Folic Acid Supplementation in the Gestational Phase of Female Rats Improves Age-Related Memory Impairment and Neuroinflammation in Their Adult and Aged Offspring

Abstract

Folic acid (FA) supplementation is important during pregnancy to avoid malformations in the offspring. However, it is unknown if it can affect the offspring throughout their lives. To evaluate the offspring, female mother rats (Dam’s) were separated into 5 groups: Four groups received the AIN-93 diet, divided into control and FA (5, 10 and 50 mg/kg), and an additional group received a FA deficient diet, the diet was performed during pregnancy and lactation. We evaluated the female offspring of these Dam’s (at 2-and 18-months-old). The aged offspring fed with FA deficient diet presented habituation, spatial and aversive memory impairment and the FA maternal supplementation prevented this. The natural aging caused an increase in the TNF-α and IL-1β levels in the hippocampus from 18-months-old offspring. FA maternal supplementation was able to prevent the increase of these cytokines. IL-4 levels decreased in the prefrontal cortex from aged control rats and FA prevented it. FA deficiency decreased the levels of IL-4 in the hippocampus of the young offspring. In addition, natural aging and FA deficiency decreased BDNF levels in the hippocampus and NGF levels in the prefrontal cortex and FA supplementation prevent it. Thus, the present study shows for the first time the effect of FA maternal supplementation on memory, cytokines and neurotrophins in the aged offspring.

Folic acid deficiency exacerbates the inflammatory response of astrocytes after ischemia‐reperfusion by enhancing the interaction between IL‐6 and JAK‐1/pSTAT3

“…For instance, folic acid reduces hippocampal myeloperoxidase activity to alleviate neuroinflammation and improve memory impairment in sepsis‐induced rats 28 . Another in vitro study indicated that lipopolysaccharide‐activated microglia respond less inflammatory to folic acid because it inhibits the activation of NF‐kB and JNK and upregulates p38 MAPK phosphorylation 4 . Besides, our previous work has shown that FD enhanced microglia immune responses via the Notch1/nuclear factor kappa B p65 pathway to increase brain injury 8 .…”

“… 28 Another in vitro study indicated that lipopolysaccharide‐activated microglia respond less inflammatory to folic acid because it inhibits the activation of NF‐kB and JNK and upregulates p38 MAPK phosphorylation. 4 Besides, our previous work has shown that FD enhanced microglia immune responses via the Notch1/nuclear factor kappa B p65 pathway to increase brain injury. 8 The current study investigated the effect of FD on the astrocytes under ischemia‐reperfusion.…”

“…Folic acid (FA), an essential nutrient in the regular human diet, is strongly associated with neuroinflammation 4,5 . Research has shown that folic acid deficiency (FD) triggers the activation of the neuroinflammatory cascade in Alzheimer's disease (AD) 6 .…”

“…3 Folic acid (FA), an essential nutrient in the regular human diet, is strongly associated with neuroinflammation. 4,5 Research has shown that folic acid deficiency (FD) triggers the activation of the neuroinflammatory cascade in Alzheimer's disease (AD). 6 In addition, Guest et al observed a negative correlation between cerebrospinal fluid folate and levels of inflammation within the central nervous system (CNS) in the healthy population.…”

Neurobehavioral alterations induced by third‐trimester gestation‐equivalent ethanol exposure are inhibited by folate administration

“…Rats in the VEH groups were given an equivalent volume of vehicle. The folate dose was based on prior preclinical work that indicated that doses between 10 and 50 mg/kg ameliorated oxidative stress and inflammatory processes (Garcez et al., 2021). We also recently reported that EtOH exposure (2.0 g/kg/day) on GDs 17–20 induced hyperactivity and anxiety and increased EtOH intake in offspring.…”