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

被引:51
作者
Attia, Ghalia Mahfouz [1 ,2 ]
Elmansy, Rasha Ahmed [3 ,4 ]
Elsaed, Wael M. [1 ,5 ]
机构
[1] Taibah Univ, Fac Med, Dept Anat, Madinah 42221, Saudi Arabia
[2] Mansoura Univ, Fac Med, Dept Histol & Cell Biol, Mansoura, Egypt
[3] Ain Shams Univ, Fac Med, Dept Anat & Embryol, Cairo, Egypt
[4] Al Qassim Univ, Unaizah Coll Med, Fac Med, Dept Anat, Buraydah, Saudi Arabia
[5] Mansoura Univ, Fac Med, Anat & Embryol Dept, Mansoura, Egypt
关键词
autophagy; apoptosis; hippocampus; epilepsy; nilotinib; TYROSINE KINASE INHIBITOR; TEMPORAL-LOBE EPILEPSY; NF-KAPPA-B; NEUROTROPHIC FACTOR; MAMMALIAN TARGET; INDUCED SEIZURES; ANTIEPILEPTIC DRUGS; PILOCARPINE MODEL; MESSENGER-RNA; ASCORBIC-ACID;
D O I
10.5114/fn.2019.84423
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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-kappa B) and Bcl-2-like protein 4 (BAX). Results: Nilotinib induced an increase in the latency of seizures, enhanced the antioxidant levels of the gamma-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-kappa B and BAX expression in nerve cells. Conclusions: Nilotinib may have promising neuroprotective and antiepileptic effects against pentylenetetrazol-induced seizures through promoting the antioxidant, antifibrotic, anti-inflammatory, antiapoptotic pathways and inhibiting autophagy.
引用
收藏
页码:146 / 160
页数:15
相关论文
共 89 条
[71]   Effects of a lyophilized aqueous extract of Feretia apodanthera Del. (Rubiaceae) on pentylenetetrazole-induced kindling, oxidative stress, and cognitive impairment in mice [J].
Taiwe, G. S. ;
Moto, F. C. O. ;
Ayissi, E. R. M. ;
Ngoupaye, G. T. ;
Njapdounke, J. S. K. ;
Nkantchoua, G. C. N. ;
Kouemou, N. ;
Omam, J. P. O. ;
Kandeda, A. K. ;
Pale, S. ;
Pahaye, D. ;
Bum, E. Ngo .
EPILEPSY & BEHAVIOR, 2015, 43 :100-108
[72]   Hippocampal gene expression dysregulation of Klotho, nuclear factor kappa B and tumor necrosis factor in temporal lobe epilepsy patients [J].
Teocchi, Marcelo Ananias ;
Dias Ferreira, Ana Erika ;
da Luz de Oliveira, Evandro Pinto ;
Tedeschi, Helder ;
D'Souza-Li, Llia .
JOURNAL OF NEUROINFLAMMATION, 2013, 10
[73]   Induction of Autophagy by Cystatin C: A Mechanism That Protects Murine Primary Cortical Neurons and Neuronal Cell Lines [J].
Tizon, Belen ;
Sahoo, Susmita ;
Yu, Haung ;
Gauthier, Sebastien ;
Kumar, Asok R. ;
Mohan, Panaiyur ;
Figliola, Matthew ;
Pawlik, Monika ;
Grubb, Anders ;
Uchiyama, Yasuo ;
Bandyopadhyay, Urmi ;
Cuervo, Ana Maria ;
Nixon, Ralph A. ;
Levy, Efrat .
PLOS ONE, 2010, 5 (03)
[74]   Brain-derived neurotrophic factor mRNA and protein are targeted to discrete dendritic laminas by events that trigger epileptogenesis [J].
Tongiorgi, E ;
Armellin, M ;
Giulianini, PG ;
Bregola, G ;
Zucchini, S ;
Paradiso, B ;
Steward, O ;
Cattaneo, A ;
Simonato, M .
JOURNAL OF NEUROSCIENCE, 2004, 24 (30) :6842-6852
[75]   Effects of Agomelatine on Oxidative Stress in the Brain of Mice After Chemically Induced Seizures [J].
Torres Aguiar, Carlos Clayton ;
Almeida, Analia Barbosa ;
Pontes Araujo, Paulo Victor ;
Vasconcelos, Germana Silva ;
Camelo Chaves, Edna Maria ;
do Vale, Otoni Cardoso ;
Macedo, Danielle Silveira ;
Almeida Moreira Leal, Luzia Kalyne ;
de Barros Viana, Glauce Socorro ;
Mendes Vasconcelos, Silvania Maria .
CELLULAR AND MOLECULAR NEUROBIOLOGY, 2013, 33 (06) :825-835
[76]   Pregabalin: latest safety evidence and clinical implications for the management of neuropathic pain [J].
Toth, Cory .
THERAPEUTIC ADVANCES IN DRUG SAFETY, 2014, 5 (01) :38-56
[77]   Mitochondrial dysfunction and oxidative stress: a contributing link to acquired epilepsy? [J].
Waldbaum, Simon ;
Patel, Manisha .
JOURNAL OF BIOENERGETICS AND BIOMEMBRANES, 2010, 42 (06) :449-455
[78]   Persistent impairment of mitochondrial and tissue redox status during lithium-pilocarpine-induced epileptogenesis [J].
Waldbaum, Simon ;
Liang, Li-Ping ;
Patel, Manisha .
JOURNAL OF NEUROCHEMISTRY, 2010, 115 (05) :1172-1182
[79]   Maternal hypoxia increases hippocampal cell susceptibility to ischemia after middle cerebral artery occlusion in rat offspring [J].
Wang, Lingxing ;
Huang, Honghong ;
Cai, Hongchao ;
Chen, Yafang .
FOLIA NEUROPATHOLOGICA, 2017, 55 (04) :317-324
[80]   Participation of metabotropic glutamate receptors in pentetrazol-induced kindled seizure [J].
Watanabe, Yusuke ;
Kaida, Yuko ;
Fukuhara, Satoko ;
Takechi, Kenshi ;
Uehara, Takashi ;
Kamei, Chiaki .
EPILEPSIA, 2011, 52 (01) :140-150