Volume 12, Issue 1 (January-Fabruary 2018)                   IJT 2018, 12(1): 39-46 | Back to browse issues page


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1- Department of Anatomy, Kasturba Medical College, Manipal University, Mangalore, India.
2- Department of Anatomy, Faculty of Medicine, Kuwait University, Jabriya, Kuwait. , madhyast@yahoo.com
Abstract:   (3736 Views)
Background: Children with seizure disorder are often treated with sodium valproate (SV) on long-term basis. SV acts mainly through gamma amino butyric acid pathways, reducing the excitatory neurotransmission and modifying the monoamine concentration. Altered monoamine concentration by SV is expected to cause movement disorder and cognitive dysfunction, considered reversible after the withdrawal of treatment, but some claim it to be irreversible. It is not clear whether such adverse effects continue during adulthood. The aim of this study was to investigate whether chronic administration of SV in juvenile rats causes movement disorder and cognitive dysfunction during their early adulthood.
Methods: Sixteen-day-old male Wistar rats from the central animal house, KMC, Mangalore, India in 2015, received either 200 or 400 mg/kg dose of SV for 45 consecutive days and another group served as control. Thirty days after discontinuation of the drug, at postnatal day 90, the rats were tested for movement disorder and cognitive function.
Results: Chronic SV treatment in juvenile rats resulted in slow movement, tremors during adulthood but did not affect muscle tone, locomotor and exploratory activities. It also caused cognitive dysfunction in adult rats.
Conclusion: Despite the reported safety of chronic SV therapy, its adverse effects such as Parkinsonism symptoms or cognitive dysfunctions should be of concern in all young patients treated with SV for many years. Persistence of cognitive impairment, tremors and generalized slow movement during adulthood after cessation of treatment that was observed in this study, warrants a close monitoring system in children who receive long-term sodium valproate.
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Type of Study: Research | Subject: General

References
1. Fagundes, SBR. Valproic Acid: Review. Rev Neurocienc 2008; 16(2): 130-6.
2. Perruca E. Pharmacological and therapeutic properties of valproate: A summary after 35 years of clinical experience. CNS Drugs 2002; 16: 695-714. [DOI:10.2165/00023210-200216100-00004]
3. King M. The new patient with a first seizure. Aust fam physician 2003;32(4):221-2.
4. Fariello RG, Varasi M, Smith MC. Valproic acid: Mechanism of action. Antiepileptic Drugs 1995; 4: 581-8.
5. Johanessen CU, Johanessen SI. Valproate: Past, Present, and Future. CNS Drug Rev 2006; 9(2): 199-216. [DOI:10.1111/j.1527-3458.2003.tb00249.x]
6. Hyuman NM, Dennis PD, Sinclair KGA. Tremor due to sodium valproate. Neurology 1979; 29: 1177-80. [DOI:10.1212/WNL.29.8.1177]
7. Lancman ME, Asconape JJ, Penry JK. Choreiform movements associated with the use of valproate. Arch Neurol 1994; 51: 702-4. [DOI:10.1001/archneur.1994.00540190086020]
8. Zadikoff C, Munhoz RP, Asante AN, Politzer N, Wennberg R, Carlen P, et al. Movement disorders in patients taking anticonvulsants. J Neurol Neurosurg Psychiatry 2007;78(2):147-51. [DOI:10.1136/jnnp.2006.100222]
9. Khwaja GA, Ranjan R, Gupta M, Chowdhry D, Hirva M. Valproate-induced reversible 'Parkinsonism Plus' syndrome. JIACM 2010;11:235-8.
10. Ramadan E, Basselin M, Taha AY, Cheon Y, Chang L, Chen M, Rapoport SI. Chronic valproate treatment blocks D2-like receptor-mediated brain signaling via arachidonic acid in rats. Neuropharmacology 2011; 61(8):1256-64. [DOI:10.1016/j.neuropharm.2011.07.025]
11. Kanemura H, Sano F, Maeda Y, Sugita K, Aihara M. Valproate sodium enhances body weight gain in patients with childhood epilepsy: A pathogenic mechanisms and open-label clinical trial of behavior therapy. Seizure 2012; 21(7):496-500. [DOI:10.1016/j.seizure.2012.05.001]
12. Madhyastha S, Somayaji SN, Rao MS, Nalini K, Bairy KL. Hippocampal brain amines in methotrexate-induced learning and memory deficit. Can J Physiol Pharmacol 2002; 80: 1076-84. [DOI:10.1139/y02-135]
13. Ludolph AC, Seelig M, Ludolph A, Novitt P, Allen CN, Spencer PS, et al. 3-Nitropropionic acid decreases cellular energy levels and causes neuronal degeneration in cortical explants. Neurodegeneration 1992; 1: 155-61.
14. Naidu PS, Singh A, Kulkarni SK. Quercetin, a bioflavonoid, attenuates haloperidol-induced orofacial dyskinesia. Neuropharmacology 2003; 44(8): 1100-6. [DOI:10.1016/S0028-3908(03)00101-1]
15. Gopala Krishna HN, Pemminati S, Dorababu P, Pai MR, Colaco N, Vineetha V. The effect of acute and chronic administration of the aqueous extract of Triphala on haloperidol induced catalepsy in mice. J Clin Diagn Res 2010; 3: 2134-8.
16. Ferre S, Guix T, Prat G, Jane F, Casas M. Is experimental catalepsy properly measured?. Pharmacol Biochem Behav 1990; 35(4): 753-7. [DOI:10.1016/0091-3057(90)90354-K]
17. Rai KS, Murthy KD, Karantha KS, Rao MS. Clitoriaternatea (Linn) root extract treatment during growth spurt period enhances learning and memory in rats. Indian J Physiol Pharmacol 2001; 45(3): 305-13.
18. Carmona-Vazquez CR, Ruiz-Garcia M, Pena-Landin DM, Diaz-Garcia L, Greenawalt SR. The prevalence of obesity and metabolic syndrome in paediatric patients with epilepsy treated in monotherapy with valproic acid. Rev Neurol 2015; 61(5): 193-201.
19. Petty SJ, Kantor S, Lawrence KM, Berkovic SF, Collins M,Hill KD, et al.Weight and fat distribution in patients taking valproate: a valproate-discordant gender-matched twin and sibling pair study. Epilepsia 2014; 55(10): 1551-7. [DOI:10.1111/epi.12745]
20. Biton V. Effect of antiepileptic drugs on bodyweight: overview and clinical implications for the treatment of epilepsy. CNS Drugs 2003; 17: 781-91. [DOI:10.2165/00023210-200317110-00002]
21. Luef GJ, Lechleitner M, Bauer G, Trinka E, Hengster P. Valproic acid modulates islet cell insulin secretion: a possible mechanism of weight gain in epilepsy patients. Epilepsy Res 2003; 55: 53-8. [DOI:10.1016/S0920-1211(03)00091-3]
22. Barros HM, Tannhauser SL, TannhauserMA,Tannhauser M. Effect of sodium valproate on the open-field behavior of rats. Braz J Med Biol Res 1992; 25(3): 281-7.
23. Teruel AF, Boix F, Escorihuela RM, Yanez P, Tobena A. Sodium valproate reduces immobility in the behavioral 'despair' test in rats. Eur J Pharmacol 1988; 152(1-2): 1-7. [DOI:10.1016/0014-2999(88)90829-1]
24. Masmoudi K, Gras-Champel V, Masson H, Andrejak M. Parkinsonism and/or cognitive impairment with valproic acid therapy: a report of ten cases. Pharmacopsychiatry 2006; 39(1): 9-12. [DOI:10.1055/s-2006-931471]
25. Armon C, Shin C, Miller P, Carwile S, Brown E, Edinger JD, et al. Reversible Parkinsonism and cognitive impairment with chronic valproate use. Neurology 1996; 47: 626-35. [DOI:10.1212/WNL.47.3.626]
26. Schreur L, Middeljans-Tijssen C, Hengstman G, Olde RM. Cognitive impairment and parkinsonism due to use of sodium valproate. Tijdschr Gerontol Geriatr 2009;40(1):29-33. [DOI:10.1007/BF03088474]
27. Jamora D, Lim SH, Pan A, Tan L, Tan EK. Valproate-induced Parkinsonism in epilepsy patients. Mov Disord 2007: 22: 130-3. [DOI:10.1002/mds.21188]
28. Onofrj M, Thomas A, Paci C. Reversible Parkinsonism induced by prolonged treatment with valproate. J Neurol 1998; 245 (12): 794-6. [DOI:10.1007/s004150050288]
29. Sasso E, Delsoldato S, Negrotti A, Mancia D. Reversible valproate-induced extrapyramidal disorders. Epilepsia 1994; 35: 391-3. [DOI:10.1111/j.1528-1157.1994.tb02449.x]
30. Alvarez-Gomez MJ, Vaamonde J, Narbona J, Barao M, Barona P, Branna T, et al. Parkinsonism syndrome in childhood after sodium valproate administration. Neuropharmacol 1993; 16: 451-5. [DOI:10.1097/00002826-199310000-00009]
31. Karas BJ, Wilder BJ, Hammond EJ, Bauman AW. Valproate tremors. Neurology 1982; 32: 428-32. [DOI:10.1212/WNL.32.4.428]
32. Pineda-Trujillo N, Carvajal-Carmona LG, Buritica O, Moreno S, Uribe C, Pineda D, et al. A novel Cys212Tyr founder mutation in parkin and allelic heterogeneity of juvenile Parkinsonism in a population from North West Colombia. Neurosci Lett 2001; 298(2): 87-90. [DOI:10.1016/S0304-3940(00)01733-X]
33. Easterford K, Clough P, Kellett M, Fallon K, Duncan S. Reversible Parkinsonism with normal β-CIT–SPECT in patients exposed to sodium valproate. Neurology 2004; 62: 1435-7. [DOI:10.1212/01.WNL.0000121228.32913.00]
34. Ximenes JCM, Neves KRT, Leal LKA, do Carmo MRS, Brito GAdC, Naffah-Mazzacoratti MdG, et al. Valproic acid neuroprotection in the 6-OHDA model of Parkinson's disease is possibly related to its anti-inflammatory and HDAC inhibitory properties. J Neurodegener Dis 2015;2015:1-13. [DOI:10.1155/2015/313702]
35. Filgueiras CC, Pohl-Guimaraes F, Krahe TE, Medina AE. Sodium valproate exposure during the brain growth spurt transiently impairs spatial learning in prepubertal rats. Pharmacol Biochem Behav 2013; 103(3): 684-91. [DOI:10.1016/j.pbb.2012.11.007]

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