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EFFECTS OF SELECTED NEUROACTIVE CHEMICALS ON CALCIUM TRANSPORTING SYSTEMS IN RAT CEREBELLUM AND ON SURVIVAL OF CEREBELLAR GRANULE CELLS
Citation:
Kodavanti, P., W. Mundy, H. Tilson, AND G. Harry. EFFECTS OF SELECTED NEUROACTIVE CHEMICALS ON CALCIUM TRANSPORTING SYSTEMS IN RAT CEREBELLUM AND ON SURVIVAL OF CEREBELLAR GRANULE CELLS. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-94/071 (NTIS PB94141595).
Description:
This investigation examined the effects of several neuroactive chemicals on Ca2+ -transporting systems and cytotoxicity in vitro. 5Ca2+ -uptake as a measure of Ca2+s -sequestration, was determined n mitochondria and microsomes, isolated from cerebella of adult male Long-Evans hooded rats by differential centriguation. a+ -extrusion, measured as Ca2+ -ATPase activity, was determined in synaptosomes, repared by sucross density gradient. ytotoxicity (LDH leakage) was assessed in primary cultures of-N-methyl-D-aspartic cid cerebellar granule cells from 6-8 days old Long-Evans rats. N-methyl D-aspartic acid (NMDA) did not alter synaptosomal Ca2+ -ATPase activity or Ca uptake in mitochondria and microsomes. owever, chlorpromazine (CPZ), aluminum (AL), permethrin (PER), and deltamethrin (DEL) inhibited Ca2+ sequestration by mitochondria and microsomes. he LC50 values (uM) for CPZ, AL, PER and DEL were 67.8, 671, 4:24 and 91.2 for mitochondrial 45Ca2+ -uptake, and 129.9, 1384, 50 and 200 for microsomal Ca -uptake, respectively.CPZ, PER and DEL also inhibited synaptosomal Ca2+-ATPase activity in a concentration-dependent manner with IC50 values of 62.5, 400, and 246.9 uM, indicating an effect on the Ca2+-extrusion process. AL increased Ca2+ -ATPase activity (EC50= 833uM). lthough NMDA did not exhibit Ca2+-transport systems it was cytotoxic at 25OuM and high concentrations after 2 hrs of exposure. imilarly, CPZ was cytotoxic at concentrations of 25 and 10uM after 1 and 4 hrs exposure. owever, PER, DEL, and AL were not cytotoxic at anyconcentrate up to 5OOuM. f all the chemicals-tested, CPZ was the most potent in inhibiting Ca2+-transporting systems, and was also cytotoxic.