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.
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Abbreviations
- FA:
-
folic acid
- Dams:
-
Female mother rat
- Hcy:
-
Homocysteine
- HHcy:
-
Hiperhomocisteinemia
- NMDA:
-
N-methyl-d-aspartate
- SAH, SAM:
-
S-adenosyl-methionine
- ROS:
-
Reactive oxygen species
- CNS:
-
Central nervous system (CNS)
- SZ:
-
Schizophrenia
- TBARS:
-
Thiobarbituric acid reactive species
- MAD:
-
Malondialdehyde
- DNPH:
-
Dinitrophenylhydrazine
- EDTA:
-
Ethylenediaminetetraacetic acid
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Acknowledgments
The Laboratory of Neurosciences (Brazil) is one of the centers of the National Institute for Translational Medicine (INCT-TM) and also one of the members of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). This research was supported by grants from CNPq, Instituto Cérebro e Mente, and UNESC. JQ and AIZ are CNPq fellows.
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The animals were used according to the NIH Guide for the Care and Use of Laboratory Animals. The local Ethical Committee for Animal Research (CEUA 100-2014-01/UNESC) approved the protocol and all experiments. All efforts were made to minimize animal suffering and to reduce the number of animals used in the experiment.
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The authors declare that there is no conflict of interests regarding the publication of this paper. Zugno and Budni had full access to all the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis.
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Canever, L., Alves, C.S.V., Mastella, G. et al. 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. Mol Neurobiol 55, 2301–2319 (2018). https://doi.org/10.1007/s12035-017-0493-7
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DOI: https://doi.org/10.1007/s12035-017-0493-7