Neuropediatrics
DOI: 10.1055/s-0044-1788032
Original Article

Dysregulated Apoptosis and Autophagy in Childhood Epilepsy: Correlation to Clinical and Pharmacological Patterns

Ahmed El-Abd Ahmed
1   Department of Pediatrics, Faculty of Medicine, South Valley University, Qena, Egypt
,
2   Department of Medical Biochemistry, Faculty of Medicine, South Valley University, Qena, Egypt
,
Asmaa A. Abdelfatah
1   Department of Pediatrics, Faculty of Medicine, South Valley University, Qena, Egypt
,
Ali Helmi Bakri
1   Department of Pediatrics, Faculty of Medicine, South Valley University, Qena, Egypt
› Author Affiliations
Funding None.

Abstract

Objectives We aimed to assess the serum levels of caspase-3 as a marker of apoptosis and microtubule-associated protein 1A/1B-light chain 3 (MAP1-LC3) as an autophagy marker in epileptic children with various clinical and pharmacological types.

Methods This case–control study was carried out on 90 participants (50 pediatric patients with epilepsy and 40 healthy matched children), the patients were categorized into three groups: Group (A): 25 pharmacosensitive epilepsy, Group (B): 25 pharmacoresistant epilepsy, and Group (C): 40 (age, sex, and body mass index) matched healthy children selected as controls. Serum caspase-3 and MAP1-LC3 were measured in all study groups, using commercially available ELISA kits.

Results Serum caspase-3 was significantly higher among epileptic children, especially in the pharmacoresistant group, cases managed with multiple antiepileptic drugs, and cases with abnormal EEG findings. Conversely, circulating MAP1-LC3 levels showed a significant reduction in epilepsy cases, particularly in pharmacoresistant cases, in cases treated with multiple antiepileptic drugs, and in cases with abnormal EEG data. A significant negative correlation between serum caspase-3 and MAP1-LC3 was found among epileptic children (r =  −0.369, p = 0.0083). Serum caspase-3 was a more valid biomarker in helping diagnose childhood epilepsy, while serum MAP1-LC3 was more valid in predicting pharmacoresistant type.

Conclusion The study reveals that serum caspase-3 levels were significantly elevated, particularly in pharmacoresistant cases and those managed with multiple drugs. Conversely, MAP1-LC3 levels were significantly reduced in epilepsy cases, suggesting potential involvement of altered apoptosis and autophagy in childhood epilepsy.

Ethical Approval and Consent to Participate

Cases and controls were collected correspondingly with the guidelines established in the Declaration of Helsinki. This study was approved by the Ethics Committee of the Faculty of Medicine, South Valley University, Qena, Egypt (Ethical approval code: SVU-MED-PED025-1-23-2-544). Informed written consent was taken from parents or caregivers of the included participants for participation in the study and publication.


Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request, after obtaining the permission of our institute.


Authors' Contributions

Study concept and design: A.E-A.A., M.H.H., A.H.B. Literature research, statistical analysis, and data interpretation: A.E-A.A., M.H.H., A.A.A., A.H.B. Selection of the participants and their clinical evaluation: A.E-A.A., A.A.A., A.H.B. Biochemical assays: M.H.H. First draft of the manuscript: M.H.H. All authors approved the final version of the manuscript.




Publication History

Received: 28 March 2024

Accepted: 06 June 2024

Article published online:
04 July 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Pearl PL. Epilepsy syndromes in childhood. Continuum (Minneap Minn) 2018; 24 (1, Child Neurology): 186-209
  • 2 Perrotta G. Epilepsy: from pediatric to adulthood. Definition, classifications, neurobiological profiles and clinical treatments. J Neurol Neurol Sci Disord 2020; 6 (01) 14-29
  • 3 Sokolova T, Litovchenko A, Paramonova N. et al. Glioneuronal apoptosis and neuroinflammation in drug resistant temporal lobe epilepsy. Neurol Neuropsychiatry Psychosom 2023; 15 (01) 36-42
  • 4 Ichimiya T, Yamakawa T, Hirano T. et al. Autophagy and autophagy-related diseases: a review. Int J Mol Sci 2020; 21 (23) 8974
  • 5 Zhu H, Wang W, Li Y. Molecular mechanism and regulation of autophagy and its potential role in epilepsy. Cells 2022; 11 (17) 2621
  • 6 Bonam SR, Bayry J, Tschan MP, Muller S. Progress and challenges in the use of MAP1LC3 as a legitimate marker for measuring dynamic autophagy in vivo. Cells 2020; 9 (05) 1321
  • 7 Henshall DC, Simon RP. Epilepsy and apoptosis pathways. J Cereb Blood Flow Metab 2005; 25 (12) 1557-1572
  • 8 Ali NH, Al-Kuraishy HM, Al-Gareeb AI. et al. Autophagy and autophagy signaling in epilepsy: possible role of autophagy activator. Mol Med 2023; 29 (01) 142
  • 9 Kwan P, Arzimanoglou A, Berg AT. et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010; 51 (06) 1069-1077
  • 10 Abdelfatah AA, Ahmed AE, Hassan MH, Bakry AH. Hematological and biochemical parameters in various clinical and pharmacological types of childhood epilepsy. SVU Int J Med Sci 2024; 7 (01) 376-385
  • 11 Wang L, Song LF, Chen XY. et al. MiR-181b inhibits P38/JNK signaling pathway to attenuate autophagy and apoptosis in juvenile rats with kainic acid-induced epilepsy via targeting TLR4. CNS Neurosci Ther 2019; 25 (01) 112-122
  • 12 Bartolini E, Campostrini R, Kiferle L. et al. Epilepsy and brain channelopathies from infancy to adulthood. Neurol Sci 2020; 41 (04) 749-761
  • 13 Bulteau C. The vulnerability of the immature brain. Handb Clin Neurol 2020; 173: 89-97
  • 14 Niu X, Zhu H-L, Liu Q, Yan J-F, Li M-L. MiR-194-5p serves as a potential biomarker and regulates the proliferation and apoptosis of hippocampus neuron in children with temporal lobe epilepsy. J Chin Med Assoc 2021; 84 (05) 510-516
  • 15 Li N, Pan J, Liu W, Li Y, Li F, Liu M. MicroRNA-15a-5p serves as a potential biomarker and regulates the viability and apoptosis of hippocampus neuron in children with temporal lobe epilepsy. Diagn Pathol 2020; 15 (01) 46
  • 16 Aaberg KM, Bakken IJ, Lossius MI. et al. Comorbidity and childhood epilepsy: a nationwide registry study. Pediatrics 2016; 138 (03) e20160921
  • 17 Yildiz EP, Gunes D, Bektas G. et al. Predictive factors of drug-resistant epilepsy in children presenting under 2 years of age: experience of a tertiary center in Turkey. Acta Neurol Belg 2018; 118 (01) 71-75
  • 18 Roy PL, Ronquillo LH, Ladino LD, Tellez-Zenteno JF. Risk factors associated with drug resistant focal epilepsy in adults: a case control study. Seizure 2019; 73: 46-50
  • 19 Ullah S, Ali N, Khan A, Ali S, Nazish HR. The epidemiological characteristics of epilepsy in the province of Khyber Pakhtunkhwa, Pakistan. Front Neurol 2018; 9: 845
  • 20 Beghi E. The epidemiology of epilepsy. Neuroepidemiology 2020; 54 (02) 185-191
  • 21 Ross EE, Stoyell SM, Kramer MA, Berg AT, Chu CJ. The natural history of seizures and neuropsychiatric symptoms in childhood epilepsy with centrotemporal spikes (CECTS). Epilepsy Behav 2020; 103 (Pt A): 106437
  • 22 Balestrini S, Arzimanoglou A, Blümcke I. et al. The aetiologies of epilepsy. Epileptic Disord 2021; 23 (01) 1-16
  • 23 Babtain FA. Impact of a family history of epilepsy on the diagnosis of epilepsy in Southern Saudi Arabia. Seizure 2013; 22 (07) 542-547
  • 24 Ekinci O, Arman AR, Işik U, Bez Y, Berkem M. EEG abnormalities and epilepsy in autistic spectrum disorders: clinical and familial correlates. Epilepsy Behav 2010; 17 (02) 178-182
  • 25 Hunza K, Abeer M, Zina AS. et al. Consanguinity, family history, and risk of epilepsy: a case control study. Gulf Med J 2012; 1 (01) 32-36
  • 26 Bakri AH, Hassan MH, Ahmed AE-A. et al. Serum levels of growth-associated protein-43 and Neurotrophin-3 in childhood epilepsy and their relation to zinc levels. Biol Trace Elem Res 2023; 201 (02) 689-697
  • 27 Huang Y, Liu X, Liao Y. et al. MiR-181a influences the cognitive function of epileptic rats induced by pentylenetetrazol. Int J Clin Exp Pathol 2015; 8 (10) 12861-12868
  • 28 Kegler A, Caprara ALF, Pascotini ET. et al. Apoptotic markers are increased in epilepsy patients: a relation with manganese superoxide dismutase Ala16Val polymorphism and seizure type through IL-1β and IL-6 pathways. BioMed Res Int 2020; 2020: 6250429
  • 29 Henshall DC, Clark RS, Adelson PD, Chen M, Watkins SC, Simon RP. Alterations in bcl-2 and caspase gene family protein expression in human temporal lobe epilepsy. Neurology 2000; 55 (02) 250-257
  • 30 Sitovskaya D, Zabrodskaya Y, Parshakov P. et al. Expression of cytoskeletal proteins (GFAP, Vimentin), proapoptotic protein (Caspase-3) and protective protein (S100) in the epileptic focus in adults and children with drug-resistant temporal lobe epilepsy associated with focal cortical dysplasia. Int J Mol Sci 2023; 24 (19) 1449
  • 31 Naseer MI, Ullah I, Ullah N. et al. Neuroprotective effect of vitamin C against PTZ induced apoptotic neurodegeneration in adult rat brain. Pak J Pharm Sci 2011; 24 (03) 263-268
  • 32 Henshall DC, Meldrum BS. Cell death and survival mechanisms after single and repeated brief seizures. In: Jasper's Basic Mechanisms of the Epilepsies;. 2012; 262-276
  • 33 Othman MS, Obeidat ST, Aleid GM. et al. Green synthetized selenium nanoparticles using Syzygium aromaticum (clove) extract reduce pentylenetetrazol-induced epilepsy and associated cortical damage in rats. Appl Sci (Basel) 2023; 13 (02) 1050
  • 34 Yang DS, Stavrides P, Mohan PS. et al. Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits. Brain 2011; 134 (Pt 1): 258-277
  • 35 Ying C, Ying L, Yanxia L, Le W, Lili C. High mobility group box 1 antibody represses autophagy and alleviates hippocampus damage in pilocarpine-induced mouse epilepsy model. Acta Histochem 2020; 122 (02) 151485
  • 36 Dazzo E, Nobile C. Epilepsy-causing Reelin mutations result in impaired secretion and intracellular degradation of mutant proteins. Hum Mol Genet 2022; 31 (05) 665-673
  • 37 Shacka JJ, Lu J, Xie Z-L, Uchiyama Y, Roth KA, Zhang J. Kainic acid induces early and transient autophagic stress in mouse hippocampus. Neurosci Lett 2007; 414 (01) 57-60
  • 38 Li Q, Han Y, Du J. et al. Alterations of apoptosis and autophagy in developing brain of rats with epilepsy: changes in LC3, P62, Beclin-1 and Bcl-2 levels. Neurosci Res 2018; 130: 47-55
  • 39 Mao X-Y, Zhou H-H, Jin W-L. Redox-related neuronal death and crosstalk as drug targets: focus on epilepsy. Front Neurosci 2019; 13: 512
  • 40 Chung Y, Lee J, Jung S, Lee Y, Cho JW, Oh YJ. Dysregulated autophagy contributes to caspase-dependent neuronal apoptosis. Cell Death Dis 2018; 9 (12) 1189
  • 41 Hussein AM, Adel M, El-Mesery M, Abbas KM, Ali AN, Abulseoud OA. L-carnitine modulates epileptic seizures in pentylenetetrazole-kindled rats via suppression of apoptosis and autophagy and upregulation of hsp70. Brain Sci 2018; 8 (03) 45
  • 42 Vega-García A, Orozco-Suárez S, Villa A. et al. Cortical expression of IL1-β, Bcl-2, Caspase-3 and 9, SEMA-3a, NT-3 and P-glycoprotein as biological markers of intrinsic severity in drug-resistant temporal lobe epilepsy. Brain Res 2021; 1758: 147303
  • 43 Ali SO, Shahin NN, Safar MM, Rizk SM. Therapeutic potential of endothelial progenitor cells in a rat model of epilepsy: Role of autophagy. J Adv Res 2019; 18: 101-112