THE ROLE OF FERROPTOSIS IN THE PATHOGENESIS OF SYMPTOMATIC EPILEPSY: A CLINICAL AND NEUROIMAGING STUDY
Keywords:
symptomatic epilepsy, ferroptosis, iron metabolism, GPX4, cognitive impairment, neuroimagingAbstract
Objective: To investigate the role of iron metabolism disorders and ferroptosis mechanisms in the pathogenesis of symptomatic epilepsy.
Materials and methods: A prospective controlled cohort study was conducted involving 80 patients with symptomatic epilepsy and 30 healthy individuals. Clinical and neurological manifestations, cognitive functions (MMSE, TMT), iron metabolism parameters, ferroptosis markers (GPX4, ACSL4, MDA), MRI and EEG data were evaluated.
Results: Patients with symptomatic epilepsy showed significant cognitive function decline (MMSE: 24.3±2.5 vs 28.7±1.3 points, p<0.01), iron metabolism disorders with elevated ferritin levels (320±25 vs 210±20 ng/ml, p<0.01), decreased GPX4 expression by 1.8-fold (p<0.01), increased ACSL4 by 2.3-fold (p<0.01), and elevated MDA to 6.1±0.5 nmol/mg protein (p<0.001). SWI-MRI revealed iron accumulation in the basal ganglia, hippocampus, and thalamus in 50% of patients.
Conclusion: Iron metabolism disorders and ferroptosis activation play a key role in the pathogenesis of symptomatic epilepsy, opening prospects for developing pathogenetically targeted therapy.
References
Thijs RD, Surges R, O'Brien TJ, Sander JW. Epilepsy in adults. Lancet. 2019;393(10172):689-701.
Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512-521.
Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017;171(2):273-285.
Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060-1072.
Yang WS, SriRamaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1-2):317-331.
Doll S, Proneth B, Tyurina YY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13(1):91-98.
Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014;13(10):1045-1060.
Helmstaedter C, Witt JA. Epilepsy and cognition - A bidirectional relationship? Seizure. 2017;49:83-89.
Li J, Cao F, Yin HL, et al. Ferroptosis: past, present and future. Cell Death Dis. 2020;11(2):88.
Xie Y, Hou W, Song X, et al. Ferroptosis: process and function. Cell Death Differ. 2016;23(3):369-379.
