Early Neurodevelopmental Anomalies in Young Rats from Adult female Treated with Valproic Acid

  • Authors

    • Landry Martial Miguel Faculty of Health Sciences
    • Archange Emmanuel Mboungou Malonga Faculty of Health Sciences
    • Didier Gesril Njilo Tchatchouang Faculty of Health Sciences
    • Childérick Lékana Faculty of Health Sciences
    • Choupette Ravelle Dobhat-Doukakini Faculty of Health Sciences
    • Emmanuel Grace Nkounkou Matondo Faculty of Health Sciences
    • Ruphin Bertrand Bolanga Public Health National Laboratory
    • Donatien Moukassa General Hospital Edith Lucie Mbongo Ondimba
    • Ange Antoine Abena Dénis Sassou N’Guesso University
  • Valproic Acid, Rat, Sensorimotor Development, Lethality.
  • Background: the influence of VPA on murine fertility, and on offspring is well documented: VPA decreases the fertility rate (by 25%) and the number of fÅ“tus. Furthermore, VPA causes behavioral alterations in rodents similar to the symptoms observed in autism.

    Objective: in this study we investigated the effects of exposure of non-pregnant adult rats to VPA in the offspring of these animals.

    Material and methods: non-pregnant adult rats were divided into 3 groups; (1) distilled water group, (2) VPA 200 mg / kg group and (3) VPA 400 mg/kg group. The products were administered orally daily for 30 days. At the end of treatments, all rats were put into monogamous mating with breeding males. The zootechnical characteristics (gestation period, litter size, mortality rate) were then noted. The young rats were then subjected to a battery of behavioral tests (reversal and anti-gravity reflexes, cliff avoidance, suspension, motor coordination and eye opening), carried out at different stages of life to assess sensorimotor development. Morphological abnormalities were also sought, as well as the mortality rate on the 28th day of life.

    Results: An increase in the mortality rate and a decrease in the mean lifespan were found in female rats exposed to VPA. Young rats from female rats exposed to VPA showed decreased success rates and performance in behavioral testing. Morphodevelopmental abnormalities such as adictalia or stump necrosis were found in the VPA groups. The offspring mortality rate of female rats exposed to VPA 200 mg/kg was 100%.

    Conclusion: VPA administered to non-pregnant adult rats causes developmental abnormalities, decreased success rates for performance testing, deformities and increased mortality in young rats from the treated rats by VPA.



  • References

    1. [1] Ardinger HH, Atkin JF, Blackston RD, Elsas LJ, Clarren SK, Livingstone S et al., (1988). Verification of the fetal valproate syndrome phenotype. American journal of medical genetics, 29 (1): 171–85. https://doi.org/10.1002/ajmg.1320290123.

      [2] Chateauvieux S, Morceau F, Dicato M, and Diederich M (2010). “Molecular and therapeutic potential and toxicity of valproic acid,†Journal of Biomedicine and Biotechnology. ID 479364, 18 p. https://doi.org/10.1155/2010/479364.

      [3] Choleris E, Thomas AW, Kavaliers M, and al., (2001). A detailed ethological analysis of the mouse open fifield test: effects of diazepam, chlordiazepoxide and an extremely low frequency pulsed magnetic fifield. Neurosci. Biobehav. Rev, 25: 235–60. https://doi.org/10.1016/S0149-7634(01)00011-2.

      [4] Christianson AL, Chesler N, Kromberg JG (1994). Fetal valproate syndrome: clinical and neuro-developmental features in two sibling pairs. Developmental medicine and child neurology, 36 (4): 361–9. PMID: 7512516. https://doi.org/10.1111/j.1469-8749.1994.tb11858.x.

      [5] Cuturic M, Abramson RK (2005). Acute hyperammonemic coma with chronic valproic acid therapy. Ann Pharmacother, 39: 2119-22. https://doi.org/10.1345/aph.1G167.

      [6] Genton P, Semah F, and Trinka E (2006). “Valproic acid in epilepsy: pregnancy-related issues,†Drug Safety, 29 (1): 1– 21. https://doi.org/10.2165/00002018-200629010-00001.

      [7] Gerstner T, Buesing D, Longin E and al., (2006). Valproic acid induced encephalopathy - 19 new cases in Germany from 1994 to 2003 - a side effect associated to VPA-therapy not only in young children. S eizure, 15: 443-8. https://doi.org/10.1016/j.seizure.2006.05.007.

      [8] Gibbons C, Hopkins M, Beaulieu K, Oustric P and Blundell JE (2009). Issues in measuring and interpreting human appetite (Satiety / Satiation) and Its contribution to obesity. Curr. Obes. Rep., 8, 77–87. https://doi.org/10.1007/s13679-019-00340-6.

      [9] Hall CS (1938). Emotional behavior in the rat. The relationship between emotionality and ambulatory activity. J Comp Psychol, 22: 345–52. https://doi.org/10.1037/h0059253.

      [10] Harden CL and Sethi NK (2008). “Epileptic disorders in pregnancy: an overview,†Current Opinion in Obstetrics and Gynecology, 20 (6): 557–62. https://doi.org/10.1097/GCO.0b013e3283184059.

      [11] Hartung T (2010). Comparative analysis of the revised Directive 2010/6106 / EU for the protection of laboratory animals with its predecessor 86/609 / EEEEC - t4 report. ALTEX - Alternatives to animal experimentation, 27 (4): 285-303 https://doi.org/10.14573/altex.2010.4.285.

      [12] Ibrahim, MA (2012). Evaluation of hepatotoxicity of valproic acid in albino mice, histological and histochemical studies. Life Sci. J., 9 (4): 153-159.

      [13] Kolozsi E, Mackenzie RN, Roullet FI, DeCatanzaro D, Foster JA (2009). Prenatal exposure to valproic acid leads to reduced expression of synaptic adhesion molecule neuroligin 3 in mice. Neuroscience, 163 (4): 1201–10. https://doi.org/10.1016/j.neuroscience.2009.07.021.

      [14] Lheureux PE, Penaloza A, Zahir S, Gris M (2005). Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence? Crit Care 2005; 9: 431-40. https://doi.org/10.1186/cc3742.

      [15] Meador KJ, Baker GA, Browning N et al. , “Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs,†New England Journal of Medicine, 2009; 360 (16): 1597–1605. https://doi.org/10.1056/NEJMoa0803531.

      [16] Ornoy A (2009). “Valproic acid in pregnancy: how much are we endangering the embryo and fetus?†Reproductive Toxicology, 2009; 28 (1): 1–10. https://doi.org/10.1016/j.reprotox.2009.02.014.

      [17] Rath A, Naryanan TJ, Chowdhary GV, Murthy JM (2005). Valproate-induced hyperammonemic encephalopathy with normal liver function. Neurol India, 53: 226-8 https://doi.org/10.4103/0028-3886.16420.

      [18] Roullet FI, Lai JK, Foster JA (2013). In utero exposure to valproic acid and autism – a current review of clinical and animal studies. Neurotoxicol Teratol, 36: 47–56. https://doi.org/10.1016/j.ntt.2013.01.004.

      [19] Roullet FI, Wollaston L, Decatanzaro D, Foster JA (2010). Behavioral and molecular changes in the mouse in response to prenatal exposure to the anti-epileptic drug valproic acid. Neuroscience, 170 (2): 514-22. https://doi.org/10.1016/j.neuroscience.2010.06.069.

      [20] Tabatabaei AR, Abbott FS (1999). Assessing the mechanism of metabolism dependent valproic acid-induced in vitro cytotoxicity. Chem Res Toxicol, 12: 323-30. https://doi.org/10.1021/tx9801864.

      [21] Teitelbaum P, Teitelbaum O, Nye J, Fryman J, Maurer RG (1998). Movement analysis in infancy may be useful for early diagnosis of autism. Proceedings of the National Academy of Sciences of the United States of Proc. Natl. Acad. Sci. USA, 95: 13982–13987, Psychology https://doi.org/10.1073/pnas.95.23.13982.

      [22] Thorsten Gerstner †, Nellie Bell & Stephan König (2008). Oral valproic acid for epilepsy - long-term experience in therapy and side effects. Expert Opin. Pharmacother, 9 (2): 1-8 https://doi.org/10.1517/14656566.9.2.285.

      [23] Tomson T, Battino D (2005). Teratogenicity of antiepileptic drugs: state of the art. Curr Opin Neurol, 18: 135–40 https://doi.org/10.1097/01.wco.0000162854.67767.06.

      [24] Ubeda-Martin N, Alonso-Aperte E, Achon M, Varela-Moreiras G, Puerta J, and Perez de Miguelsanz J (1998). “Morphological alterations induced by valproate and its concomitant administration of folic acid or S-adenosylmethionine in pregnant rats,†Nutricion Hospitalaria, 13 (1): 41–9.

      Verrotti A, D'Egidio C, Mohn A, Coppola, and Chiarelli F (2011). “Weight gain following treatment with valproic acid: pathogenetic mechanisms and clinical implications,†Obesity Reviews, 2011; 12 (501): 32-43. https://doi.org/10.1111/j.1467-789X.2010.00800.x
  • Downloads

  • How to Cite

    Martial Miguel, L., Emmanuel Mboungou Malonga, A., Gesril Njilo Tchatchouang, D., Lékana, C., Ravelle Dobhat-Doukakini, C., Grace Nkounkou Matondo, E., Bertrand Bolanga, R., Moukassa, D., & Antoine Abena, A. (2021). Early Neurodevelopmental Anomalies in Young Rats from Adult female Treated with Valproic Acid. International Journal of Pharmacology and Toxicology, 9(2), 75-83. https://doi.org/10.14419/ijpt.v9i2.31605