Department of Neurosciences, Case Western Reserve University School of Medicine, 2109 Adelbert Road, Cleveland, Ohio 44106, USA.
Nature. 2011 Jul 13;475(7355):196-200. doi: 10.1038/nature10199.
Spinal cord injuries often occur at the cervical level above the phrenic motor pools, which innervate the diaphragm. The effects of impaired breathing are a leading cause of death from spinal cord injuries, underscoring the importance of developing strategies to restore respiratory activity. Here we show that, after cervical spinal cord injury, the expression of chondroitin sulphate proteoglycans (CSPGs) associated with the perineuronal net (PNN) is upregulated around the phrenic motor neurons. Digestion of these potently inhibitory extracellular matrix molecules with chondroitinase ABC (denoted ChABC) could, by itself, promote the plasticity of tracts that were spared and restore limited activity to the paralysed diaphragm. However, when combined with a peripheral nerve autograft, ChABC treatment resulted in lengthy regeneration of serotonin-containing axons and other bulbospinal fibres and remarkable recovery of diaphragmatic function. After recovery and initial transection of the graft bridge, there was an unusual, overall increase in tonic electromyographic activity of the diaphragm, suggesting that considerable remodelling of the spinal cord circuitry occurs after regeneration. This increase was followed by complete elimination of the restored activity, proving that regeneration is crucial for the return of function. Overall, these experiments present a way to markedly restore the function of a single muscle after debilitating trauma to the central nervous system, through both promoting the plasticity of spared tracts and regenerating essential pathways.
脊髓损伤通常发生在膈神经运动池以上的颈部水平，膈神经运动池支配膈肌。呼吸功能受损是导致脊髓损伤死亡的主要原因，这凸显了开发恢复呼吸活动策略的重要性。在这里，我们表明，在颈脊髓损伤后，与周围神经网（PNN）相关的软骨素硫酸盐蛋白聚糖（CSPGs）在膈神经运动神经元周围的表达上调。用软骨素酶 ABC（简称 ChABC）消化这些具有强烈抑制作用的细胞外基质分子本身可以促进未受损的束的可塑性，并恢复瘫痪的膈肌的有限活动。然而，当与外周神经自体移植物联合使用时，ChABC 治疗导致含有 5-羟色胺的轴突和其他球脊纤维的长时间再生，并显著恢复膈肌功能。恢复和最初切断移植物桥后，膈肌的紧张性肌电图活动出现异常的整体增加，这表明脊髓回路在再生后发生了相当大的重塑。这种增加伴随着恢复活动的完全消除，证明再生对于功能的恢复至关重要。总的来说，这些实验提供了一种在中枢神经系统受到严重创伤后显著恢复单一肌肉功能的方法，既可以促进未受损束的可塑性，又可以再生重要的通路。
