Dilek Bayram, Sedat Bilgic, Deniz Tastemir Korkmaz, Sebile Azirak, Mehmet Kaya Ozer

Thymoquinone reduced RIPK1-dependent apoptosis caused by valproic acid in rat brain

Aim: Valproic acid (VPA) is a commonly used antiepileptic drug and known to have a neurotoxic effect, but its mechanism is not yet understood. In the present study, we aimed to determine how the VPA causes cell death in the brain and to evaluate the protective effects of thymoquinone (TQ) on VPA-induced brain damage. Materials and Methods: Male Sprague–Dawley albino rats were divided into three groups: control, VPA (500 mg/kg/day) and VPA + TQ (500 mg/kg/day + 50 mg/kg/day) with seven rats in. At the end of the experiment, rats were sacrificed and brain samples were taken to measure the expression levels of Receptor-interacting serine/threonine-protein kinase-1 (RIPK1) and -3 (RIPK3) genes by quantitative real-time PCR (qRT-PCR), NADPH oxidase-4 (NOX4) and, caspase-3 (CAS-3) expression by immunohistochemistry and the structural changes in the brain tissue by histologically. Results: RIPK1 gene expression levels were significantly increased in the VPA group compared to the controls (p

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1. Umka J, Mustafa S, ElBeltagy M, Thorpe A, Latif L, Bennett G, et al. Valproic acid reduces spatial working memory and cell proliferation in the hippocampus. NeuroSci 2010;166:15-22.
2. Tung EW, Winn LM. Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: a role for oxidative stress in valproic acid-induced neural tube defects. Mol Pharma 2011;80:979-87.
3. Fujiki R, Sato A, Fujitani M, Yamashita T. A proapoptotic effect of valproic acid on progenitors of embryonic stem cell-derived glutamatergic neurons. Cell Death & Dis 2013;4:677-84.
4. Chen S, Wu H, Klebe D, Hong Y, Zhang J. Valproic acid: A new candidate of therapeutic application for the acute central nervous system injuries. Neurochem Res 2014;39:1621-33.
5. Zhang C, Zhu J, Zhang J, Li H, Zhao Z, Liao Y, et al. Neuroprotective and anti-apoptotic effects of valproic acid on adult rat cerebral cortex through ERK and Akt signaling pathway at acute phase of traumatic brain injury. Brain Res 2014;1555:1-9.
6. Lovett M, Skidmore DL, Mohamed IS. Valproateinduced pseudoatrophy: Expanding the clinical and imaging spectrum. Pediatric Neurol 2014;51:284-5.
7. McLachlan RS. Pseudoatrophy of the brain with valproic acid monotherapy. Can J Neurol Sci 1987;14:294-6.
8. Galimberti CA, Diegoli M, Sartori I, Uggetti C, Brega A, Tartara A, et al. Brain pseudoatrophy and mental regression on valproate and a mitochondrial DNA mutation. Neurology 2006;67:1715-7.
9. Christensen J, Gronborg TK, Sorensen MJ, Schendel D, Parner ET, Pedersen LH, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 2013;309:1696-703.
10. Bollino D, Balan I, Aurelian L. Valproic acid induces neuronal cell death through a novel calpain-dependent necroptosis pathway. J Neurochem 2015;133:174-86.
11. Orozco S, Yatim N, Werner MR, Tran H, Gunja SY, Tait SWG, et al. RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis. Cell Death Differ 2014;21:1511-21.
12. Liu Y, Liu T, Lei T, Zhang D, Du S, Girani L, et al. RIP1/RIP3-regulated necroptosis as a target for multifaceted disease therapy (Review). Int J Mol Med 2019;44:771-86.
13. Zhang D, Lin J, Han J. Receptor-interacting protein (RIP) kinase family. Cell Mol Immunol 2010;7:243-9.
14. Christofferson DE, Yuan J. Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol 2010;22:263-8.
15. Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ, Leder P. The death domain kinase RIP mediates the TNFinduced NF-kappaB signal. Immunity 1998;8:297- 303.
16. Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 2009;137:1112- 23.
17. Mazaheri Y, Torbati M, Azadmard-Damirchi S, Savage GP. A comprehensive review of the physicochemical, quality and nutritional properties of Nigella sativa oil. Food Rev Inter 2019;35:342-62.
18. Bilgic S, Korkmaz DT, Azirak S, Güvenc AN, Kocaman N, Ozer MK. Olanzapine-induced renal damages and metabolic side effects: the protective effects of thymoquinone. J Turgut Ozal Med Cent 2018;25:70-5.
19. Savran M, Asci H, Armagan I, Erzurumlu Y, Azırak S, Ozer MK, et al. Thymoquinone could be protective against valproic acid-induced testicular toxicity by antioxidant and anti-Inflammatory mechanisms. Andrologia 2020;52:13623-35.
20. Morsy BM, Safwat GM, Hussein DA, Samy RM. The protective effect of Nigella Sativa oil extract against neurotoxicity induced by Valproic acid. Int J Bioassays 2017;6:5474-84.
21. Nishimura T, Sakai M, Yonezawa H. Effects of valproic acid on fertility and reproductive organs in male rats. J Toxicol Sci 2000;25:85-93.
22. Atta MS, Almadaly EA, El-Far AH, Saleh RM, Assar DH, Al Jaouni SK, et al. Thymoquinone defeats diabetes-induced testicular damage in rats targeting antioxidant, inflammatory and aromatase expression. Int J Mol Sci 2017;18:919-27.
23. Tastemir-Korkmaz D, Bilgic S, Azirak S, Guvenc AN, Kocaman N, Ozer MK. The protective effect of resveratrol against risperidone-induced brain damage and metabolic side effects. Cukurova Med J 2018;43:108-23.
24. Cui H, Zhu Y, Jiang D. The RIP1–RIP3 Complex Mediates Osteocyte Necroptosis after Ovariectomy in Rats. PLOS ONE 2016;11:1-12.
25. Refaiy A, Muhammad E, ElGanainy E. Semiquantitative smoothelin expression in detection of muscle invasion in transurethral resection and cystectomy specimen in cases of urinary bladder carcinoma. African J Urol 2011;17:6-10.
26. Chiu CT, Wang Z, Hunsberger JG, Chuang DM. Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder. Pharma Rev 2013;65:105-42.
27. Aktas I, Bayram D. Investigation of the effects of silymarin on valproic acid-induced kidney damage in rats. Harran Üniv Vet Fak Derg 2020;9:42-8.
28. Morrell MJ, Isojärvi J, Taylor AE, Dam M, Ayala R, Gomez G, et al. Higher androgens and weight gain with valproate compared with lamotrigine for epilepsy. Epilepsy Res 2003;54:189-99.
29. Verrotti A, D’Egidio C, Mohn A, Coppola G, Chiarelli F. Weight gain following treatment with valproic acid: pathogenetic mechanisms and clinical implications. Obesity Rev 2011;12:32-43.
30. McLachlan RS. Pseudoatrophy of the brain with valproic acid monotherapy. Canadian J Neurol Sci 1987;14:294-96.
31. Papazian O, Cafiizales E, Alfonso I, Archila R, Duchowny M, Aicardi J. Reversible dementia and apparent brain atrophy during valproate therapy. Ann Neurol 1995;38:687-91.
32. Yamanouchi H, Takako O, Imataka G, Nakagawa E, Eguchi M. Reversible altered consciousness with brain atrophy caused by valproic acid. Pediatric Neurol 2003;28:382-4.
33. Wang C, Luan Z, Yang Y, Wang Z, Cui Y, Gu G. Valproic acid induces apoptosis in differentiating hippocampal neurons by the release of tumor necrosis factor-α from activated astrocytes. Neurosci Lett 2011;497:122-7.
34. Bittigua P, Sifringer M, Genz K, Reith E, Pospischil D, Govindarajalu S, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci USA 2002;99:15089-94.
35. Brandt C, Gastens AM, Sun M, Hausknecht M, Loscher W. Treatment with valproate after status epilepticus: effect on neuronal damage, epileptogenesis, and behavioral alterations in rats. Neuropharmacology 2006;51:789-804.
36. Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, et al. Mood stabilizer valproate promotes ERK pathwaydependent cortical neuronal growth and neurogenesis. J Neurosci 2004;24:6590-9.
37. Dillon CP, Weinlich R, Rodriguez DA, Cripps JG, Quarato G, Gurung P, et al. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell 2014;157:1189-202.
38. Lou Z, Wang AP, Duan XM, Hu GH, Song GL, Zuo ML, et al. Upregulation of NOX2 and NOX4 mediated by TGF-β signaling pathway exacerbates cerebral ischemia/reperfusion oxidative stress injury. Cell Physiol Biochem 2018;46:2103-13.
39. Schiavone S, Neri M, Trabace L, Turillazzi E. The NADPH oxidase NOX2 mediates loss of parvalbumin interneurons in traumatic brain injury: human autoptic immunohistochemical evidence. Sci Rep 2017;7:8752.
40. Li Z, Tian F, Shao Z, Shen X, Qi X, Li H, et al. Expression and clinical significance of non-phagocytic cell oxidase 2 and 4 after human traumatic brain injury. Neurol Sci: Off J Ital Neurol Soc Ital Soc Clin Neurophysiol 2015;36:61-71.