Marmolino D, Manto M
Laboratoire de Neurologie Expérimentale, ULB-Erasme, Bruxelles, Belgium.
Neurosignals. 2010;18(4):210-22. doi: 10.1159/000322544. Epub 2010 Dec 30.
Copper plays key roles in brain metabolism. Disorders of copper metabolism impact on neural signaling. The intracellular and extracellular concentrations of copper are tightly regulated. Pregabalin is a drug with multiple modes of action and has a high-affinity binding site for the alpha2delta subunit of voltage-gated calcium channels.
Assessment of neuroprotective effects of pregabalin using cell culture, transcription studies, microdialysis and neurophysiological assessment in rats.
In vitro, copper decreased markedly the survival of neuronal cells and enhanced the production of nitric oxide (NO). Transcription of NO synthase (NOS) 1-3 and PGC-1a (a key regulator of mitochondrial biogenesis) was activated. In vivo, copper impaired the NMDA-mediated regulation of glutamate in the brain, increased the production of NO and enhanced markedly the excitability of the motor cortex. Pregabalin had antagonistic effects both in vitro and in vivo.
Our experiments highlight that pregabalin antagonizes the neurotoxic effects of copper. We argue that pregabalin exerts neuroprotective effects by silencing the overexcitability state induced by copper. We propose a possible use of pregabalin for treatment of disruption of copper homeostasis.
铜在脑代谢中起关键作用。铜代谢紊乱会影响神经信号传导。细胞内和细胞外的铜浓度受到严格调控。普瑞巴林是一种具有多种作用模式的药物，对电压门控钙通道的α2δ亚基具有高亲和力结合位点。
利用细胞培养、转录研究、微透析和对大鼠的神经生理学评估来评估普瑞巴林的神经保护作用。
在体外，铜显著降低神经元细胞的存活率并增强一氧化氮（NO）的产生。一氧化氮合酶（NOS）1 - 3和PGC - 1α（线粒体生物发生的关键调节因子）的转录被激活。在体内，铜损害大脑中NMDA介导的谷氨酸调节，增加NO的产生并显著增强运动皮层的兴奋性。普瑞巴林在体外和体内均具有拮抗作用。
我们的实验表明普瑞巴林可拮抗铜的神经毒性作用。我们认为普瑞巴林通过使铜诱导的过度兴奋状态失活来发挥神经保护作用。我们提出普瑞巴林可能用于治疗铜稳态破坏。
