Neuroprotective mechanisms of sildenafil and selenium in PTZ-kindling model: Implications in epilepsy

Seizures induced in PTZ-kindling model are associated with pathological changes in the brain specifically in the hippocampus region. These changes are accompanied by excessive production of ROS and activation of iNOS leading to accumulation of NO centrally, thereby generating a status of oxidative and nitrative stress with subsequent lipid peroxidation and neurodegeneration. Additionally, the seizures-induced hypoxia will trigger VEFG-mediated pathological angiogenesis along with increased HO-1 expression that together are still insufficient to protect hippocampal neurons against PTZ insult, thus allowing for sustained seizures and leading to exacerbated neuronal loss. Sildenafil treatment of PTZ-kindled mice activates NO/cGMP pathway as a result of PDE-5 inhibition. Accumulated NO, in the presence of a powerful antioxidant as selenium-the important element for TrxR activity-will further activate VEGF at the expenses of nitrative stress and lipid peroxidation. Moreover, VEGF activation by sildenafil will promote iNOS expression and stimulate NO/cGMP pathway that, in the presence of antioxidants like selenium, will preferentially mediate the loop of angiogenesis. The newly formed blood vessels shall keep providing nutrients and antioxidants to hippocampal neurons, thereby retarding seizures-induced neurodegeneration and mediating neuroprotection. 4-HNE: 4-Hydroxynonenal; cGMP: cyclic guanosine monophosphate; GMP: guanosine monophosphate; GTP: guanosine triphosphate; HIF-1: hypoxia inducible factor-1; HO-1: hemeoxygenase-1; iNOS: inducible nitric oxide synthase; NADPH: Nicotinamide adenine dinucleotide phosphate; NO: nitric oxide; ONOO-: peroxynitrite; PDE-5: phosphodiesterase-5; PTZ: pentylenetetrazol; ROS: reactive oxygen species; sGS: soluble guanylyl cyclase; Trx: thioredoxin; TrxP: thioredoxin peroxidase; TrxR: thioredoxin reductase; VEGF: vascular endothelial growth factor. N.B. Measured parameters are highlighted in red color.205