Spinal astrocyte glutamate receptor 1 overexpression after ischemic insult facilitates behavioral signs of spasticity and rigidity
Spinal astrocyte glutamate receptor 1 overexpression after ischemic insult facilitates behavioral signs of spasticity and rigidity
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DOI：
10.1523/jneurosci.0989-07.2007
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发表时间：
2007-10-17
影响因子：
5.3
通讯作者：
Marsala, Martin
中科院分区：
文献类型：
--
作者：
Hefferan, Michael P.;Kucharova, Karolina;Marsala, Martin
利用大鼠缺血性截瘫模型，我们研究了脊髓AMA受体的表达及其在介导痉挛和僵硬中的作用。通过短暂阻断降主动脉结合全身性低血压诱导脊髓缺血。在踝关节屈曲前和屈曲过程中，通过同时测量外周肌阻力（PMR）和肌电图（EMG）确定痉挛/僵硬。此外，从腓肠肌记录霍夫曼反射（H反射）和运动诱发电位（MEP）。给动物植入鞘内导管用于药物递送，并注射AMPA受体拮抗剂NGX 424（tezampanel）、谷氨酸受体1（GluR 1）反义或载体。鞘内注射赋形剂无效，鞘内注射NGX 424对PMR产生剂量依赖性抑制[ED 50为0.44 μ g（0.33-0.58）]，以及强直和踝关节屈曲诱发的EMG活动。还观察到MEP和H反射的类似抑制。从痉挛动物的腰脊髓组织的蛋白质印迹分析表明，GluR 1的显着增加，但减少GluR 2和GluR 4蛋白。共聚焦和电子显微镜分析显示，从痉挛动物的脊髓切片反应性星形胶质细胞的GluR 1免疫反应性增加。选择性GluR 1敲低鞘内反义治疗导致痉挛和僵硬的有效减少，并同时下调神经元/星形胶质细胞GluR 1在腰髓。用AMPA处理大鼠星形胶质细胞培养物导致剂量依赖性谷氨酸释放，NGX 424阻断了这种作用。这些数据表明，AMPA/红藻氨酸受体拮抗剂可以代表一种新的治疗方法，在调节痉挛/僵硬的脊髓起源和星形胶质细胞可能是一个潜在的目标，这样的治疗。
Using a rat model of ischemic paraplegia, we examined the expression of spinal AMA receptors and their role in mediating spasticity and rigidity. Spinal ischemia was induced by transient occlusion of the descending aorta combined with systemic hypotension. Spasticity/ rigidity were identified by simultaneous measurements of peripheral muscle resistance (PMR) and electromyography (EMG) before and during ankle flexion. In addition, Hoffman reflex (H-reflex) and motor evoked potentials (MEPs) were recorded from the gastrocnemius muscle. Animals were implanted with intrathecal catheters for drug delivery and injected with the AMPA receptor antagonist NGX424 (tezampanel), glutamate receptor 1 (GluR1) antisense, or vehicle. Where intrathecal vehicle had no effect, intrathecal NGX424 produced a dose-dependent suppression of PMR [ED50 of 0.44 mu g (0.33-0.58)], as well as tonic and ankle flexion-evoked EMG activity. Similar suppression of MEP and H-reflex were also seen. Western blot analyses of lumbar spinal cord tissue from spastic animals showed a significant increase in GluR1 but decreased GluR2 and GluR4 proteins. Confocal and electron microscopic analyses of spinal cord sections from spastic animals revealed increased GluR1 immunoreactivity in reactive astrocytes. Selective GluR1 knockdown by intrathecal antisense treatment resulted in a potent reduction of spasticiy and rigidity and concurrent downregulation of neuronal/astrocytic GluR1 in the lumbar spinal cord. Treatment of rat astrocyte cultures with AMPA led to dose-dependent glutamate release, an effect blocked by NGX424. These data suggest that an AMPA/kainate receptor antagonist can represent a novel therapy in modulating spasticity/rigidity of spinal origin and that astrocytes may be a potential target for such treatment.