Abstract
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.
Highlights
The phosphatase and tensin homolog deleted on chromosome ten (PTEN) was initially studied extensively for its fundamental role in tumorigenicity: the multiple functions performed by PTEN in Central Nervous System (CNS) in both physiological and pathological conditions were initially underestimated and became the focus of several studies only recently
It has been demonstrated that a death stimulus may result in a subcellular redistribution of PTEN that, in normal conditions localized in the cytosol, translocates into mitochondria in cultured hippocampal cells treated with staurosporine, suggesting the involvement of PTEN in mitochondria-dependent apoptosis [13]
By Western Blotting analysis we have shown that PTEN inhibitor is able to increase the level of phosphorylated Akt, the major downstream target of PTEN, in the hippocampus 6 hours after kainate stimulation compared to the administration of kainate alone
Summary
The phosphatase and tensin homolog deleted on chromosome ten (PTEN) was initially studied extensively for its fundamental role in tumorigenicity: the multiple functions performed by PTEN in Central Nervous System (CNS) in both physiological and pathological conditions were initially underestimated and became the focus of several studies only recently. PTEN gene encodes for a phosphatase specific for both protein and lipid substrates [7, 8]. Both these activities can be involved in the regulation of neuronal death [6, 9]. PTEN regulates the function and surface expression of N-methyl-D-aspartate receptors (NMDARs), a key subtype of excitatory glutamate receptor known to mediate excitotoxicity-induced neuronal death [9]. Despite the fundamental proapoptotic role played by the lipid and protein phosphatase activities, the regulation of neuronal death by PTEN appears much more complex. In spite of all these pieces of evidence, the role of PTEN in regulating neuronal death is still far from being fully understood
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