Evidence for a role of Hsp70 in the neuroprotection induced by heat shock pre-treatment against 3,4-methylenedioxymethamphetamine toxicity in rat brain.
3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') produces acute hyperthermia which increases the severity of the selective serotoninergic neurotoxicity produced by the drug in rats. Heat shock protein 70 (Hsp70) is a major inducible cellular protein expressed in stress conditions and which is thought to exert protective functions. MDMA (12.5 mg/kg, i.p.), given to rats housed at 22 degrees C, produced an immediate hyperthermia and increased Hsp70 in frontal cortex between 3 h and 7 days after administration. MDMA, given to rats housed at low ambient temperature (4 degrees C) produced transient hypothermia followed by mild hyperthermia but no increase in Hsp70 expression, while rats treated at elevated room temperature (30 degrees C) showed enhanced hyperthermia and similar expression of Hsp70 to that seen in rats housed at 22 degrees C. Fluoxetine-induced inhibition of 5-HT release and hydroxyl radical formation did not modify MDMA-induced Hsp70 expression 3 h later. Four- or 8-day heat shock (elevation of basal rectal temperature by 1.5 degrees C for 1 h) or geldanamycin pre-treatment induced Hsp70 expression and protected against MDMA-induced serotoninergic neurotoxicity without affecting drug-induced hyperthermia. Thus, MDMA-induced Hsp70 expression depends on the drug-induced hyperthermic response and not on 5-HT release or hydroxyl radical formation and pre-induction of Hsp70 protects against the long-term serotoninergic damage produced by MDMA.
Escobedo
Isabel
I
Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
Peraile
Ines
I
Orio
Laura
L
Colado
M Isabel
MI
O'Shea
Esther
E
D000818:Animals; D001831:Body Temperature; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D001923:Brain Chemistry / Q000187:drug effects / Q000528:radiation effects; D004843:Epistasis, Genetic; D005473:Fluoxetine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006213:Hallucinogens / Q000633:toxicity*; D006361:Heating; D008297:Male; D017551:Microdialysis / Q000379:methods; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013997:Time Factors
D005473:Fluoxetine; D018840:HSP70 Heat-Shock Proteins; D006213:Hallucinogens; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D017382:Reactive Oxygen Species; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors