Regulation of Keap1-Nrf2 axis in temporal lobe epilepsy—hippocampal sclerosis patients may limit the seizure outcomes

• Published in: Neurological sciences 2023-12, Vol.44 (12), p.4441-4450
• Main Authors: Kishore, Madhamanchi, Pradeep, Madhamanchi, Narne, Parimala, Jayalakshmi, Sita, Panigrahi, Manas, Patil, Anuja, Babu, Phanithi Prakash
• Format: Article
• Language: English
• Subjects: Antioxidants; Antioxidants - metabolism; Convulsions & seizures; Cyclin-dependent kinase inhibitor p21; Epilepsy; Epilepsy, Temporal Lobe; Excitotoxicity; GTP-binding protein; Heat shock proteins; Hippocampal Sclerosis; Hippocampus; Histone methyltransferase; Histone Methyltransferases; Histone-Lysine N-Methyltransferase - metabolism; Histones; Hsp90 protein; Humans; Immunofluorescence; Kelch-Like ECH-Associated Protein 1 - metabolism; Medicine; Medicine & Public Health; Methylation; Methyltransferase; NADP - metabolism; Neurology; Neuroradiology; Neurosciences; Neurosurgery; NF-E2-Related Factor 2 - metabolism; Original Article; Oxidative Stress; Psychiatry; Quinones; Reactive oxygen species; Reactive Oxygen Species - metabolism; Sclerosis; Seizures; Temporal lobe
• ISSN: 1590-1874; 1590-3478
• DOI: 10.1007/s10072-023-06936-0

Background Accumulation of reactive oxygen species (ROS) exacerbates neuronal loss during seizure-induced excitotoxicity. Keap1 (Kelch-like ECH-associated protein1)-nuclear factor erythroid 2–related factor 2 (Nrf2) axis is one of the known active antioxidant response mechanisms. Our study focused on finding the factors influencing Keap1-Nrf2 axis regulation in temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS) patients. Methods Based on post-surgical follow-up data, patient samples ( n = 26) were categorized into class 1 (completely seizure-free) and class 2 (only focal-aware seizures/auras), as suggested by International League Against Epilepsy (ILAE). For molecular analyses, double immunofluorescence assay and Western blot analysis were employed. Results A significant decrease in expression of Nrf2 ( p < 0.005), HO-1; p < 0.02) and NADPH Quinone oxidoreductase1 (NQO1; p < 0.02) was observed in ILAE class 2. Keap1 ( p < 0.02) and histone methyltransferases (HMTs) like SetD7 (SET7/9; SET domain-containing 7 histone lysine methyltransferase) ( p < 0.009) and enhancer of zeste homolog 2 (EZH2; p < 0.02) and methylated histones viz., H3K4me1 ( p < 0.001), H3K9me3 ( p < 0.001), and H3K27me3 ( p < 0.001) was upregulated in ILAE class 2. Nrf2-interacting proteins viz., p21 ( p < 0.001) and heat shock protein 90 (HSP90; p < 0.03) increased in class 1 compared to class 2 patients. Conclusion Upregulation of HMTs and methylated histones can limit phase II antioxidant enzyme expression. Also, HSP90 and p21 that interfere with Keap1-Nrf2 interaction could contribute to a marginal increase in HO-1 and NQO1 expression despite histone methylation and Keap1. Based on our findings, we conclude that TLE-HS patients prone to seizure recurrence were found to have dysfunctional antioxidant response, in part, owing to Keap1-Nrf2 axis. Graphical abstract The significance of Keap1-Nrf2 signaling mechanism in generation of phase II antioxidant response. Keap1-Nrf2 controls antioxidant response through regulation of phase II antioxidant enzymes like HO-1 (heme oxygenase-1), NQO1 (NADPH-Quinone Oxidoreductase1), and glutathione S-transferase (GST). Release of Nrf2 from negative regulation by Keap1 causes its translocation into nucleus, forming a complex with cAMP response-element binding protein (CBP) and small Maf proteins (sMaf). This complex subsequently binds antioxidant response element (ARE) and elicits and antioxidant response involving expression of ph