In the present study we evaluated the long-term effects of lithium administration to a knock-out double transgenic mouse model (Smn-/-; SMN1A2G+/-; SMN2+/+) of Spinal Muscle Atrophy type III (SMA-III). This model is characterized by very low levels of the survival motor neuron protein, slow disease progression and motor neuron loss, which enables to detect disease-modifying effects at delayed time intervals. Lithium administration attenuates the decrease in motor activity and provides full protection from motor neuron loss occurring in SMA-III mice, throughout the disease course. In addition, lithium prevents motor neuron enlargement and motor neuron heterotopy and suppresses the occurrence of radial-like glial fibrillary acidic protein immunostaining in the ventral white matter of SMA-III mice. In SMA-III mice long-term lithium administration determines a dramatic increase of survival motor neuron protein levels in the spinal cord. These data demonstrate that long-term lithium administration during a long-lasting motor neuron disorder attenuates behavioural deficit and neuropathology. Since low level of survival motor neuron protein is bound to disease severity in SMA, the robust increase in protein level produced by lithium provides solid evidence which calls for further investigations considering lithium in the long-term treatment of spinal muscle atrophy.

中文翻译：

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在缓慢进行的SMA小鼠模型中长期给予锂的保护作用。

在本研究中，我们评估了锂对III型脊髓萎缩症（SMA-III）的基因敲除双转基因小鼠模型（Smn-/-; SMN1A2G +/-; SMN2 + / +）的长期影响。该模型的特点是存活的运动神经元蛋白水平非常低，疾病进展缓慢和运动神经元丢失，从而能够在延迟的时间间隔内检测出疾病改善作用。在整个疾病过程中，锂的施用减弱了运动活性的降低，并提供了针对SMA-III小鼠中运动神经元丢失的全面保护。此外，锂可防止SMA-III小鼠腹侧白质中运动神经元增大和运动神经元异位，并抑制放射状神经胶质原纤维酸性蛋白的免疫染色。在SMA-III小鼠中，长期服用锂决定了脊髓中存活运动神经元蛋白水平的急剧增加。这些数据表明，在长期运动神经元疾病期间长期给予锂可减轻行为缺陷和神经病理学。由于低水平的存活运动神经元蛋白与SMA中疾病的严重程度有关，因此锂产生的蛋白水平的强劲增加提供了有力的证据，这就需要对锂在长期治疗脊髓性肌萎缩症中进行进一步研究。