Mukherjee Piali, Thomas Sunil, Pasinetti Giulio Maria
Department of Psychiatry, Mount Sinai School of Medicine, 1 Gustav L,, Levy Place, New York, NY 10029, USA.
J Neuroinflammation. 2008 Jan 29;5:5. doi: 10.1186/1742-2094-5-5.
The complement system is thought to be involved in the pathogenesis of numerous neurological diseases. We previously reported that pre-treatment of murine cortico-hippocampal neuronal cultures with the complement derived anaphylatoxin C5a, protects against glutamate mediated apoptosis. Our present study with C5a receptor knock out (C5aRKO) mice corroborates that the deficiency of C5a renders C5aRKO mouse more susceptible to apoptotic injury in vivo. In this study we explored potential upstream mechanisms involved in C5a mediated neuroprotection in vivo and in vitro.
Based on evidence suggesting that reduced expression of glutamate receptor subunit 2 (GluR2) may influence apoptosis in neurons, we studied the effect of human recombinant C5a on GluR2 expression in response to glutamate neurotoxicity. Glutamate analogs were injected into C5aRKO mice or used to treat in vitro neuronal culture and GluR2 expression were assessed in respect with cell death.
In C5aRKO mice we found that the neurons are more susceptible to excitotoxicity resulting in apoptotic injury in the absence of the C5a receptor compared to WT control mice. Our results suggest that C5a protects against apoptotic pathways in neurons in vitro and in vivo through regulation of GluR2 receptor expression.
Complement C5a neuroprotects through regulation of GluR2 receptor subunit.
补体系统被认为参与多种神经疾病的发病机制。我们之前报道过，用补体衍生的过敏毒素C5a预处理小鼠皮质-海马神经元培养物，可保护其免受谷氨酸介导的细胞凋亡。我们目前对C5a受体敲除（C5aRKO）小鼠的研究证实，C5a的缺乏使C5aRKO小鼠在体内更容易受到凋亡性损伤。在本研究中，我们探讨了体内和体外C5a介导神经保护作用的潜在上游机制。
基于有证据表明谷氨酸受体亚基2（GluR2）表达降低可能影响神经元凋亡，我们研究了重组人C5a对谷氨酸神经毒性反应中GluR2表达的影响。将谷氨酸类似物注射到C5aRKO小鼠体内或用于处理体外神经元培养物，并根据细胞死亡情况评估GluR2表达。
在C5aRKO小鼠中，我们发现与野生型对照小鼠相比，在缺乏C5a受体的情况下，神经元更容易受到兴奋性毒性作用，导致凋亡性损伤。我们的结果表明，C5a通过调节GluR2受体表达在体外和体内保护神经元免受凋亡途径的影响。
补体C5a通过调节GluR2受体亚基发挥神经保护作用。
