Pemberian Asam Valproat pada Induk Tikus Bunting Menghambat Sintesis Insulin pada Sel Otak Anak Tikus
Abstract
Asam valproat memengaruhi aktivitas histone deacetylase yang berperan dalam ekspresi gen selama organogenesis. Insulin berperan dalam proliferasi dan diferensiasi sel-sel saraf dentate gyrus hipokampus. Penelitian ini bertujuan mempelajari pengaruh pemaparan asam valproat pada induk bunting terhadap ekspresi gen insulin pada dentate gyrus. Penelitian dilakukan di UPHL IPB pada bulan Mei 2015 hingga Desember 2016 dengan 84 ekor anak tikus yang dilahirkan oleh induk tikus kontrol yang diberi asam valproat 250 mg pada umur kebuntingan 10, 13, dan 16 hari digunakan untuk pengamatan kadar glukosa, insulin, DNA, RNA, dan rasio RNA/DNA serta pengamatan mikroskopis otak. Pengamatan dilakukan selang waktu empat minggu, dimulai dari umur 4 sampai 32 minggu. Anak tikus yang dilahirkan oleh induk tikus yang diberi asam valproat selama kebuntingan mempunyai kadar glukosa otak yang lebih tinggi (p<0,01) dan insulin yang lebih rendah (p<0,05). Selama periode pertumbuhan, anak tikus yang dilahirkan oleh induk tikus yang diberi asam valproat mengalami peningkatan kadar glukosa dan penurunan kadar insulin (p<0.05). Pengamatan mikroskopis sel-sel dentate gyrus menunjukkan degenerasi sel dan tidak terlihat reaksi imunoreaktif terhadap insulin, namun terjadi penurunan konsentrasi DNA, RNA, serta rasio RNA/DNA (p<0,05). Pemberian asam valproat pada induk tikus pada umur kebuntingan 10, 13, dan 16 hari memengaruhi organogenesis otak anak tikus sehingga menyebabkan kerusakan sel-sel saraf penghasil insulin otak yang ditunjukkan oleh penurunan sekresi dan kadar insulin. [MKB. 2017;49(3):156–64]
Kata kunci: Asam valproat, dentate gyrus, insulin, organogenesis
Valproic Acid Administration in Pregnant Rats Inhibits Insulin Synthesis n in Brain Cells of the Offsprings
Valproic acid affects the activity of histone deacetylase which eventually affects gene expression during organogenesis. Insulin plays a role in regulating the proliferation and differentiation of the dentate gyrus. This experiment was designed to study the effects of valproic acid administration on the expression of insulin gene in the dentate gyrus of pregnant rats. This study was carried out at the Laboratory Animal Management Unit (UPHL) of Bogor Agricultural University from May 2015 to December 2016, with eighty four newborn rats from control rats and VA-administered rats at the age of 10, 13, and 16 days of pregnancy. The measurements were done for glucose, insulin, DNA, and RNA concentrations in dentate gyrus and to observe the microscopic condition of the brain at the ages of 4 to 32 weeks with 4 weeks interval. Rats born form mothers administered by 250 mg valproic acid during pregnancy had higher glucose concentrations (p<0.01) and lower insulin concentrations (p<0.05) in the dentate gyrus. During the post-natal growth phase, rats born from mothers administered with valproic acid had increased glucose concentrations and decreased insulin concentrations (p<0.05). Microscopic observations of the dentate gyrus showed degeneration of nerve cells with no immunoreaction to insulin was seen in dentate gyrus cells. However, the concentrations of DNA, RNA, and the ratio of RNA/DNA in the dentate gyrus cells decreased (p<0.05). The administration of valproic acid to pregnant rats at the age of 10, 13, and 16 days of pregnancy destructs brain organogenesis of the offsprings which eventually disturbs insulin production in the dentate gyrus indicated by decreased insulin secretion and concentrations. [MKB. 2017;49(3):156–64]
Key words: Dentate gyrus, insulin, organogenesis, valproic acid
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Blázquez E, Velazquez E, Carneiro CH, Albusac JMR. Insulin in the brain: its pathophysiological implications for states related with central insulin resistance, type 2 diabetes and alzheimer’s disease. Front Endocrinol. 2014;161(5):161.
Desai M, Li T, Ross MG. Fetal hypothalamic neuroprogenitor cell culture: preferential differentiation paths induced by leptin and insulin. Endocrinology. 2011;152(8):3192–201.
Ghafari S, Asadi E, Shabani R, Golalipour MJ. Hippocampal neuronal apoptosis in rat offspring due to gestational diabetes. Int J Morphol. 2016;34(1):205–11.
Kleinridders A, Ferris HA, Cai W, Ronald Kahn C. Insulin action in brain regulates systemic metabolism and brain function. Diabetes. 2014;63(7):2232–43.
Ximenes JCM,Verde ECL, Naffah-Mazzacoratti MG, Viana GSB.Valproic acid, a drug with multiple molecular targets related to its potential neuroprotective action. Neurosci Med. 2012;3:107–23.
Shahien R, Beiruti K. Preventive agents for migraine: focus on the antiepileptic drugs. J Cent Nerv Syst Dis. 2012;4:37–49.
Karen J, Rodriguez A, Friman T, Dencker D, Sundberg S, Scholz B. Effects of the histone deacetylase inhibitor valproic acidon human pericytes in vitro. Plos One. 2011;6(9):1–11.
Kuwabara T, Mohamedi NK, Onuma Y, Yuzuru I, Warashina M. Terashima K, dkk. Insulin biosynthesis in neuronal progenitors derived from adult hippocampus and the olfactory bulb. EMBO Mol Med. 2011;3(12):742–54.
Schwartz MW, Guyenet SJ, Cirulli V. The hypothalamus and beta-cell connection in the gene-targeting era. Diabetes. 2010;59(12):2991–3.
Sanchez AM, Rutter GA, Latreille M. MiRNAs in β-cell development, identity, and disease. Front Genet. 2017;7(266):1–19.
Dahlan MS. Statistik untuk kedokteran dan kesehatan: deskriptif, bvariat, dan multivariant. Jakarta: Epidemiologi Indonesia; 2014.
Aluclu MU, Tuncer MC, Guzel A, Aluclu MA, Akkus M. The effects of valproic acid on sciatic nerve of fetal rats and protective effects of folic acid and vitamin E. Int J Morphol. 2009;27(2):285–94.
Clancy B, Finlay BL, Darlington RB, Anand KJS. Extrapolating brain development from experimental species to humans.Neurotoxicology. 2007;28(5):1–7.
Nigrovic LE, Kimia AA, Shah SS, Neuman MI. Relationship between cerebrospinal fluid glucose and serum glucose. N Engl J Med. 2012;366 (6):576–8.
Gray SM, Meijer RI, Barrett EJ. Insulin regulates brain function, but how does it get there?. Diabetes. 2014;63(12):3992–7.
Giavini E, Menegola E. Teratogenic activity of HDAC inhibitors. Curr Pharm. 2014;20:1–6.
Rajendran P, Kidane AI, Yu TW, Dashwood WM, Bisson WH, Löhr CV, Ho E, dkk. HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates. Epigenetics. 2013;8(6): 612–23.
Parenrengi A, Tonnek S, Tenriulo A. Analisis rasio RNA/DNA udang windu Penaeus monodon hasil seleksi tumbuh cepat. J Ris Akuakultur. 2013;8(1):1–12.
Nishijima T, Piriz J, Duflot S, Fernandez AM, Gaitan G, Pinedo UG, dkk. Neuronal activity drives localizedblood-brain-barrier transportof serum insulin-like growth factor-i into the CNS. Neuron. 2010;67(5):834–46.
DOI: https://doi.org/10.15395/mkb.v49n3.1119
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