Fluoride is one of the essential trace elements for human health and is found throughout the environment, for example, in soil, air, and tap water[1]. Although fluoride has been used around the world to prevent and control dental caries, long-term excessive fluoride intake can cause damage to many systems in the body[2, 3]. Nowadays, the toxic side effects of fluoride on the brain have become a topic of research focus in environmental toxicology[4]. High dosage of fluoride can penetrate many areas of the brain, such as the hippocampus, cerebellum, and cortex, by crossing the blood-brain barrier[5], eventually leading to drowsiness, insomnia, headache, dizziness, and deterioration in learning and memory capacity[6]. Currently, the possible mechanisms underlying such effects involve cholinergic pathways, oxidative stress, hippocampal calcium signaling, and synaptic plasticit[7, 8, 9].
In recent years, several studies have found that decreased glucose utilization occurs in a variety of neurological diseases. Improving the status of brain glucose metabolism has become an emerging strategy in the treatment of many chronic nervous system diseases such as Alzheimer’s disease, stroke, and depression[10, 11, 12]. As one of the major pathways of glucose metabolism, abnormal glycolysis is considered to be an initiating or promoting factor in many neurological diseases[13]. Compared with those in normal mice, the protein expression and transcription levels of the glycolysis enzymes lactate dehydrogenase A (LDHA), pyruvate kinase M (PKM), and hexokinase 2 (HK) are inhibited in Alzheimer’s disease mice, and the contents of lactate and NAD + are decreased. However, measurement of cell oxygen consumption rates indicated the activation of mitochondrial OXPHOS levels when glycolysis inflow was insufficient and energy supply was low. Promoting glycolysis and reducing OXPHOS activation can thus improve the role of astrocytes in supporting neuronal activity and function[14].
In addition to the glycolysis catalyzed by LDH, pyruvate (an intermediate of glucose metabolism) is also metabolized by OXPHOS[15]. Recent studies have shown that pyruvate dehydrogenase A1 (PDHA1), dihydrolipoamide acetyltransferase (DLAT), and dihydrolipoamide dehydrogenase (DLD), which encode either subunit E1, E2, or E3 of the pyruvate dehydrogenase (PDH) complex respectively, are promoted to different degrees in traumatic brain injury[16]. Isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and malate dehydrogenase 2 (MDH2) enzymes related to the tricarboxylic acid cycle showed a similar increasing trend with the extension of injury time[17]. Glycolysis preconditioning of astrocytes attenuates trauma-induced neurodegeneration and shifts brain metabolic patterns from neuron-dominated mitochondrial respiration to astrocyte-mediated glycolysis[18].
Increasing evidence has shown that sodium butyrate (SB) can enhance neuronal activity by promoting the transport of lactic acid, a glycolytic product of astrocytes, and further maintains the energy metabolism homeostasis of the central nervous system, ultimately reducing cognitive decline in Alzheimer’s disease mice[19, 20]. Butyric acid, the active ingredient of SB, belongs to the short-chain fatty acids (SCFAs), which are produced by intestinal flora fermenting dietary fiber[21]. Butyric acid is an endogenous substance in the human body and therefore has little toxicity[22]. According to the gut–brain axis hypothesis, SCFAs can achieve bidirectional communication between the brain and the gut by regulating intestinal homeostasis and neuroimmunology[23]. In addition, SB is one of the most commonly used histone deacetylase inhibitors and has been shown to have neuroprotective effects in various neurological disease models, such as of Alzheimer’s disease, ischemic stroke, and neonatal hypoxic encephalopathy[24, 25, 26]. However, whether SB can protect the hippocampus from fluoride-induced neurotoxicity and imbalanced metabolism, and the possible mechanism of its potential protective effect, has not been studied in depth.
The PI3k/AKT signaling pathway is involved in the maintenance of central nervous system homeostasis[27]. In addition, PI3K/AKT/HIF-1α may be involved in the transformation of cell metabolism. The activation of PI3K/AKT/HIF-1α can directly promote the transition in cancer cell metabolism from OXPHOS to aerobic glycolysis[28, 29]. In addition, the mechanism involves alterations in the PI3K/AKT/HIF-1α signaling pathway, and the addition of the PI3K inhibitor LY294002 leads again to inhibition glycolysis, which had been restored after treatment with antagonists[30]. Therefore, we speculate that the neuroprotective effect of SB is related to PI3K/AKT/HIF-1α.
In this study, HE staining and Morris water maze confirmed that long-term excessive fluoride exposure induced hippocampal damage and spatial learning and memory impairment in mice. The results of Western blot and biochemical tests showed that glycolysis was inhibited in the hippocampi of fluorosis mice and SB could ameliorate fluorosis-induced neurotoxicity, which might be linked with its function in regulating glycolysis and pyruvate metabolism as well as inhibition of the PI3K/AKT/HIF-1α pathway.