Trifluoperazine protects brain plasma membrane Ca(2+)-ATPase from oxidative damaging.
In the central nervous system (CNS), a number of different pathological processes such as necrosis, Parkinson's and Alzheimer's diseases are related to disturbance in calcium homeostasis associated with oxidative stress. Here we compare the susceptibility of rat brain plasma membrane Ca(2+)-ATPase (PMCA) and sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) isoforms to in vitro oxidative stress, and investigate a putative role of trifluoperazine (TFP), an antipsychotic drug that is also a powerful inhibitor of Ca(2+)-transporter proteins, in protecting these enzymes. It is shown that, in rat brain, PMCA is very sensitive to the damage induced by preincubation with Fe(2+)-ascorbate, or Fe(2+)-ascorbate plus H2O2, while SERCA is resistant. Inhibition of PMCA activity promoted by Fe(2+)/ascorbate medium is fully prevented by the presence of microM concentrations of either butylated hydroxytoluene (BHT) or TFP, but only partially protected, or reversed, by dithiothreitol (DTT), pointing to some protein cysteine(s) as one of the main targets for a lipid peroxidation-dependent damaging mechanism. However, when 0.5-1 mM H2O2 is added together with Fe(2+)/ascorbate, both BHT and TFP only partially prevent ATPase activity inhibition, and DTT does not confer any protection, suggesting two possible additional mechanisms involving both lipid peroxidation and direct damage to PMCA at amino acid residues other than cysteines. A possible use of micromolar concentrations of TFP as a direct antioxidant protector for PMCA under oxidative stress conditions is discussed.
Souza dos Santos
Patricia
P
Instituto de Bioquímica Médica, CCS, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Saraiva
Dayvison Francis
DF
Ferraz da Costa
Danielly Cristiny
DC
Scofano
Helena Maria
HM
de Carvalho-Alves
Paulo Cesar
PC
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000648:ultrastructure*; D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects* / Q000201:enzymology; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005290:Ferric Compounds / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D014268:Trifluoperazine / Q000494:pharmacology*
D000975:Antioxidants; D014150:Antipsychotic Agents; D005290:Ferric Compounds; D017382:Reactive Oxygen Species; D002084:Butylated Hydroxytoluene; D014268:Trifluoperazine; C024823:ferric sulfate; D053499:Plasma Membrane Calcium-Transporting ATPases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D004229:Dithiothreitol