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Folate deficiency effects on neurotransmitter metabolism. A, Tissue content of 5-HIAA and of 5-HT. B, NA levels in amygdala and hippocampus. Tissue contents are reported per milligram of wet weight. *p 0.05, ND versus FD; # p 0.05, Ung/ versus Ung/. n 8 -10 animals per group.
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Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegenerative conditions like stroke and dementia. Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression. We hypothesized that the pathogenic mechanisms include...
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... 1986). We observed an overall trend of lower 5-HIAA/5-HT ratios in folate-deficient animals, which was statistically significant in amygdala and striatum (supplemental Table 1, available at www. jneurosci.org as supplemental material). 5-HIAA levels were also significantly reduced in hippocampus, amygdala, and striatum of folate-deficient animals (Fig. 5A). In addition, folate deficiency caused a significant increase in norepinephrine levels in amygdala and hippocampus (Fig. 5B). Together, the effects of folate deficiency on neurotransmitter metabolism were largely independent of Ung ...
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... in amygdala and striatum (supplemental Table 1, available at www. jneurosci.org as supplemental material). 5-HIAA levels were also significantly reduced in hippocampus, amygdala, and striatum of folate-deficient animals (Fig. 5A). In addition, folate deficiency caused a significant increase in norepinephrine levels in amygdala and hippocampus (Fig. 5B). Together, the effects of folate deficiency on neurotransmitter metabolism were largely independent of Ung ...
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... 1986). We observed an overall trend of lower 5-HIAA/5-HT ratios in folate-deficient animals, which was statistically significant in amygdala and striatum (supplemental Table 1, available at www. jneurosci.org as supplemental material). 5-HIAA levels were also significantly reduced in hippocampus, amygdala, and striatum of folate-deficient animals (Fig. 5A). In addition, folate deficiency caused a significant increase in norepineph- rine levels in amygdala and hippocampus (Fig. 5B). Together, the effects of folate deficiency on neurotransmitter metabo- lism were largely independent of Ung ...
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... in amygdala and striatum (supplemental Table 1, available at www. jneurosci.org as supplemental material). 5-HIAA levels were also significantly reduced in hippocampus, amygdala, and striatum of folate-deficient animals (Fig. 5A). In addition, folate deficiency caused a significant increase in norepineph- rine levels in amygdala and hippocampus (Fig. 5B). Together, the effects of folate deficiency on neurotransmitter metabo- lism were largely independent of Ung ...
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... As the methylation of dUMP to dTMP requires folic acid, under folate depletion the intracellular dUTP level increases. Interestingly, it was demonstrated that folate deficiency strongly repressed neurogenesis 100 and inhibited proliferation of adult hippocampal progenitors 101 . Accordingly, the observed expression of dUTPase during neurogenesis suggests that the elimination of dUTP and the biosynthesis of dTTP is of utmost important in neuronal function. ...
The enzyme dUTPase has an essential role in maintaining genomic integrity. In mouse, nuclear and mitochondrial isoforms of the enzyme have been described. Here we present the isoform-specific mRNA expression levels in different murine organs during development using RT-qPCR. In this study, we analyzed organs of 14.5-day embryos and of postnatal 2-, 4-, 10-week- and 13-month-old mice. We demonstrate organ-, sex- and developmental stage-specific differences in the mRNA expression levels of both isoforms. We found high mRNA expression level of the nuclear isoform in the embryo brain, and the expression level remained relatively high in the adult brain as well. This was surprising, since dUTPase is known to play an important role in proliferating cells, and mass production of neural cells is completed by adulthood. Thus, we investigated the pattern of the dUTPase protein expression specifically in the adult brain with immunostaining and found that dUTPase is present in the germinative zones, the subventricular and the subgranular zones, where neurogenesis occurs and in the rostral migratory stream where neuroblasts migrate to the olfactory bulb. These novel findings suggest that dUTPase may have a role in cell differentiation and indicate that accurate dTTP biosynthesis can be vital, especially in neurogenesis.
... After 12 weeks of intervention, FD exacerbated the depressive behavior, which was caused by CUMS. Several other studies have also revealed the effects of FD on depression, consistent with our study [48,49]. As a reliable predictor of amyloid load in the brain and biomarkers in AD [50,51], the ratio of Aβ1-42 to Aβ1-40 was elevated in CUMS rats, which means CUMS caused AD-related pathological changes in depressive-behavior rats. ...
Depression is often considered one of the prevalent neuropsychiatric symptoms of Alzheimer’s disease (AD). β-amyloid (Aβ) metabolism disorders and impaired microglia phagocytosis are potential pathological mechanisms between depression and AD. Folate deficiency (FD) is a risk factor for depression and AD. In this study, we used a chronic unpredictable mild stress (CUMS) rat model and a model of Aβ phagocytosis by BV2 cells to explore the potential mechanisms by which FD affects depression and AD. The results revealed that FD exacerbated depressive behavior and activated microglia in CUMS rats, leading to an increase in intracellular Aβ and phagocytosis-related receptors for advanced glycation end products (RAGE). Then, in vitro results showed that the expression of the RAGE receptor and M2 phenotype marker (CD206) were upregulated by FD treatment in BV2 cells, leading to an increase in Aβ phagocytosis. However, there was no significant difference in the expression of toll-like receptor 4 (TLR4) and clathrin heavy chain (CHC). Furthermore, when using the RAGE-specific inhibitor FPS-ZM1, there was no significant difference in Aβ uptake between folate-normal (FN) and FD BV2 cell groups. In conclusion, these findings suggest FD may promote microglia phagocytosis Aβ via regulating the expression of RAGE or microglia phenotype under Aβ treatment.
... FA can also protect cerebellum against homocysteine-mediated oxidative stress 54 . There is an evidence that lack of FA can provoke cognitive decline, anxiety and depression 55,56 . Thus, experiments on mice demonstrated that FA exhibits antidepressant properties in forced swimming test (FST) and tail suspension test (TST) which seem to be mediated by the serotonergic and noradrenergic systems 57 . ...
Spinocerebellar ataxia type 2 (SCA2) is a polyglutamine disorder caused by a pathological expansion of CAG repeats in ATXN2 gene. SCA2 is accompanied by cerebellar degeneration and progressive motor decline. Cerebellar Purkinje cells (PCs) seem to be primarily affected in this disorder. The majority of the ataxia research is focused on the motor decline observed in ataxic patients and animal models of the disease. However, recent evidence from patients and ataxic mice suggests that SCA2 can also share the symptoms of the cerebellar cognitive affective syndrome. We previously reported that SCA2-58Q PC-specific transgenic mice exhibit anxiolytic behavior, decline in spatial memory, and a depressive-like state. Here we studied the effect of the activation of the small conductance calcium-activated potassium channels (SK channels) by chlorzoxazone (CHZ) combined with the folic acid (FA) on the PC firing and also motor, cognitive and affective symptoms in SCA2-58Q mice. We realized that CHZ-FA combination improved motor and cognitive decline as well as ameliorated mood alterations in SCA2-58Q mice without affecting the firing rate of their cerebellar PCs. Our results support the idea of the combination therapy for both ataxia and non-motor symptoms in ataxic mice without affecting the firing frequency of PCs.
... A previous study indicated that supplementation with folic acid improved cognitive function in older people [35]. In an animal experiment, folates along with vitamins B6 and B12 were associated with DNA methylation in neurons [36]. In a randomized, double-blind, placebo-controlled, multicenter trial, a diet with probiotic supplements could shift gut microbiota status, which was inversely associated with BDNF levels in the blood among older people [37]. ...
This study aims to examine the relationships of dietary α-carotene and β-carotene intake with cognitive function. The data were selected from the National Health and Nutrition Examination Survey (NHANES) 2011–2014. A total of 2009 participants were included in this analysis. Dietary α-carotene and β-carotene intake were averaged by two 24-h dietary recalls. The Consortium to Establish a Registry for Alzheimer’s Disease Word Learning subset (CERAD W-L), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST) were used to evaluate cognitive function. Logistic regression and restricted cubic spline models were applied to explore the associations of dietary α-carotene and β-carotene intake with cognitive performance. After adjusting for all confounding factors, compared with individuals in the lowest quartile of β-carotene dietary intake, those in the highest quartile had lower risks of both CERAD W-L decline [odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.44–0.90] and AFT decline (OR = 0.66, 95% CI: 0.47–0.94). In addition, the third quartile of β-carotene dietary intake had a significantly decreased risk of lower DSST (OR = 0.67, 95% CI: 0.48–0.83). Compared with the lowest quartile of α-carotene intake, the OR of AFT decline in the highest intake quartile was 0.66 (95% CI: 0.46, 0.94). For males, both dietary α-carotene and β-carotene intake were associated with a decreased risk of AFT decline (OR = 0.42, 95% CI: 0.25–0.71; OR = 0.51, 95% CI: 0.30–0.85, respectively). For females, dietary α-carotene intake was associated with a decreased risk of CERAD W-L decline (OR = 0.55, 95% CI: 0.33–0.91) and dietary β-carotene intake was associated with decreased risks of both CERAD W-L and AFT decline (OR = 0.37, 95% CI: 0.21–0.64; OR = 0.58, 95% CI: 0.37–0.91, respectively). Our results suggested that higher dietary α-carotene and β-carotene intake had inverse effects on cognitive function decline among older adults.
... There are several studies investigating the effects of various diets on adult hippocampal neurogenesis (AHN) starting from high-fat diets [43] to those deficient in thiamine [28,44], zinc [45], folate [46], omega-3 fatty acids [47], flavonoids [48] and curcumin [49], with different effects of AHN. One interesting such study looked at AHN in the MCD diet in C57BL/6J male mice, showing that 4 weeks of MCD food induced a decrease in the proliferation, differentiation and survival of NSCs into mature neurons [17]. ...
The treatment of acute life-threatening events in patients suffering from chronic pathologies is problematic, as physicians need to consider multisystemic drug effects. Regarding Cerebrolysin, a Sonic Hedgehog signaling pathway amplifier and one of the few approved neurotrophic treatments for stroke patients, concerns of excessive Hedgehog pathway activation that could accelerate NAFLD progression to cirrhosis seem valid. We investigated stroke patients treated with Cerebrolysin that presented elevated levels of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT). We also investigated the efficiency of Cerebrolysin in reversing the neurogenesis inhibition within the hippocampus in a mouse model of NAFLD by evaluating behavior and histological outcomes. NeuN, BrdU and Iba1 positive signals in the cortex and hippocampus of the animals were also observed. Clinically, Cerebrolysin improved AST levels in a majority of stroke patients with hepatic damage. The same treatment in an experimental setup was able to reverse anxiety-like behavior in MCD mice, reducing their freezing time from 333.61 ± 21.81 s in MCD animals to 229.17 ± 26.28 in treated ones. The use of Cerebrolysin did not improve short-term memory nor rescued cell multiplication in the hippocampus after MCD food intake. Understanding the neuroprotective and neurotrophic effects that drugs have on NAFLD patients can significantly contribute to a suitable therapeutic approach.
... Folic acid plays an essential role in the proliferation and differentiation of hippocampal NSCs. In the absence of folate, the number of proliferating cells in the hippocampal DG is significantly reduced, and hippocampal neurons undergo plasticity changes, leading to hippocampal volume atrophy, and memory and cognitive dysfunction (Kronenberg et al., 2008). There are numerous mechanisms by which the brain folate deficiency causes morphological changes in the hippocampus, such as the abnormal metabolism of homocysteine to glutamate (Hama et al., 2020), which in turn leads to enhanced excitotoxicity triggering neuronal apoptosis; improper folate intake and abnormal metabolism can reduce the genomic stability and cause neuronal apoptosis. ...
Folates, provided by food, are commonly used antidepressant synergists in late-onset depression (LOD). However, increased intake of folic acid in the elderly population might lead to the accumulation of unmetabolized folic acid in the systemic circulation, leading to enhanced deterioration of the central nervous system function. In addition, folates cannot access the brain directly because of the blood-brain barrier. Choroid plexus (CP) 5-methyltetrahydrofolate (5-MTHF) brain transport plays a critical role in regulating the cerebrospinal fluid (CSF) 5-MTHF content. Luteolin is a natural flavonoid that has antidepressant effects and is involved in the anti-folate resistance pathway. It remains unclear whether the antidepressant effects of luteolin are associated with the CP 5-MTHF brain transport. In this study, 20-21-month-old Wistar rats were exposed to the chronic unpredictable mild stress (CUMS) protocol for 6 consecutive weeks to explore the long-term effects of luteolin on behavior, 5-MTHF levels, hippocampal neurogenesis, and folate brain transport of the CP. In vitro primary hippocampal neural stem cells (NSCs) cultured in media containing 10% CSF from each group of rats and choroid plexus epithelial cells (CPECs) cultured in media containing 20 μM luteolin were treated with 100 μM corticosterone and 40 mg/ml D-galactose. We found that aged rats exposed to CUMS showed a significantly reduced sucrose preference, decreased locomotion activity in the open field test and accuracy of the Morris water maze test, increased immobility time in the forced swimming test, accelerated dysfunctional neurogenesis and neuronal loss in the dentate gyrus of LOD rats, as well as decreased CSF and hippocampus 5-MTHF levels, and zona occludens protein 1 (ZO-1), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC) protein levels. In vitro assays showed media containing 10% aged CSF or LOD+ Luteolin-CSF significantly increased the viability of CORT + D-gal-injured NSCs and alleviated dysfunctional neurogenesis and neuronal loss compared with the CORT + D-gal medium. However, media containing 10% LOD-CSF had no such effect. In the meantime, induction of CORT + D-gal significantly decreased the ZO-1, PCFT, RFC, and folate receptor alpha (FR-α) protein levels and transepithelial electrical resistance in rat CPECs. As expected, luteolin treatment was effective in improving these abnormal changes. These findings suggested that luteolin could ameliorate CUMS-induced LOD-like behaviors by enhancing the folate brain transport.
... These effects add up and convey a significance to the general, umbrella-like mechanism. However, external factors such as folate intake may modulate each of these distinct, narrow pathways in a different magnitude or manner [62][63][64]. Consequently, in determining the level of rumination in cases of different folate statuses, some of these pathways will become less important, while others will become more so. ...
... In the suboptimal folate intake group, the genetics of rumination may be best determined by the specific pathways and processes most sensitive to folate deficiency. Indeed, DNA synthesis and repair [65], early prenatal development [66], prenatal brain development [67] and levels of C-C chemokines [68] and homocysteine [69] have been demonstrated to be influenced by folate levels, even in interaction with genetics [63,70,71], and have shown associations with neuropsychiatric phenotypes [63,72,73], as well. Adverse effects of genetic, intrauterine or immunometabolic factors on these phenotypes may be compensated by sufficient folate intake, although our results suggested that developmental timing is crucial in folate's compensatory impact in case of these biological pathways and rumination, as adult folate intake has not showed association with rumination. ...
... In the suboptimal folate intake group, the genetics of rumination may be best determined by the specific pathways and processes most sensitive to folate deficiency. Indeed, DNA synthesis and repair [65], early prenatal development [66], prenatal brain development [67] and levels of C-C chemokines [68] and homocysteine [69] have been demonstrated to be influenced by folate levels, even in interaction with genetics [63,70,71], and have shown associations with neuropsychiatric phenotypes [63,72,73], as well. Adverse effects of genetic, intrauterine or immunometabolic factors on these phenotypes may be compensated by sufficient folate intake, although our results suggested that developmental timing is crucial in folate's compensatory impact in case of these biological pathways and rumination, as adult folate intake has not showed association with rumination. ...
Past-oriented rumination and future-oriented worry are two aspects of perseverative negative thinking related to the neuroticism endophenotype and associated with depression and anxiety. Our present aim was to investigate the genomic background of these two aspects of perseverative negative thinking within separate groups of individuals with suboptimal versus optimal folate intake. We conducted a genome-wide association study in the UK Biobank database (n = 72,621) on the “rumination” and “worry” items of the Eysenck Personality Inventory Neuroticism scale in these separate groups. Optimal folate intake was related to lower worry, but unrelated to rumination. In contrast, genetic associations for worry did not implicate specific biological processes, while past-oriented rumination had a more specific genetic background, emphasizing its endophenotypic nature. Furthermore, biological pathways leading to rumination appeared to differ according to folate intake: purinergic signaling and circadian regulator gene ARNTL emerged in the whole sample, blastocyst development, DNA replication, and C-C chemokines in the suboptimal folate group, and prostaglandin response and K+ channel subunit gene KCNH3 in the optimal folate group. Our results point to possible benefits of folate in anxiety disorders, and to the importance of simultaneously taking into account genetic and environmental factors to determine personalized intervention in polygenic and multifactorial disorders.
... In E. coli, dut mutations that inactivate deoxyuridine triphosphatase and increase the dUTP pool are synthetically lethal with UNG overexpression, whereas ung mutation partially rescues growth defects and chromosome fragmentation in the dut background [53,54]. Fetal neocortical and hippocampal neurons but not embryonic fibroblasts from ung −/− knockout mice show enhanced sensitivity to MTX [55,56]. No increase in the sensitivity to raltitrexed, an MTX analog, is observed in chicken ung −/− DT40 lymphoma cells [57]. ...
Uracil–DNA glycosylases are enzymes that excise uracil bases appearing in DNA as a result of cytosine deamination or accidental dUMP incorporation from the dUTP pool. The activity of Family 1 uracil–DNA glycosylase (UNG) activity limits the efficiency of antimetabolite drugs and is essential for virulence in some bacterial and viral infections. Thus, UNG is regarded as a promising target for antitumor, antiviral, antibacterial, and antiprotozoal drugs. Most UNG inhibitors presently developed are based on the uracil base linked to various substituents, yet new pharmacophores are wanted to target a wide range of UNGs. We have conducted virtual screening of a 1,027,767-ligand library and biochemically screened the best hits for the inhibitory activity against human and vaccinia virus UNG enzymes. Although even the best inhibitors had IC50 ≥ 100 μM, they were highly enriched in a common fragment, tetrahydro-2,4,6-trioxopyrimidinylidene (PyO3). In silico, PyO3 preferably docked into the enzyme’s active site, and in kinetic experiments, the inhibition was better consistent with the competitive mechanism. The toxicity of two best inhibitors for human cells was independent of the presence of methotrexate, which is consistent with the hypothesis that dUMP in genomic DNA is less toxic for the cell than strand breaks arising from the massive removal of uracil. We conclude that PyO3 may be a novel pharmacophore with the potential for development into UNG-targeting agents.
... Folate is important for hematopoiesis and function of red, white and new blood cells. Folate is also vital for biochemical functions in mammals including one-carbon methyl transfer reactions, the synthesis of purine, RNA, pyrimidine, and DNA by methylation, preventing changes in the DNA and abnormal cell development (Blount et al. 1997;Choi and Mason 2000;Kronenberg et al. 2008;Figueiredo et al. 2009), gene expression, and neurotransmitter functions (Ghoshal et al. 2006;Pogribny et al. 2008). Furthermore, folate contributes significantly to amino acids synthesis (Fournier et al. 2002;Shinohara et al. 2006), and is an important agent in the formation of the primary methylating agent, S-adenosylmethionine (SAM) (Bailey and Gregory 1999;Linhart et al. 2008). ...
Folate has gained significant attention due to its vital role in biological methylation and epigenetic machinery. Folate, or vitamin (B 9), is only produced through a de novo mechanism by plants and microorganisms in the rumen of mature animals. Although limited research has been conducted on folate in ruminants, it has been noted that ruminal synthesis could not maintain folate levels in high yielding dairy animals. Folate has an essential role in one-carbon metabolism and is a strong antiproliferative agent. Folate increases DNA stability, being crucial for DNA synthesis and repair, the methylation cycle, and preventing oxidation of DNA by free radicals. Folate is also critical for cell division, metabolism of proteins, synthesis of purine and pyrimidine, and increasing the de novo delivery of methyl groups and S-adenosylmethionine. However, in ruminants, metabolism of B 12 and B 9 vitamins are closely connected and utilization of folate by cells is significantly affected by B 12 vitamin concentration. Supplementation of folate through diet, particularly in early lactation, enhanced metabolic efficiency, lactational performance, and nutritional quality of milk. Impaired absorption, oxidative degradation, or deficient supply of folate in ruminants affects DNA stability, cell division, homocysteine remethylation to methionine, de novo synthesis of S-adenosylmethionine, and increases DNA hypomethylation, uracil misincorporation into DNA, chromosomal damage, abnormal cell growth, oxidative species, premature birth, low calf weight, placental tube defects, and decreases production and reproduction of ruminant animals. However, more studies are needed to overcome these problems and reduce enormous dietary supplement waste and impaired absorption of folate in ruminants. This review was aimed to highlight the vital role of folic acid in ruminants performance.
... This decrease correlated with a decrease in the number of correct visits the arms of the eight arm radial maze. These data are in agreement with the results of other studies reporting that an increase in the Hcy concentration due to the folate deficient diet leads to the reduction in the serotonin and 5 oxyin dolacetic acid levels and to changes in the neurogenesis in mouse hippocampus [88]. ...
The article presents current views on maternal hyperhomocysteinemia (HHcy) as an important factor causing prenatal stress and impaired nervous system development in fetuses and newborns in early ontogenesis, as well as complications in adulthood. Experimental data demonstrate that prenatal HHcy (PHHcy) affects the morphological maturation of the brain and activity of its neurotransmitter systems. Cognitive deficit observed in the offspring subjected to PHHcy in experimental studies can presumably cause the predisposition to various neurodegenerative diseases, as the role of maternal HHcy in the pathogenesis such diseases has been proven in clinical studies. The review also discusses molecular mechanisms of the HHcy neurotoxic action on the nervous system development in the prenatal and early postnatal periods, which include oxidative stress, apoptosis activation, changes in the DNA methylation patterns and microRNA levels, altered expression and processing of neurotrophins, and neuroinflammation induced by an increased production of pro-inflammatory cytokines. Special attention is given to the maternal HHcy impact on the placenta function and its possible contribution to the brain function impairments in the offspring. Published data suggest that some effects of PHHcy on the developing fetal brain can be due to the disturbances in the transport functions of the placenta resulting in an insufficient supply of nutrients necessary for the proper formation and functioning of brain structures.
