Botulinum toxin type A impairs spinal control of movement following its axonal transport and transcytosis

Abstract

Background and purpose: Recent preclinical studies suggest that botulinum toxin type A (BoNT-A) reduces abnormal muscle tone following its traffic to second order spinal synapses. However, possible consequences of such actions on spinal neuromotor control that coordinates skilled movement have not been characterized. Therefore, we studied the central effect of BoNT-A on different motor functions and coordination in rats. Experimental approach: The lower limb motor pools were targeted by BoNT-A injection into both sciatic nerves (2 U per nerve) in combination with blockage of spinal transcytosis by intrathecal BoNT-A-specific antitoxin (5 iu). Motor effects on balance, fatigue, swimming, gait and digit abduction were followed up to day 56 post BoNT-A. Afterwards, the rats’ gastrocnemius was injected with tetanus toxin (TeNT) to evoke muscle spasm and exaggerated monosynaptic reflex. Immunodetection of BoNT-A-cleaved synaptosomal-associated protein 25 was performed in muscles and spinal cord at day 78 post BoNT-A. Key results: After sciatic injection, BoNT-A was anterogradely and retrogradely transported to muscle and spinal cord. Combined peripheral and central trans-synaptic BoNT-A action induced more pronounced deficits of examined motor functions vs its isolated peripheral action. Centrally mediated alleviation of TeNT-evoked muscle spasm was not accompanied by changes in monosynaptic reflex excitability. Conclusions and implications: Present results suggest that BoNT-A trans-synaptic actions in motor system involves spinal premotor circuits participating in normal locomotion and involuntary muscle spasm. This proposes the need for investigation of non-canonical modes and sites of toxin action on neuromotor control to fully understand its therapeutically desirable effect in movement disorders.