Introduction: Botulinum toxin type A (BTxA) is used to treat a wide variety of conditions including cervical dystonia, achalasia, and facial rhytides. Although diffusion outside the intended area of effect is a known complication of BTxA injection, there is no agent currently available to reverse or accelerate recovery from BTxA spread. Though self-limited, the effects of unwanted muscle paralysis can last from weeks to months. The mechanism of recovery from the toxin involves neuronal sprouting that acts as a temporary “crutch,” allowing for some synaptic transmission before the sprouts retract and the original endplates recover. Neurturin (NTN), a polypeptide neurotrophic factor in the glial cell line-derived neurotrophic factor (GDNF) family of ligands, plays a critical role in the development of the peripheral nervous system and has been shown to induce neuronal sprouting. Therefore, NTN may be able to modulate motor recovery from BTxA poisoning. The purpose of this study was to assess if injection of NTN leads to accelerated recovery from BTxA injections in mice.
Methods: 41 mice underwent muscle force testing. Eight mice served as positive and negative controls, while a further 18 received injections of 5pg of BTxA into the left and right gastrocnemius at t= -7days. At t=0, they received injections of 100pg of NTN into the left gastrocnemius, and vehicle solution (0.1% BSA) in the right. Three animals were randomly selected to undergo muscle force testing at each of 6 time points (t=0, 7, 14, 21, 28, 35days). Another group of 15 animals was repeated using 100ng of NTN for rescue of the left gastrocnemius.
Results: Animals were grouped according to days post-NTN rescue (t=0 to t=35days). NTN treated muscles had statistically significant increased peak tetanic forces in comparison to the non-NTN treated muscles by t = 21days (p-value 0.045, Student’s t-test) in the 100pg group. Significant differences in the 100ng group were seen as early as t=7 d (p-value 0.0009).
Conclusions: NTN accelerates recovery from BTxA poisoning of mouse gastrocnemius muscles. The magnitude of the effect is not dose-dependent between the 100pg and 100ng groups. The mechanism is likely explained by induction of novel nerve sprouting—pending in vivo architecture studies will provide additional information. The ease of delivery (injection) of NTN makes it an ideal therapy that is both effective and simple to employ. Our study suggests NTN may serve as a novel therapy for reversal of unintended BTxA spread, and could significantly reduce muscle paralysis time.