The Evaluation of Folic Acid-Deficient or Folic Acid-Supplemented Diet in the Gestational Phase of Female Rats and in Their Adult Offspring Subjected to an Animal Model of Schizophrenia

Abstract

Although folic acid (FA) supplementation is known to influence numerous physiological functions, especially during pregnancy, little is known about its direct effects on the mothers' health. However, this vitamin is essential for the health of the mother and for the normal growth and development of the fetus. Thus, the aim of this study was (1) to evaluate the cognitive effects and biochemical markers produced by the AIN-93 diet (control), the AIN-93 diet supplemented with different doses of FA (5, 10, and 50 mg/kg), and a FA-deficient diet during pregnancy and lactation in female mother rats (dams) and (2) to evaluate the effect of maternal diets on inflammatory parameters in the adult offspring which were subjected to an animal model of schizophrenia (SZ) induced by ketamine (Ket). Our study demonstrated through the Y-maze test that rats subjected to the FA-deficient diet showed significant deficits in spatial memory, while animals supplemented with FA (5 and 10 mg/kg) showed no deficit in spatial memory. Our results also suggest that the rats subjected to the FA-deficient diet had increased levels of carbonylated proteins in the frontal cortex and hippocampus and also increased plasma levels of homocysteine (Hcy). Folate was able to prevent cognitive impairments in the rats supplemented with FA (5 and 10 mg/kg), data which may be attributed to the antioxidant effect of the vitamin. Moreover, FA prevented protein damage and elevations in Hcy levels in the rats subjected to different doses of this vitamin (5, 10, and 50 mg/kg). We verified a significant increase of the anti-inflammatory cytokine (interleukin-4 (IL-4)) and a reduction in the plasma levels of proinflammatory cytokines (interleukin-6 (IL-6)) and TNF-α) in the dams that were subjected to the diets supplemented with FA (5, 10, and 50 mg/kg), showing the possible anti-inflammatory effects of FA during pregnancy and lactation. In general, we also found that in the adult offspring that were subjected to an animal model of SZ, FA had a protective effect in relation to the levels of IL-4, IL-6, and TNF-α, which indicates that the action of FA persisted in the adult offspring, since FA showed a lasting effect on the inflammatory response, which was similar in both the dams and their offspring. In conclusion, the importance of supplementation with FA during pregnancy and lactation should be emphasized, not only for the benefit of the offspring but also for the health of the mother. All this is due to the considerable protective effect of this vitamin against oxidative damage, cognitive impairment, hyperhomocysteinemia, immune function, and also its ability in preventing common processes in post-pregnancy stages, as well as in reducing the risks of neurodevelopmental disorders and enhancing fetal immune development.

Gestational folic acid supplementation does not affects the maternal behavior and the early development of rats submitted to neonatal hypoxia‐ischemia but the high supplementation impairs the dam's memory and the Na+, K+ ‐ ATPase activity in the pup's hippocampus

“…As expected, no differences between the FA‐supplemented and the SD diets were observed, both for food consumption and weight. Canever et al (2018) did not found differences in the weight of the pregnant rats during gestation that were supplemented with FA. Contrary to the present study, they found that FA‐supplemented dams had an increase in the food intake when compare, especially, with FA‐deficient, and this difference was associated with the vitamin supplementation itself.…”

“…Similarly, Sittig et al, (2012) found memory and motivation impairment in young rats that had received FA supplemented diets (5.3 mg/kg) and these data were associated to suppress thyroid hormones receptors function in the hippocampus. Canever et al, (2018) evaluated the FA supplementation during pregnancy and lactation and they found an improvement in the memory of the FA‐supplemented dams (5 and 10 mg/kg of FA) in the Y‐maze test. Despite the similarity, this study supplemented the mothers for a longer period and in different doses.…”

“…In contrast, it was evidenced improving in early reflexes, spatial learning and motor function (Wang et al, 2017). Fewer studies have focused on the effects of FA supplementation in pregnant rats, but Canever et al, (2018) reported that FA‐supplemented dams presented an improvement in spatial memory. In contrast, Sittig et al, (2012) identified memory and motivation deficits in young rats supplemented with FA.…”

Combined effects of intrinsic host gene (TRAPPC9) and extrinsic nutrient (folate) on resistance against S. aureus induced bovine mastitis

“…Folic acid plays a positive role in preventing in ammation, oxidative stress, and some diseases possibly by mediating the expression of cytokines (IL-1β, IL-6, TNF-α and others) [17,19,43,44]. During female pregnancy and lactation, appropriate folate intake reduced the expression of IL-6 and TNF-α of dams and their offspring [45]. Our in vitro experiments showed similar results that appropriately supplementary folic acid (5 µg/mL) reduced the in ammation of the mammary epithelial cells induced by either S. aureus or MRSA may through in uencing the expression of interleukins genes (IL-1β, IL-6, and IL-8).…”

Ontogeny and programming of the fetal temporal cortical endocannabinoid system by moderate maternal nutrient reduction in baboons ( Papio spp.)

“…, ) and pharmacological targeting of the ECS has great potential for treatment of schizophrenia (disorder, programmed by maternal folic acid deficiency (Canever et al. )), autism spectrum disorder and epilepsy (Di Marzo ). Based on the facts that epilepsy occurs naturally in baboons (Szabo and Salinas ) and these NHP express all components of the ECS (Brocato et al.…”