Prenatal stress and febrile seizures effects on the epigenetic mechanisms involved in cognitive function following treatment with Searsia chirindensis.

Abstract

Febrile seizures are of growing concern in the health fraternity within the African continent. These seizures predominantly affect children between the ages of 3 months and 5 years of age. Stress during pregnancy may influence the functioning of the hypothalamic-pituitary-adrenal (HPA) axis in the developing foetus. This has a tendency to increase the brain’s vulnerability to a number of insults including febrile seizures. Current treatment for febrile seizures often has undesirable side effects hence the need to find more effective alternatives. Searsia chirindensis (Searsia) is commonly used to treat conditions associated with the heart, rheumatism and brain abnormalities. The focus of this study was to investigate whether exposure to prenatal stress and early life febrile seizures may affect the expression of genes that play a role in neuronal plasticity. For this we looked at the expression of the MeCP2 and REST genes in the hippocampus. Furthermore, we investigated whether neuronal malformations and the resulting cognitive deficits associated with exposure to early life stress influences the concentration of the neurotrophic factor, BDNF and whether further exposure to febrile seizures exacerbates the stress effect. We also investigated whether treating febrile convulsions with Searsia attenuates the negative effects caused by stress on febrile seizure development as well as any cognitive effects that may be caused by the exposure to stress and febrile seizures. Fourteen day old (PND 14) pups were divided into the following groups 1) Normally reared Sprague-Dawley offspring injected with saline (NSS). (2) Prenatally stressed offspring injected with saline (SS). (3) Normally reared offspring with febrile seizures (NSFS). (4) Prenatally stressed offspring with febrile seizures (SFS). (5) Normally reared offspring treated with Searsia (NS-S). (6) Prenatally stressed offspring treated with Searsia (S-S). (7) Normally reared offspring with febrile seizures and treated with Searsia (NSFS-S). (8) Prenatally stressed offspring with febrile seizures and treated with Searsia (SFS-S). Lipopolysaccharide and kainic acid were used to induce the febrile seizures. The Morris water maze (MWM) was used to assess learning and memory function and the elevated plus maze (EPM) was used to assess anxiety-like behaviour in these young rats. MeCP2/REST genes expression and the concentration of BDNF as well as AChE were quantified using an immunoassay on hippocampal tissue. Our results showed that exposure to prenatal stress (SS) and febrile seizures (NSFS) may impair cognitive behavioural function in the short-term. However, in the NSFS animals, there seems to be an attempt to counteract the effects of febrile seizures with time. Furthermore, exposure to prenatal stress impeded the release of the neurotrophic factor, BDNF, while attenuating REST gene expression in febrile seizure animals. These factors may contribute to the hindering of neurogenic properties in the young, thus leading to neuronal plasticity deficits and possibly cognitive malfunction in later life. Treatment with Searsia attenuated the transient cognitive impairments present following a seizure by influencing the concentration of hippocampal acetylcholine and activating MeCP2 gene expression. This suggests a role for Searsia in the management of febrile seizures and in attenuating the development of chronic cognitive deficits.