Fluoride-induced Neurodevelopmental Toxicity- AMPK as a Possible Target

Abstract

Inorganic fluoride is widely used in dental practices to treat problems like dental caries and prevent bone-related issues. Exposure to excess amounts of fluoride both through drinking water or other sources impairs vital functions of the body and can prove to be toxic, especially for the central nervous system. Sodium fluoride (NaF) crosses the blood-brain barrier in early developmental stages and causes impairments related to learning and memory, anxiety, decreased locomotor ability, and in some cases, depression-like behaviour, especially in children. Major mechanisms involved in this toxicity include reduction in levels of nicotinic and muscarinic receptors, autophagy, and apoptosis in neurons, decreased glucose consumption, inhibition of enzymes involved in the generation of energy and transmission of the synapse, mitochondrial dysfunction, and increased oxidative stress leading to inflammation and neuronal cell death. Out of all these, an increase in oxidative stress was reported to be one of the main mechanisms of fluoride-induced neurotoxicity. Based on these inferences, various natural compounds having antioxidant properties, like curcumin, aloe vera, quercetin, epigallocatechin gallate, etc. have been studied for their protective role in sodium fluoride-induced neurotoxicity. Involvement of other pathways like Nrf2/Keap pathways, SIRT3, etc., have warranted a need for further detailed study to identify other potential therapeutic targets like AMPK to prevent/treat fluoride-induced neurotoxicity. The present review captures fluoride, its role in neurodevelopment, and mechanisms & pathways involved by which fluoride can hurt neurodevelopment & how AMPK can be a possible therapeutic target.

Keywords: AMPK; Sodium fluoride; cognitive impairment; mitochondrial dysfunction.; neurodevelopmental toxicity; oxidative stress.