title: Neuroprotective and anti-inflammatory roles of the phosphatase and tensin homolog deleted on chromosome Ten (PTEN) Inhibition in a Mouse Model of Temporal Lobe Epilepsy.
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.
authors.affiliation: Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience, University of Torino, Orbassano, Torino, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Grande
authors.affiliation: Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience, University of Torino, Orbassano, Torino, Italy; Department of Internal Medicine, University of Genova, Genova, Italy.
authors.forename: Giusi
authors.initials: G
authors.lastname: Manassero
authors.affiliation: Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience, University of Torino, Orbassano, Torino, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vercelli
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D056654:CA3 Region, Hippocampal / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000633:toxicity; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010750:Phosphoproteins; C528900:glial fibrillary astrocytic protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; D007608:Kainic Acid