dizocilpine-maleate and Manganese-Poisoning

Manganese is essential for life, yet chronic exposure to this metal can cause a neurodegenerative disease named manganism that affects motor function. In the present study we have evaluated Mn neurotoxicity after its administration in the rat striatum. The participation of the calcium-dependent protease calpain and the apoptosis-related protease caspase-3, in Mn-induced cell death was monitored in the striatum and globus pallidus. Mn induced the activation of both proteases, although calpain activation seems to be an earlier event. Moreover, while the broad-spectrum caspase inhibitor QVD did not significantly prevent Mn-induced cell death, the specific calpain inhibitor MDL-28170 did. The role of NMDA glutamate receptors on calpain activity was also investigated; blockage of these receptors by MK-801 and memantine did not prevent calpain activation, nor Mn-induced cell death. Finally, studies in striatal homogenates suggest a direct activation of calpain by Mn ions. Altogether the present study suggests that additional mechanisms to excitotoxicity are involved in Mn-induced cell death, placing calpain as an important mediator of acute Mn neurotoxicity in vivo.

Topics: Analysis of Variance; Animals; Calpain; Caspase 3; Cell Death; Corpus Striatum; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Fluoresceins; Globus Pallidus; Male; Manganese; Manganese Poisoning; Memantine; Nerve Tissue Proteins; Neurons; Organic Chemicals; Rats; Rats, Wistar; Time Factors

The effects of manganese on the activities of GS, PAG, SDH and Na(+)-K(+)-ATPase were investigated and the impact of MK-801, Tau and DM on manganese-induced neurotoxicity were observed in rats. Seventy Wistar rats were divided into seven groups, 10 animals for each group. The first group was the control group, the second to fourth groups were 8, 40 and 200 micromol/kg MnCl(2) groups, the fifth to seventh groups were 0.3 micromol/kg MK-801, 1 micromol/kg Tau and 13.5 micromol/kg DM pretreatment groups. The animals were injected with manganese chloride for 25 days and pretreated for every other day. Manganese resulted in the reduction of GS, SDH and Na(+)-K(+)-ATPase activities, and the increase of PAG activity. The percentage of positive area and integral optical density of glutamate immunocreative cell were significantly increased in the group given 200 micromol/kg MnCl(2) alone. Pretreatment with MK-801, Tau and DM can antagonize neurotoxicity induced by manganese in the certain extent.

Topics: Animals; Cerebral Cortex; Chlorides; Corpus Striatum; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Glutamate-Ammonia Ligase; Glutaminase; Hippocampus; Manganese Compounds; Manganese Poisoning; Neuroprotective Agents; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase; Taurine