Laboratory of Molecular Neuropharmacology, Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia.
Br J Pharmacol. 2020 Jan;177(1):65-76. doi: 10.1111/bph.14846. Epub 2019 Nov 6.
Botulinum toxin type A (BoNT/A) injections into hyperactive muscles provide effective treatment for spasticity and dystonias, presumably due to its local effects on extrafusal and intrafusal motor fibres. A recent discovery of toxin's retrograde axonal transport to CNS might suggest additional action sites. However, in comparison to cholinergic peripheral terminals, functional consequences of BoNT/A direct central action on abnormally increased muscle tone are presently unknown. To address this question, the central effects of BoNT/A were assessed in experimental local spastic paralysis.
Local spastic paralysis was induced by injection of tetanus toxin (1.5 ng) into rat gastrocnemius. Subsequently, BoNT/A (5 U·kg ) was applied i.m. into the spastic muscle or intraneurally (i.n.) into the sciatic nerve to mimic the action of axonally transported toxin. Functional role of BoNT/A transcytosis in spinal cord was evaluated by lumbar i.t. application of BoNT/A-neutralizing antitoxin. BoNT/A effects were studied by behavioural motor assessment and cleaved synaptosomal-associated protein 25 (SNAP-25) immunohistochemistry.
Tetanus toxin evoked muscular spasm (sustained rigid hind paw extension and resistance to passive ankle flexion). Subsequent injections of BoNT/A, i.m. or i.n, reduced tetanus toxin-evoked spastic paralysis. Beneficial effects of i.n. BoNT/A and occurrence of cleaved SNAP-25 in ventral horn were prevented by i.t. antitoxin.
Axonally transported BoNT/A relieves muscle hypertonia induced by tetanus toxin, following the trans-synaptic movement of BoNT/A in the CNS. These results suggest that such direct, centrally mediated reduction of abnormal muscle tone might contribute to the effectiveness of BoNT/A in spasticity and hyperkinetic movement disorders.
A型肉毒毒素（BoNT/A）注射到过度活跃的肌肉中为痉挛和肌张力障碍提供了有效的治疗，这可能是由于其对梭外和梭内运动纤维的局部作用。最近发现毒素逆行轴突运输到中枢神经系统可能提示了额外的作用部位。然而，与胆碱能周围末端相比，BoNT/A 对异常增加的肌肉张力的直接中枢作用的功能后果目前尚不清楚。为了解决这个问题，在实验性局部痉挛性瘫痪中评估了 BoNT/A 的中枢作用。
通过向大鼠腓肠肌注射破伤风毒素（1.5ng）诱导局部痉挛性瘫痪。随后，将 BoNT/A（5U·kg）肌内注射到痉挛肌肉或坐骨神经内注射（i.n.）以模拟轴突转运毒素的作用。通过腰椎 i.t.应用 BoNT/A 中和抗毒素评估 BoNT/A 经细胞转运在脊髓中的功能作用。通过行为运动评估和裂解突触相关蛋白 25（SNAP-25）免疫组织化学研究 BoNT/A 的作用。
破伤风毒素引起肌肉痉挛（持续的刚性后爪伸展和抵抗被动踝关节弯曲）。随后注射 BoNT/A，肌内或神经内，可减轻破伤风毒素引起的痉挛性瘫痪。i.t.抗毒素可预防 i.n. BoNT/A 的有益作用和腹角中裂解的 SNAP-25 的发生。
轴突转运的 BoNT/A 缓解了破伤风毒素诱导的肌肉张力过高，这是 BoNT/A 在中枢神经系统中的跨突触运动的结果。这些结果表明，这种直接的、中枢介导的异常肌肉张力降低可能有助于 BoNT/A 在痉挛和运动障碍中的有效性。
