Mechanisms underlying blood-brain barrier dysfunction in brain pathology and epileptogenesis: Role of astroglia
Mechanisms underlying blood-brain barrier dysfunction in brain pathology and epileptogenesis: Role of astroglia
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DOI：
10.1111/j.1528-1167.2012.03703.x
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发表时间：
2012-11-01
期刊：
影响因子：
5.6
通讯作者：
Steinhaeuser, Christian
中科院分区：
文献类型：
--
作者：
Kovacs, Richard;Heinemann, Uwe;Steinhaeuser, Christian
星形胶质细胞越来越被认为是神经元的平等伙伴，也有助于神经系统疾病，如癫痫。活化的星形胶质细胞是内侧颞叶癫痫和阿蒙角硬化症患者的共同标志。癫痫持续状态时血脑屏障（BBB）开放具有短期致癫痫作用，因为血清中的离子成分干扰神经元兴奋性。从长远来看，星形胶质细胞对白蛋白的摄取诱导转化生长因子β（TGF β）介导的信号级联反应，导致星形胶质细胞性质的变化。星形胶质细胞内向整流性K+通道的下调和水通道、水通道蛋白4的改变的表面表达导致空间K+缓冲的紊乱，从而使组织更容易癫痫发作。在癫痫动物模型中，星形胶质细胞缝隙连接蛋白Cx43和Cx 30的表达发生改变，海马组织缝隙连接通讯也发生改变。虽然缝隙连接通讯可能发挥促癫痫和抗癫痫作用，Cx43和Cx 30的双重敲除导致自发性癫痫样事件的发生。癫痫发作与脑血流量的大量增加有关，以满足增加的能量需求。微循环水平的血流动力学反应是由星形胶质细胞-周细胞相互作用介导的，与空间K+缓冲具有共同的机制。虽然许多星形胶质细胞的机制，包括空间K+缓冲，一氧化氮，腺苷，和代谢型谷氨酸受体（mGluR）介导的信号被改变癫痫，很少有人知道这些改变如何影响神经血管耦合。总之，星形胶质细胞激活神经元功能的改变之前，可能是至关重要的癫痫发生。因此，星形胶质细胞是开发抗癫痫药物的一个有前途的新靶点。
Astrocytes are increasingly recognized as equal partners to neurons, also contributing to neurologic disorders such as epilepsy. Activated astrocytes are a common hallmark in patients with mesial temporal lobe epilepsy and Ammon's horn sclerosis. Bloodbrain barrier (BBB) opening during status epilepticus has short-term proepileptic effects, as the ionic composition of serum interferes with neuronal excitability. In the long run, astrocytic uptake of albumin induces transforming growth factor beta (TGF beta)mediated signaling cascades, leading to changes in astrocytic properties. Down-regulation of astrocytic inward rectifier K+ channels and altered surface expression of the water channel, aquaporin 4 results in disturbances in spatial K+ buffering, thereby rendering the tissue more seizure prone. The expression of astrocytic gap junctional proteins connexin 43 (Cx43) and connexin 30 (Cx30) is altered in epilepsy, and changes in gap junctional communication were found in sclerotic hippocampal tissue in animal models of epilepsy. Although gap junctional communication might exert both proepileptic and antiepileptic effects, double knock out of Cx43 and Cx30 resulted in occurrence of spontaneous epileptiform events. Seizures are associated with massive increases in cerebral blood flow in order to cover the increased energy demand. Hemodynamic responses at the microcirculation level are mediated by astrocytepericyte interactions, sharing common mechanisms with spatial K+ buffering. Although many of the astrocytic mechanisms involving spatial K+ buffering, nitric oxide, adenosine, and metabotropic glutamate receptor (mGluR)-mediated signalling are altered in epilepsy, little is known how these alterations affect neurovascular coupling. In conclusion, astrocytic activation preceding alterations in neuronal function might critically contribute to epileptogenesis. Therefore, astrocytes represent a promising new target for the development of antiepileptic drugs.