Title : Role of fluoride in changes of metalloproteinases activity in brain
Abstract:
Fluorine is a strong neurotoxin which causes the degeneration of structures such as hippocampus, prefrontal cortex, and cerebellum. Fluorine exposure inhibits the activity of brain receptors and decreases the production of neurotransmitters. Exposure to fluorine in childhood can decrease the intelligence quotient and causes problems with learning and concentration. The Extracellular Matrix (ECM) of the central nervous system serves as the environment for neurons and glial cells, and at the same time, it plays the role of a modifier of these cells. Changes in the structure and the functioning of synapses are caused by ECM enzymes. These enzymes, especially matrix metalloproteinases (MMPs), accompany both physiological processes, such as learning or memorizing, and pathological processes. Metalloproteinases 9 and 2 (MMP-9 and MMP-2) seem to be particularly interesting. Also, tissue inhibitors of metalloproteinases-3 and -2 (TIMP-3 and TIMP-2) are very important in the process of neuroplasticity. There is no data regarding the influence of low concentrations of fluorine on the expression of proteins of these enzymes and their inhibitors in the brain. The aim of the research is to analyze the role of MMP-9, MMP-2 and their inhibitors TIMP-3 and TIMP-2 in the neurotoxicity of fluorine. In the research, the rats were exposed to sodium fluoride (50 mg/L) already in the prenatal period until they reached the age of three months. After this time, the hippocampus, prefrontal cortex, cerebellum, and striatum were collected. In all of the aforementioned structures, the expression of proteins MMP-9, MMP-2, TIMP-3 and TIMP-2 was carried out by means of ELISA. Gene expression of these enzymes was carried out using RT real time PCR. The immunolocalization of these proteins was performed using immunohistochemistry and microscopic visualization. On the basis of the results, it can be concluded that fluorine influences the expression of MMP-9, MMP-2, TIMP-3 and TIMP-2. In the study group, a statistically significant expression of MMP-2 was observed in the prefrontal cortex, striatum, and cerebellum, and a decrease in the expression of MMP-9 was noted in the prefrontal cortex and cerebellum in relation to the control group. We also saw the difference between TIMP-3 and TIMP-2 levels in the study group compared to control. Our research suggests that changes in the expression of metalloproteinases and their inhibitors in the brain, caused by fluorine, could be an important factor of neurotoxicity of fluorine. The disorders of neuroplasticity processes can be considered as a biochemical basis for the decrease in the intelligence quotient caused by fluorine.
