Effects of prenatal exposure to hyperhomocysteinemia on neural plasticity and cognitive functions in rats

Effects of Prenatal Exposure to Hyperhomocysteinemia on Neural Plasticity and Cognitive Functions in RatsHomocysteine (Hcy), a sulphur containing amino acid, is derived from the metabolism of methionine. Experimental data from animals implicate that hiperhomocysteinemia causes oxidative stres, apoptosis, defects in neuroplasticity and neural development and cognitive disfunction. This study was performed to evaluate effects of maternal hyperhomocysteinemia on brain of offsprings.Pregnant Wistar albino rats were randomly divided into Hcy and control groups. Half of pups from both groups were sacrified on the first postnatal day (PND-1) to assay the levels of LPO products (LPO; as malondialdehyde + 4-hydroxyalkenals), glutathione (GSH), DNA fragmentation, p53 mRNA expression, Bcl-2 protein, gial fibrillary acidic protein (GFAP), S100B protein, neural cell adhesion molecules (NCAM) and polysialylated form of NCAM (PSA-NCAM) in the pup brain. The other half of pups from both groups were feeded with normal diet until they become 82 days old. Then a learning test, Morris water maze, was performed and the offsprings were sacrified to analyze NCAM, PSA-NCAM, GFAP, S100B protein levels in the hippocampus.Daily administration of methionine via drinking water to pregnant rats resulted in higher plasma level of hcy at the end of pregnancy compared to control group (Control: 6 µM/L and Hcy group: 26 µM/L; P<0.001). Brain homogenates of Hcy group compared to controls had significantly higher LPO products especially in mitochondrial fraction (mitochondrial fraction p<0.001, nuclear fraction p<0.001, cytosolic fraction p<0.01). DNA fragmentation was observed in Hcy group. Pups from hyperhomocysteinemic dams had significantly lower Bcl-2 protein level (mitochondrial fraction p<0.001, nuclear fraction p<0.05); they had also increased p53 m RNA (p<0.001), decreased GFAP (p<0.01) and S100B (p<0.001) protein levels compared to control group. Expression of NCAM-140 and PSA-NCAM were lower in Hcy group (p<0.001, for both). In comparison to control group, level of NCAM-180 expression was significantly lower in hippocampal homogenats from Hcy group (p<0.001). Levels of GFAP and S100B were not different in hippocampus of young adult offsprings from both groups. In Morris water maze task, spatial learning and memory consalidation were impaired in Hcy group.As a result the data implicates that pups from pregnant rats exposed to the higher level of homocysteine show increased oxidative stres, apoptosis, defects in neuroplasticity. Young adult offspring from hyperhomocysteinemic rats also shown cognitive impairment due to delayed brain maturation.