The Roles Of Oxidative Stress,Glutamate,NMDA Receptor In Neurotoxicity Of Aluminum In Rats～1

IObi ectivej Aluminum (Al) neurotoxicity has been associated with a number of neurodegenerative disorders. Excessive Al exposure and accumulation in brain has been implicated in the etiology of dialysis encephalophathy, Alzheimer?s disease (AD), amyotrophic lateral sclorosis and Parkinsonism dementia of Guam. Food additive, comprising of Al, is main source for normal person Al uptake in China. This mode of Al exposure is serious, but government does not pay more attention to it. Recently, oxidative stress represents an important early event in the neurodegenerative process. One of the important theories involves in the etiology of AD is oxidative stress hypothesis. Glutamate, the principal excitatory amino acid neurotransmitter in central nervous system (CNS), has been documented to participate in synaptic transmission, such as long term potentiation (LTP), but excessive activation of glutamate receptor, especially the NMDA receptor, has been postulated to underlie the neuronal death that occurs after ischemic or traumatic brain injury as well as that associated with a number of neurodegenerative disorders. Oxidative stress and Foundation item: The project supported by Education Commission Natural Science Foundation of Jiangsu Province (No.98KJB330001). glutamate-mediated excitotoxicity are always converging and represent sequential as well as interacting processes that provide a final common pathway for cell vulnerability in the brain, furthermore, both oxidative stress and excitotoxicity are responsible for the neuronal apoptosis of neurodegenerative disorders. The present study aims to elucidate the mechanism of Al neurotoxicity and investigate the role of oxidative stress and glutamate in the mechanisms. IMethodsl Sprague-Dawley rats were randomly divided into four groups by their body weight. Aluminum chloride was supplemented in diet at doses of 0 (A), 11.2(B), 55.9 (C) and 111.9mg Al3~/kg BW (D) for successive 90d. The changes of the body weight and food efficiency were registered and calculated. Neurobehavioral testing consisted of open field and passive-avoidance conditioning and performanced at the time of aluminum pre-treatment and post-treatment. After completing the period of Al treatment, the values of aluminum, iron, zinc and copper were measured by atomic absorption spectroscopy (AAS). The activities of SOD and GSH-Px and the concentration of MDA were detected by spectrophotometry. The contents of amino acid neurotransmitters, glutamate (Glu), aspartate (Asp), glutamine (Gin), taurine (Tau), y -aminobutyrate (GABA), and glycine (Gly), in hippocarnpus were detected by high-performance liquid chromatography (HPLC). Moreover, glutamate-immunoreactive (glutamate-JR) neurons in hippocampus were stained by immunocytochemical method. The structure, numbers and staining intensities of these neurons were observed by microscope. In normal brain tissue, astrocytes (but not neurons) possess the enzyme glutamine synthetase (GS) which rapidly amidates glutamate to form the non-neuroactive amino acid, glutamine. Glutamine is subsequently released by astrocytes for uptake by glutamatergic neurons which deamidate it when they require glutamate for neurotransmission. This lutamate-glutamine cycle?makes neurons entirely dependent on astrocytes for their supplies of glutamate. The activity of GS in hippocampus was measured in present study by...