Fluoride-Induced Neuron Apoptosis and Expressions of Inflammatory Factors by Activating Microglia in Rat Brain

Abstract

Excessive exposure to fluoride results in structural and functional damages to the central nervous system (CNS), and neurotoxicity of fluoride may be associated with neurodegenerative changes. Chronic microglial activation appears to cause neuronal damage through producing proinflammatory cytokines and is involved in many neurodegenerative disorders. It is not known about effects on microglia of fluoride. In the present study, healthy adult Wistar rats were exposed to 60 and 120 ppm fluoride in drinking water for 10 weeks, and control rats received deionized water. After 10 weeks, rats were sacrificed under anesthesia then apoptosis in neuron and inflammatory factors secreted by microglia were determined. We found that apoptosis of neurons in fluoride-treated rat brain increased and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive immunofluorescence increased with increasing fluoride concentrations. Bax protein expression increased and Bcl-2 protein expression decreased in fluoride-treated rat brain compared with that of the control rat brain. The microglia in the hippocampus and cortex of fluoride-treated rats were activated by immunostaining with OX-42, a marker of activated microglia, and OX-42-positive microglia cells were more abundant in the hippocampus than in the cortex. The levels of IL-1β and IL-6 protein expression in OX-42-labeled microglial cells were significantly increased in the cortex and hippocampus of rats exposed to fluoride, and TNF-α immunoreactivity in microglial cells of the hippocampus was significantly higher in the 120 ppm fluoride-treated group than that in the control group. Our results indicate that fluoride induced neuron apoptosis and expressions of inflammatory factors by activating microglia in rat brain.

Salvianolic acid B ameliorates depressive-like behaviors in chronic mild stress-treated mice: involvement of the neuroinflammatory pathway

“…Recent studies have suggested that neuroinflammation is accompanied by the activation of microglial cells and the release of inflammatory mediators, which activates cellular cascades and results in neural apoptosis in the brain [47,48] . Our results indicate that SalB blocks the CMS-induced increases in apoptosis in both the hippocampus and cortex and prevents the decrease of hippocampal volume and cell density.…”

The Influence of Fluorine on the Disturbances of Homeostasis in the Central Nervous System

“…These cytokines are responsible for the initiation of inflammatory states and the death of neurons [59]. Research shows that the exposure of adult rats to fluorine causes the activation of microglia in the hippocampus and cerebral cortex and that it initiates an inflammatory state through the synthesis of proinflammatory cytokines—Il-1B, Il-6 and TNF-α (the concentration in drinking water, 60 and 120 mg/L) [60]. …”

“…Furthermore, among adult rats supplied with fluorine in drinking water, there was an increased expression of the proapoptotic protein Bax and a decreased expression of the apoptosis inhibiting Bcl-2. The analysis carried out by means of the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) method confirmed the increased intensity of apoptotic processes in brain structures of the animals (the concentration in drinking water, 60 and 120 mg/L) [60]. …”

“…An excessive intake of fluoride is also responsible for the increase in AGE synthesis in CNS which leads to synthesis of transcription factors and proinflammatory substances including NF-kB, interleukins and MAP kinases [43]. Moreover, fluorine causes glial cell activation which is involved in inflammation in the brain and change in the expression of proteins which regulate neuron differentiation and proliferation and initiate apoptosis such as NCAM, GFAP, BDNF, JNK, Bax and Bcl2 [17, 30, 60, 61, 101]. The accumulation of this element in CNS causes cytological changes within neurons (changes in tubulin expression and concentration of Nissl bodies) and changes in neuron activity and their energy metabolism [1, 4, 9, 15, 30].…”

“…The accumulation of fluorine in the nervous system influences the synthesis of neurotransmitters, the activity of enzymes, the expression of receptors and the plasticity of neurons [105–107]. Numerous analyses carried out in in vivo and in vitro models confirmed that prolonged exposure to high concentrations of fluorine leads to the degeneration of neurons [1, 60]. …”