Grande Valentina, Manassero Giusi, Vercelli Alessandro
Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience, University of Torino, Orbassano, Torino, Italy.
Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience, University of Torino, Orbassano, Torino, Italy; Department of Internal Medicine, University of Genova, Genova, Italy.
PLoS One. 2014 Dec 12;9(12):e114554. doi: 10.1371/journal.pone.0114554. eCollection 2014.
Excitotoxic damage represents the major mechanism leading to cell death in many human neurodegenerative diseases such as ischemia, trauma and epilepsy. Caused by an excess of glutamate that acts on metabotropic and ionotropic excitatory receptors, excitotoxicity activates several death signaling pathways leading to an extensive neuronal loss and a consequent strong activation of astrogliosis. Currently, the search for a neuroprotective strategy is aimed to identify the level in the signaling pathways to block excitotoxicity avoiding the loss of important physiological functions and side effects. To this aim, PTEN can be considered an ideal candidate: downstream the excitatory receptors activated in excitotoxicity (whose inhibition was shown to be not clinically viable), it is involved in neuronal damage and in the first stage of the reactive astrogliosis in vivo. In this study, we demonstrated the involvement of PTEN in excitotoxicity through its pharmacological inhibition by dipotassium bisperoxo (picolinato) oxovanadate [bpv(pic)] in a model of temporal lobe epilepsy, obtained by intraperitoneal injection of kainate in 2-month-old C57BL/6J male mice. We have demonstrated that inhibition of PTEN by bpv(pic) rescues neuronal death and decreases the reactive astrogliosis in the CA3 area of the hippocampus caused by systemic administration of kainate. Moreover, the neurotoxin administration increases significantly the scanty presence of mitochondrial PTEN that is significantly decreased by the administration of the inhibitor 6 hr after the injection of kainate, suggesting a role of PTEN in mitochondrial apoptosis. Taken together, our results confirm the key role played by PTEN in the excitotoxic damage and the strong anti-inflammatory and neuroprotective potential of its inhibition.
兴奋性毒性损伤是导致许多人类神经退行性疾病（如缺血、创伤和癫痫）细胞死亡的主要机制。由过量作用于代谢型和离子型兴奋性受体的谷氨酸引起，兴奋性毒性激活多种死亡信号通路，导致广泛的神经元丢失以及随后星形胶质细胞增生的强烈激活。目前，寻找神经保护策略旨在确定信号通路中可阻断兴奋性毒性的水平，同时避免重要生理功能丧失和副作用。就此而言，PTEN可被视为一个理想的候选对象：在兴奋性毒性中激活的兴奋性受体下游（已证明抑制这些受体在临床上不可行），它参与体内神经元损伤和反应性星形胶质细胞增生的第一阶段。在本研究中，我们通过在2月龄C57BL/6J雄性小鼠腹腔注射红藻氨酸建立的颞叶癫痫模型中，利用双过氧（吡啶甲酸）氧钒酸钾[bpv(pic)]对PTEN进行药理学抑制，证明了PTEN参与兴奋性毒性。我们已经证明，bpv(pic)对PTEN的抑制可挽救神经元死亡，并减少全身注射红藻氨酸所致海马CA3区的反应性星形胶质细胞增生。此外，神经毒素给药显著增加了线粒体PTEN原本稀少的含量，而在注射红藻氨酸6小时后给予抑制剂可使其显著降低，这表明PTEN在线粒体凋亡中发挥作用。综上所述，我们的结果证实了PTEN在兴奋性毒性损伤中所起的关键作用，以及抑制PTEN具有强大的抗炎和神经保护潜力。
