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

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Epilepsy is one of the furthermost common neurodegenerative diseases affecting above 50 million individuals worldwide. The pathogenesis of epileptic seizures is not satisfactorily explored, and hence more effective anti-convulsive therapies are indispensable. Current study aimed to investigate the mechanisms of the potential neuroprotective effects of sildenafil/selenium on chemically-induced convulsions in mice.

Kindling model was induced using pentylenetetrazol (PTZ; 35 mg/Kg, 11 doses, intraperitoneally, every other day). PTZ-insulted groups were treated intraperitoneally with sildenafil (20 mg/Kg), selenium (0.2 mg/Kg) or their combination; 30 min before PTZ administration.

PTZ-kindled model showed a significant loss of neuronal cells concurrently with nitrative/oxidative stress and lipid peroxidation. This was associated with enhanced expression of inducible nitric oxide synthase (iNOS), hemeoxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) along with increased activity of thioredoxin reductase (TrxR) in hippocampal tissue. Individual treatment with sildenafil or selenium showed partial neuroprotection, simultaneously with lower hippocampal expression of 4-hydroneonenal (4-HNE), nitrotyrosine, iNOS and HO-1, yet without reaching normal levels. Sildenafil, but not selenium, enhanced the expression of VEGF and the endothelial cell marker CD34. The joint treatment with sildenafil and selenium preserved hippocampal neuronal count, improved kindling score, blunted lipid peroxides and nitrotyrosine levels, concomitantly with iNOS inhibition, normalization of TrxR activity and HO-1 expression, and evident neo-angiogenesis.

Current study demonstrated the roles of several central signalling cascades in the sildenafil/selenium-evoked neuroprotection represented in, at least in part, amelioration of nitrative/oxidative stress alongside modulation of angiogenesis. Thus, sildenafil combined with selenium could be repurposed as a potential therapeutic regimen for delaying epilepsy progression.

Graphical abstract

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.

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