Effects of altered maternal folate and vitamin B12 on neurobehavioral outcomes in F1 male mice

Kumar, Mohit; Mahajan, Aatish; Sapehia, Divika; Kaur, Jyotdeep; Sandhir, Rajat

doi:10.1016/j.brainresbull.2019.07.031

Cited by 10 publications

(7 citation statements)

References 45 publications

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“…However, future work on the precise mechanism by which Hcy activates mTOR and consequently downregulates autophagy will be an interesting area to explore. A few recent studies reported the transgenerational effect of Hcy in brain pathologies [ 84 , 85 ] and that opens up the possibilities of some epigenetic modifications in the brain during HHcy. In the backdrop of this present work, it will be interesting to study further to check whether epigenetic suppression of the autophagic pathway could be an early step and might be a reason for the neuronal damage reported widely in HHcy.…”

Section: Discussionmentioning

confidence: 99%

Defective quality control autophagy in Hyperhomocysteinemia promotes ER stress and consequent neuronal apoptosis through proteotoxicity

Kaur,

Sharma,

Chatterjee

et al. 2023

Cell Commun Signal

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Homocysteine (Hcy), produced physiologically in all cells, is an intermediate metabolite of methionine and cysteine metabolism. Hyperhomocysteinemia (HHcy) resulting from an in-born error of metabolism that leads to accumulation of high levels of Hcy, is associated with vascular damage, neurodegeneration and cognitive decline. Using a HHcy model in neuronal cells, primary cortical neurons and transgenic zebrafish, we demonstrate diminished autophagy and Hcy-induced neurotoxicity associated with mitochondrial dysfunction, fragmentation and apoptosis. We find this mitochondrial dysfunction is due to Hcy-induced proteotoxicity leading to ER stress. We show this sustained proteotoxicity originates from the perturbation of upstream autophagic pathways through an aberrant activation of mTOR and that protetoxic stress act as a feedforward cues to aggravate a sustained ER stress that culminate to mitochondrial apoptosis in HHcy model systems. Using chemical chaperones to mitigate sustained ER stress, Hcy-induced proteotoxicity and consequent neurotoxicity were rescued. We also rescue neuronal lethality by activation of autophagy and thereby reducing proteotoxicity and ER stress. Our findings pave the way to devise new strategies for the treatment of neural and cognitive pathologies reported in HHcy, by either activation of upstream autophagy or by suppression of downstream ER stress.

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Section: Discussionmentioning

confidence: 99%

Defective quality control autophagy in Hyperhomocysteinemia promotes ER stress and consequent neuronal apoptosis through proteotoxicity

Kaur,

Sharma,

Chatterjee

et al. 2023

Cell Commun Signal

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“…A number of authors report about altered spatial navigation, short-term and long-term memory of rats and mice with pre- and postnatal hHcy [ 31 , 32 , 33 , 57 , 60 , 71 , 72 , 73 , 74 ]. In our study we found a significant violation of learning and memory of Hcy rats in T maze and Morris water tests where the hippocampus plays a major role [ 48 , 75 ].…”

Section: Discussionmentioning

confidence: 99%

“…In chronic models of hHcy a decreased expression of CBS and CSE, responsible for endogenous H 2 S generation along with reduced plasma level of H 2 S was shown [ 35 , 36 , 74 , 82 , 85 ]. In high methionine diet mice global methylation and DNA methyltransferase-1 (DNMT1) expression were increased and hyper-methylation of the CBS promoter downregulated CBS expression in bone marrow-derived endothelial progenitor cells [ 84 ].…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Alleviates Anxiety, Motor, and Cognitive Dysfunctions in Rats with Maternal Hyperhomocysteinemia via Mitigation of Oxidative Stress

et al. 2020

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Hydrogen sulfide (H2S) is endogenously produced from sulfur containing amino acids, including homocysteine and exerts neuroprotective effects. An increase of homocysteine during pregnancy impairs fetal growth and development of the offspring due to severe oxidative stress. We analyzed the effects of the H2S donor—sodium hydrosulfide (NaHS) administered to female rats with hyperhomocysteinemia (hHcy) on behavioral impairments and levels of oxidative stress of their offspring. Rats born from females fed with control or high methionine diet, with or without H2S donor injections were investigated. Rats with maternal hHcy exhibit increased levels of total locomotor activity and anxiety, decreased muscle endurance and motor coordination, abnormalities of fine motor control, as well as reduced spatial memory and learning. Oxidative stress in brain tissues measured by activity of glutathione peroxidases and the level of malondialdehyde was higher in rats with maternal hHcy. Concentrations of H2S and the activity and expression of the H2S generating enzyme—cystathionine-beta synthase—were lower compared to the control group. Administration of the H2S donor to females with hHcy during pregnancy prevented behavioral alterations and oxidative stress of their offspring. The acquisition of behavioral together with biochemical studies will add to our knowledge about homocysteine neurotoxicity and proposes H2S as a potential agent for therapy of hHcy associated disorders.

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“…30,37 Vitamin B, such as folic acid, vitamin B 12 , and vitamin B 6 , are essential for neuronal function, and their deficiency has been associated with an increased risk of neurodevelopmental disorders. 38 Therefore, vitamin B supplementation may attenuate autism-like behavior and neurodevelopmental impairment in the hippocampus of mice exposed to PM2.5 during gestation by suppressing inflammation and oxidative stress, exhibiting a preventive effect. 39,40 However, the potential mechanisms underlying vitamin B’s amelioration of PM2.5-induced neurodevelopmental impairment in offspring during pregnancy require further elucidation.…”

Section: Pm25 and Neurodevelopmental Disorders (Ndds)mentioning

confidence: 99%

Neurodevelopmental toxicity induced by PM2.5 Exposure and its possible role in Neurodegenerative and mental disorders

et al. 2023

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Recent extensive evidence suggests that ambient fine particulate matter (PM2.5, with an aerodynamic diameter ≤2.5 μm) may be neurotoxic to the brain and cause central nervous system damage, contributing to neurodevelopmental disorders, such as autism spectrum disorders, neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, and mental disorders, such as schizophrenia, depression, and bipolar disorder. PM2.5 can enter the brain via various pathways, including the blood–brain barrier, olfactory system, and gut-brain axis, leading to adverse effects on the CNS. Studies in humans and animals have revealed that PM2.5-mediated mechanisms, including neuroinflammation, oxidative stress, systemic inflammation, and gut flora dysbiosis, play a crucial role in CNS damage. Additionally, PM2.5 exposure can induce epigenetic alterations, such as hypomethylation of DNA, which may contribute to the pathogenesis of some CNS damage. Through literature analysis, we suggest that promising therapeutic targets for alleviating PM2.5-induced neurological damage include inhibiting microglia overactivation, regulating gut microbiota with antibiotics, and targeting signaling pathways, such as PKA/CREB/BDNF and WNT/β-catenin. Additionally, several studies have observed an association between PM2.5 exposure and epigenetic changes in neuropsychiatric disorders. This review summarizes and discusses the association between PM2.5 exposure and CNS damage, including the possible mechanisms by which PM2.5 causes neurotoxicity.

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Effects of altered maternal folate and vitamin B12 on neurobehavioral outcomes in F1 male mice

Cited by 10 publications

References 45 publications

Defective quality control autophagy in Hyperhomocysteinemia promotes ER stress and consequent neuronal apoptosis through proteotoxicity

Defective quality control autophagy in Hyperhomocysteinemia promotes ER stress and consequent neuronal apoptosis through proteotoxicity

Hydrogen Sulfide Alleviates Anxiety, Motor, and Cognitive Dysfunctions in Rats with Maternal Hyperhomocysteinemia via Mitigation of Oxidative Stress

Neurodevelopmental toxicity induced by PM2.5 Exposure and its possible role in Neurodegenerative and mental disorders

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