A study on the mechanisms by which minocycline protects against MDMA ('ecstasy')-induced neurotoxicity of 5-HT cortical neurons.
3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') is a selective 5-HT neurotoxin in rat brain which has been shown to produce acute neuroinflammation characterized by activation of microglia and release of interleukin-1beta (IL-1beta). We aimed to determine whether or not minocycline, a semi-synthetic tetracycline antibiotic capable of inhibiting microglial activation, could prevent the inflammatory response and reduce the toxicity induced by MDMA. Adult male Dark Agouti rats were given minocycline twice a day for 2 days (45 mg/kg on the first day and 90 mg/kg on the second day; 12-h apart, i.p.). MDMA (12.5 mg/kg; i.p.) was given after the third minocycline injection and animals were killed either 1 h later for the determination of NFkappaB binding activity, 3 h later for the determination of IL-1beta, 24 h later for the determination of microglial activation or 7 days later for the determination of [(3)H]-paroxetine binding as a measure of 5-HT neurotoxicity. MDMA increased NFkappaB activation, IL-1beta release and microglial activation both in the frontal cortex and in the hypothalamus and 7 days later produced a reduction in the density of 5-HT uptake sites in both these brain areas. Minocycline prevented the MDMA-induced increase in NFkappaB activation, IL-1beta release and microglial activation in the frontal cortex and prevented the 5-HT neurotoxicity 7 days later. However, in the hypothalamus, in spite of preventing MDMA-induced microglial activation, minocycline failed to prevent MDMA-induced NFkappaB activation, IL-1beta release and neurotoxicity. This suggests that the protective mechanism of minocycline against MDMA-induced neurotoxicity in frontal cortex involves inhibition of MDMA-induced NFkappaB activation possibly through a reduction in IL-1beta signalling.
Orio
Laura
L
Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain.
Llopis
Noemi
N
Torres
Elisa
E
Izco
Maria
M
O'Shea
Esther
E
Colado
M Isabel
MI
D000818:Animals; D004334:Drug Administration Schedule; D005334:Fever / Q000188:drug therapy; D005625:Frontal Lobe / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007031:Hypothalamus / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects; D008911:Minocycline / Q000008:administration & dosage* / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000032:analysis / Q000633:toxicity*; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D017374:Paroxetine / Q000032:analysis; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
D053583:Interleukin-1beta; D016328:NF-kappa B; D018696:Neuroprotective Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D017374:Paroxetine; D008911:Minocycline; D018817:N-Methyl-3,4-methylenedioxyamphetamine