Arsenic Unsettles the Cerebellar Balance Between Neurodegeneration and Neurogenesis: Reversal by Folic Acid

Overview

Journal Apoptosis

Publisher Springer

Date 2024 Dec 25

PMID 39720976

Authors

Ankur Das

Ankan Mitra

Swaimanti Sarkar

Sourav Ghosh

Debasish Bandyopadhyay

Sreya Chattopadhyay

Affiliations

Soon will be listed here.

Abstract

Arsenic-mediated neurodegenerative disorders affect millions of individuals globally, but the specific impact of environmental arsenic on adult cerebellar degeneration and neurogenesis is incompletely understood. Of particular concern is arsenic-induced apoptosis-driven neurodegeneration. Our major objective was to investigate the molecular signaling intricacies associated with arsenic-induced death of cerebellar neurons and to propose folic acid as a possible intervention. Swiss albino mice were treated with sodium arsenite (orally: 0.05 mg/L) and folic acid (orally:10 mg/kg) for 28 days. We observed that arsenic caused noticeable cell loss with morphological alterations in cerebellum, which was remarkably restored by folic acid. Arsenic-induced morphological alterations consequently perturbed transcriptional activities of neural stem cell factors-SOX2 and KLF9, which resulted in the suppression of pro-neurogenic mediators NeuroD1, Neurogenin2, calbindin and NeuN. Interestingly, folic acid reversed the expression of these critical pro-neurogenic mediators to mitigate these degenerative changes to promote neurogenesis. Delving deep, we found that folic acid rescued arsenic-exposed cerebellum from severe oxidative and pro-inflammatory insults by increasing antioxidants like SOD, Catalase, GSH, upregulating Nrf2 and downregulating M1 macrophages, JNK, NF-κB, and STAT3 activities. For the first time, we are reporting that arsenic induced a G1/S cell cycle arrest and triggered apoptosis in mouse cerebellum by activating the p53-p21 axis, downregulating CDKs and instigated p21-mediated suppression of SOX2 transcriptional activity. Folic acid abated such alterations by modulating the p53/p21/SOX2 axis. Collectively, the anti-apoptotic and pro-neurogenic effects of folic acid present it as a promising therapeutic candidate, warranting further research into its efficacy against metal-induced neurodegenerative disorders.

References

Muzaffar S, Khan J, Srivastava R, Gorbatyuk M, Athar M . Mechanistic understanding of the toxic effects of arsenic and warfare arsenicals on human health and environment. Cell Biol Toxicol. 2022; 39(1):85-110. PMC: 10042769. DOI: 10.1007/s10565-022-09710-8. View

Sanchez-Pena L, Petrosyan P, Morales M, Gonzalez N, Gutierrez-Ospina G, Del Razo L . Arsenic species, AS3MT amount, and AS3MT gene expression in different brain regions of mouse exposed to arsenite. Environ Res. 2010; 110(5):428-34. DOI: 10.1016/j.envres.2010.01.007. View

Tyler C, Allan A . The Effects of Arsenic Exposure on Neurological and Cognitive Dysfunction in Human and Rodent Studies: A Review. Curr Environ Health Rep. 2014; 1:132-147. PMC: 4026128. DOI: 10.1007/s40572-014-0012-1. View

Tolins M, Ruchirawat M, Landrigan P . The developmental neurotoxicity of arsenic: cognitive and behavioral consequences of early life exposure. Ann Glob Health. 2014; 80(4):303-14. DOI: 10.1016/j.aogh.2014.09.005. View

Thakur M, Rachamalla M, Niyogi S, Datusalia A, Flora S . Molecular Mechanism of Arsenic-Induced Neurotoxicity including Neuronal Dysfunctions. Int J Mol Sci. 2021; 22(18). PMC: 8471829. DOI: 10.3390/ijms221810077. View

Liu S, Piao F, Sun X, Bai L, Peng Y, Zhong Y . Arsenic-induced inhibition of hippocampal neurogenesis and its reversibility. Neurotoxicology. 2012; 33(5):1033-9. DOI: 10.1016/j.neuro.2012.04.020. View

Salman M, Tsai P . The Role of the Pediatric Cerebellum in Motor Functions, Cognition, and Behavior: A Clinical Perspective. Neuroimaging Clin N Am. 2016; 26(3):317-29. PMC: 4948592. DOI: 10.1016/j.nic.2016.03.003. View

Phillips J, Hewedi D, Eissa A, Moustafa A . The cerebellum and psychiatric disorders. Front Public Health. 2015; 3:66. PMC: 4419550. DOI: 10.3389/fpubh.2015.00066. View

Moreno-Rius J . The cerebellum under stress. Front Neuroendocrinol. 2019; 54:100774. DOI: 10.1016/j.yfrne.2019.100774. View

10.

Zhang C, Li S, Sun Y, Dong W, Piao F, Piao Y . Arsenic downregulates gene expression at the postsynaptic density in mouse cerebellum, including genes responsible for long-term potentiation and depression. Toxicol Lett. 2014; 228(3):260-9. DOI: 10.1016/j.toxlet.2014.05.007. View

11.

Hsieh R, Huang Y, Shiue H, Huang S, Lin M, Mu S . Arsenic methylation capacity and developmental delay in preschool children in Taiwan. Int J Hyg Environ Health. 2014; 217(6):678-86. DOI: 10.1016/j.ijheh.2014.02.004. View

12.

Nahar M, Inaoka T, Fujimura M . A consecutive study on arsenic exposure and intelligence quotient (IQ) of children in Bangladesh. Environ Health Prev Med. 2013; 19(3):194-9. PMC: 4019759. DOI: 10.1007/s12199-013-0374-2. View

13.

Cheng M, Yuan C, Ju Y, Liu Y, Shi B, Yang Y . Quercetin Attenuates Oxidative Stress and Apoptosis in Brain Tissue of APP/PS1 Double Transgenic AD Mice by Regulating Keap1/Nrf2/HO-1 Pathway to Improve Cognitive Impairment. Behav Neurol. 2024; 2024:5698119. PMC: 11374423. DOI: 10.1155/2024/5698119. View

14.

Hickey M, Chesselet M . Apoptosis in Huntington's disease. Prog Neuropsychopharmacol Biol Psychiatry. 2003; 27(2):255-65. DOI: 10.1016/S0278-5846(03)00021-6. View

15.

Enomoto S, Ohgidani M, Sagata N, Inamine S, Kato T . Preliminary analysis of hippocampus synaptic apoptosis and microglial phagocytosis induced by severe restraint stress. Neuropsychopharmacol Rep. 2022; 43(1):120-125. PMC: 10009418. DOI: 10.1002/npr2.12298. View

16.

Kuang H, Sun M, Lv J, Li J, Wu C, Chen N . Hippocampal apoptosis involved in learning deficits in the offspring exposed to maternal high sucrose diets. J Nutr Biochem. 2014; 25(9):985-90. DOI: 10.1016/j.jnutbio.2014.04.012. View

17.

Lin N, Xiong L, Zhang R, Zheng H, Wang L, Qian Z . Injection of Aβ1-40 into hippocampus induced cognitive lesion associated with neuronal apoptosis and multiple gene expressions in the tree shrew. Apoptosis. 2016; 21(5):621-40. DOI: 10.1007/s10495-016-1227-4. View

18.

Yang L, Greig N, Huang Y, Hsieh T, Tweedie D, Yu Q . Post-traumatic administration of the p53 inactivator pifithrin-α oxygen analogue reduces hippocampal neuronal loss and improves cognitive deficits after experimental traumatic brain injury. Neurobiol Dis. 2016; 96:216-226. PMC: 5878046. DOI: 10.1016/j.nbd.2016.08.012. View

19.

Liu X, Gao Y, Yao H, Zhou L, Sun D, Wang J . Neuroglobin involvement in the course of arsenic toxicity in rat cerebellar granule neurons. Biol Trace Elem Res. 2013; 155(3):439-46. DOI: 10.1007/s12011-013-9810-9. View

20.

Piao F, Ma N, Hiraku Y, Murata M, Oikawa S, Cheng F . Oxidative DNA damage in relation to neurotoxicity in the brain of mice exposed to arsenic at environmentally relevant levels. J Occup Health. 2005; 47(5):445-9. DOI: 10.1539/joh.47.445. View