the first approach to test NDP with BTX in a multimodal assessment of nerve recovery and regeneration following transection and neurorrhaphy. While an additive or synergistic effect between BTX and NDP was expected, NDP alone tended to outperform the combined treatment group in behavioral and electrophysiological assessments. However, and in accordance with past studies by our group and others, histologic axon count was inversely related to nerve function recovery, portraying a disadvantageous compensatory effect. Our findings of a sex bias parallel observations present in the current literature. Future work will expand on these studies focusing on nimodipine in males and females in an effort to improve nerve recovery in trauma patients.
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