Folic acid prevents behavioral impairment and Na(+), K(+) -ATPase inhibition caused by neonatal hypoxia-ischemia.

Folic acid plays an important role in neuroplasticity and acts as a neuroprotective agent, as observed in experimental brain ischemia studies. The aim of this study was to investigate the effects of folic acid on locomotor activity, aversive memory and Na(+),K(+)-ATPase activity in the frontal cortex and striatum in animals subjected to neonatal hypoxia-ischemia (HI). Wistar rats of both sexes at postnatal day 7 underwent HI procedure and were treated with intraperitoneal injections of folic acid (0.011 µmol/g body weight) once a day, until the 30th postnatal day. Starting on the day after, behavioral assessment was run in the open field and in the inhibitory avoidance task. Animals were sacrificed by decapitation 24 h after testing and striatum and frontal cortex were dissected out for Na(+),K(+)-ATPase activity analysis. Results show anxiogenic effect in the open field and an impairment of aversive memory in the inhibitory avoidance test in HI rats; folic acid treatment prevented both behavioral effects. A decreased Na(+),K(+)-ATPase activity in striatum, both ipsilateral and contralateral to ischemia, was identified after HI; a total recovery was observed in animals treated with folic acid. A partial recovery of Na(+),K(+)-ATPase activity was yet seen in frontal cortex of HI animals receiving folic acid supplementation. Presented results support that folic acid treatment prevents memory deficit and anxiety-like behavior, as well as prevents Na(+),K(+)-ATPase inhibition in the striatum and frontal cortex caused by neonatal hypoxia-ischemia.

Neonatal handling impairs intradimensional shift and alters plasticity markers in the medial prefrontal cortex of adult rats.

Stress response can be modulated by neonatal/childhood events. Neonatal handling (NH) is an animal model in which the animals are subjected to brief separations from the dam during the first days of life, and it leads to lower emotionality and behavioral changes in adulthood. The aim of this study was to observe if early events, such as (NH), may program associative learning and behavioral flexibility in adult male rats and if these changes could be related to altered neurochemistry in the medial prefrontal cortex (mPFC). We evaluated proteins related to synaptic plasticity (brain-derived neurotrophic factor [BDNF] and synaptophysin [SYP]) as well as Na+/K+-ATPase activity. Additionally, we evaluated proteins related to the dopaminergic system (tyrosine hydroxylase [TH] and phosphorylated TH [pTH]), since this system appears to be affected in some neonatal interventions. Neonatally handled animals exhibited impairment in simple discrimination and intradimensional shift but not in reversal or compound discrimination; in addition, no alteration in switching from an egocentric spatial to a cued strategy was observed. These effects were accompanied by a decrease in SYP levels and Na+/K+-ATPase activity, suggesting reduced synaptic function. These results indicate that NH increases attention to irrelevant stimuli and/or impairs associative learning, and this is accompanied by neurochemical alterations in the (mPFC).

Folic Acid Can Contribute to Memory Deficit and Na+, K+- ATPase Failure in the Hippocampus of Adolescent Rats Submitted to Hypoxia- Ischemia.

Recent findings have demonstrated a dual effect of the folic acid (FA) supplementation on the nervous system of rats. We found that FA treatment prevented memory impairment and Na(+), K(+)- ATPase inhibition in the striatum and cortex in adult rats that suffered neonatal hypoxia-ischemia (HI). However, spatial memory deficit has been associated with FA supplementation. In the present study we investigated the role of FA supplementation on spatial memory and Na(+), K(+)-ATPase activity in the hippocampus, as well as on morphologic alterations in adolescent rats submitted to neonatal HI. Wistar rats of both sexes at postnatal day (PND) 7 were submitted to Levine-Rice HI procedure. Intraperitoneal doses of FA were administered immediately before HI and repeated daily until the maximum PND 40. Hippocampal volume and striatum area were estimated and Na(+), K(+)-ATPase activity in the hippocampus was measured at PND 31. Also, the performance of the animals in the water maze was assessed and Na(+), K(+)-ATPase activity measured again at PND 52. Interestingly, HI and FA resulted in spatial memory deficits in the Morris water maze and the Na(+), K(+)-ATPase activity was impaired at PND 31 in HI rats which received FA. Additionally, Na(+), K(+)-ATPase activity in adulthood showed a decrease after HI and a recovery in supplemented animals. Hippocampal and striatal atrophy were partially reversed by FA. To conclude, the present results support the hypothesis that FA supplementation during development contributes to memory deficits caused by HI and Na(+), K(+)-ATPase failure in adolescent rats, although, in adulthood, FA has been effective in reversing enzymatic activity in the hippocampus.