Neuroprotective effect of nilotinib on pentylenetetrazol-induced epilepsy in adult rat hippocampus: involvement of oxidative stress, autophagy, inflammation, and apoptosis

Abstract

Introduction: Neuronal cell death and glial cell activation are the main pathological findings induced by seizures secondary to oxidative stress. Previous studies have explained neuronal cell death on the basis of cell necrosis and apoptosis. Recent studies have attributed the neuronal loss to autophagy. The proved antioxidant and antifibrotic effect of nilotinib favours its use in the management of epileptic seizures. Aim of the study was to analyse the neuroprotective and antiepileptic effect of nilotinib and explain its mechanism of action. Material and methods: Forty adult male rats were divided into four groups: control, pentylenetetrazol (PTZ) group (injected with PTZ 60 mg/kg, s.c.), pregabalin (Pregb)-PTZ group (pretreated with pregabalin daily 30 mg/kg; orally for 1 week) and nilotinib (NIL)-PTZ group (pretreated with nilotinib, 25 mg/kg daily for 1 week) prior to PTZ. Seizure latency was evaluated, the hippocampus tissue level of antioxidant enzymes was assessed. The histopathological changes in the hippocampus were studied using hematoxylin and eosin stain and immunohistochemical stain for brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), beclin-1, nuclear factor kappa-B (NF-κB) and Bcl-2-like protein 4 (BAX). Results: Nilotinib induced an increase in the latency of seizures, enhanced the antioxidant levels of the γ-aminobutyric acid and nuclear factor (erythroid-derived 2)-like 2 activities together with the improvement of the hippocampal histology. A reduction was reported for BDNF, GFAP, beclin-1, NF-κB and BAX expression in nerve cells. Conclusions: Nilotinib may have promising neuroprotective and antiepileptic effects against pentylenetetrazolinduced seizures through promoting the antioxidant, antifibrotic, anti-inflammatory, antiapoptotic pathways and inhibiting autophagy.

Anticonvulsant Effects of Topiramate and Lacosamide on Pilocarpine-Induced Status Epilepticus in Rats: A Role of Reactive Oxygen Species and Inflammation

“…Several studies have demonstrated different changes in CAT activity during SE. These seem to be strictly dependent on the mechanisms of the different convulsants that evoke seizure induction [33,34]. In agreement with Freitas et al [35,36] and Santos et al [37], we report that Pilo-induced SE is accompanied by an adaptive elevation of CAT activity in the hippocampus, which may be due to the excessive production of ROS during the ongoing seizures.…”

Pentoxifylline prevents epileptic seizure via modulating HMGB1/RAGE/TLR4 signalling pathway and improves memory in pentylenetetrazol kindling rats

“…It has been broadly ascertained that neuroinflammation critically contributes to the multifaceted nature of the epilepsy pathogenesis. The persistent inflammatory events in the neuronal microenvironments marked by increased pro‐inflammatory mediators that could aggravate oxidative stress cascade in hippocampal neurons leading to neuronal death 24 . The data obtained, clinically and experimentally, have reported HMGB1 as a unique pathogenic element and neuroinflammatory biomarker following the epileptic brain insult, that may serve as a molecular bridging for recurrent seizure and the drug/resistant epilepsy 4,25 …”

<p>Selenium Nanoparticles Pre-Treatment Reverse Behavioral, Oxidative Damage, Neuronal Loss and Neurochemical Alterations in Pentylenetetrazole-Induced Epileptic Seizures in Mice</p>

“…Previous reports have demonstrated the development of inflammatory response in epileptic model. 7,62 The authors attributed this effect to the disturbance in the oxidative status and the overproduction of ROS which activates nuclear factor kappa B (NF-κB) resulting in the elevation in proinflammatory cytokines. Meanwhile, the SeNPs administration suppressed the inflammation in the hippocampal tissue.…”

“…5,6 In addition, the inflammatory response including activation of glial cells and secretion of pro-inflammatory cytokines has been assumed to enhance apoptotic events resulting in neuronal loss which play a crucial role in the development of seizures. 7,8 Moreover, the dysregulation of the monoaminergic, amino acidergic and cholinergic transmission has been demonstrated during the epileptic seizures. 9,10 Current antiepileptic drugs are associated with numerous adverse impacts such as memory deficits, fatigue, tremors, gastrointestinal symptoms, osteoporosis, depression, dizziness and nausea 11 thus creating an urgent need to formulate more efficient anticonvulsant drugs with minimal side effects.…”