Johanssen Timothy, Suphantarida Nuttawat, Donnelly Paul S, Liu Xiang M, Petrou Steven, Hill Andrew F, Barnham Kevin J
Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia; Centre for Neural Engineering and Department of Electrical and Electronic Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
Neurobiol Dis. 2015 Sep;81:176-85. doi: 10.1016/j.nbd.2015.02.008. Epub 2015 Feb 17.
Excitotoxicity is the pathological process by which neuronal death occurs as a result of excessive stimulation of receptors at the excitatory synapse such as the NMDA receptor (NMDAR). Excitotoxicity has been implicated in the acute neurological damage from ischemia and traumatic brain injury and in the chronic neurodegeneration in Alzheimer's disease (AD) and Huntington's disease (HD). As a result NMDAR antagonists have become an attractive therapeutic strategy for the potential treatment of multiple neurodegenerative diseases. However NMDAR signaling is dichotomous in nature, with excessive increases in neuronal intracellular calcium through excessive NMDAR activity being lethal but moderate increases to intracellular calcium levels during normal synaptic function providing neuroprotection. Subsequently indiscriminant inhibition of this receptor is best avoided as was concluded from previous clinical trials of NMDAR antagonists. We show that the metal chaperone, PBT2, currently in clinical trials for HD, is able to protect against glutamate-induced excitotoxicity mediated through NMDARs. This was achieved by PBT2 inducing Zn(2+)-dependent increases in intracellular Ca(2+) levels resulting in preconditioning of neurons and inhibition of Ca(2+)-induced neurotoxic signaling cascade involving calpain-activated cleavage of calcineurin. Our study demonstrates that modulating intracellular Ca(2+) levels by a zinc ionophore is a valid therapeutic strategy to protect against the effects of excitotoxicity thought to underlie both acute and chronic neurodegenerative diseases.
兴奋毒性是一种病理过程，在此过程中，由于兴奋性突触（如N-甲基-D-天冬氨酸受体，NMDAR）处的受体受到过度刺激，神经元发生死亡。兴奋毒性与缺血和创伤性脑损伤所致的急性神经损伤以及阿尔茨海默病（AD）和亨廷顿舞蹈症（HD）中的慢性神经退行性变有关。因此，NMDAR拮抗剂已成为一种有吸引力治疗策略，有望用于治疗多种神经退行性疾病。然而，NMDAR信号本质上具有双重性，通过过度的NMDAR活性导致神经元细胞内钙过度增加是致命的，但在正常突触功能期间细胞内钙水平适度增加则具有神经保护作用。随后，正如之前NMDAR拮抗剂的临床试验所总结的那样，最好避免不加区分地抑制这种受体。我们发现，目前正在进行HD临床试验的金属伴侣蛋白PBT2能够保护神经元免受由NMDAR介导的谷氨酸诱导的兴奋毒性。这是通过PBT2诱导细胞内Ca(2+)水平依赖锌离子增加来实现的，从而使神经元产生预处理，并抑制由钙蛋白酶激活的钙调神经磷酸酶裂解所引发的Ca(2+)诱导的神经毒性信号级联反应。我们的研究表明，通过锌离子载体调节细胞内Ca(2+)水平是一种有效的治疗策略，可以预防被认为是急性和慢性神经退行性疾病基础的兴奋毒性作用。
