engleski

Centrally transported botulinum toxin type A relieves local spastic paralysis

Introduction: Injections of botulinum neurotoxin type A (BoNT/A) provide an essential treatment for muscle hyperactivity disorders such as spasticity and dystonias. Recently discovered BoNT/A enzymatic action in motor regions of the central nervous system (CNS) indicate the possible involvement of central action in its therapeutic effect. Centrally transported BoNT/A was shown to be a prerequisite to its antinociceptive activity, while up to now, the functional role of BoNT/A axonal transport in the motor nervous system has been unknown. Here, we studied the central effect of BoNT/A in experimental focal muscular hyperactivity evoked by tetanus toxin (TeNT). Methods: Localized muscle rigidity was induced by low-dose intramuscular (IM) TeNT into rat gastrocnemius (1 to 1.5 ng). Pharmacologic response to intramuscular and intrasciatic injection of BoNT/A (5 U/kg) and intraperitoneal R(+) baclofen (3 mg/kg) was assessed by different motor parameters and tests. BoNT/A transcytosis in the CNS was investigated by intrathecal BoNT/A antitoxin and cleaved synaptosomal-associated protein 25 (SNAP-25) immunohistochemistry. Results: TeNT injected into the calf muscle induced local spastic paralysis. Intramuscular and intrasciatic BoNT/A and baclofen reduced TeNT-evoked hind-paw extension and ankle flexion resistance, while intrasciatic BoNT/A improved rotarod performance. Intrasciatic BoNT/A led to accumulation of toxin enzymatic activity in the CNS without any paralytic effect in normal animals. The effect of intrasciatic BoNT/A on local spasticity and the occurrence of cleaved SNAP-25 in the ventral horn were prevented by intrathecal antitoxin, indicating that the toxin is transcytosed by extracellular movement into second-order synapses. Conclusion: Central effects of BoNT/A do not measurably affect normal motor function ; however, in our experiments, they eliminated local spastic paralysis induced by TeNT. Present results suggest that the central effects of BoNT/A might account for clinically observed improvements of muscle function in spastic conditions and dystonias that are not concurrent with local muscle paralysis

Axonal transport ; Botulinum toxin type A ; Local spastic paralysis ; Tetanus toxin ; Transcytosis ; Ventral horn

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