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Title: IDENTIFICATION AND CHARACTERIZATION OF METALLOTHIONEIN-1 AND 2 GENE EXPRESSION IN THE CONTEXT OF (±)3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA)-INDUCED TOXICITY TO BRAIN DOPAMINERGIC NEURONS

Author
item XIE, T - JOHNS HOPKINS UNIV
item TONG, L - JOHNS HOPKINS UNIV
item MCCANN, U - JOHNS HOPKINS UNIV
item YUAN, J - JOHNS HOPKINS UNIV
item BECKER, K - NIH
item MECHAN, A - JOHNS HOPKINS UNIV
item CHEADLE, C - NIH
item Donovan, David
item RICAURTE, A - JOHNS HOPKINS UNIV

Submitted to: Journal of Neuroscience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/2/2004
Publication Date: 8/11/2004
Citation: Xie, T., Tong, L., Mccann, U., Yuan, J., Becker, K., Mechan, A., Cheadle, C., Donovan, D.M., Ricaurte, A. 2004. Identification and characterization of metallothionein-1 and 2 gene expression in the context of (±)3,4-methylenedioxymethamphetamine (mdma)-induced toxicity to brain dopaminergic neurons. Journal of Neuroscience. 24(32):7043-7050.

Interpretive Summary: In Parkinsons Disease and some forms of drug abuse, dopamine neurons are destroyed. In a search for changes in gene expression that are indicative of dopamine neuron degeneration, a mouse cDNA microarray was used in conjunction with a mouse dopamine neuron degeneration model, namely MDMA-induced (MDMA is the drug ecstasy). Interestingly, two methallothionein genes (Mt-1and Mt-2) emerged as candidate genes which each show upregulation in the ventral midbrain dopamine neurons within 4-12 hours post MDMA treatment. Mt1 & 2 double knock-out mice were more vulnerable to MDMA-induced toxicity to DA neurons than wild-type mice. The known function of Mt-1 and Mt-2 are consistent with the results with knockout mice further suggesting that these genes are possibly a part of a neuroprotective system.

Technical Abstract: In mice, the recreational drug (+/-)3,4-methylenedioxymethamphetamine [MDMA ("ecstasy")] produces a selective toxic effect on brain dopamine (DA) neurons. Using cDNA microarray technology in combination with an approach designed to facilitate recognition of relevant changes in gene expression, the present studies sought to identify genes potentially involved in murine MDMA-induced toxicity to DA neurons. Of 15,000 mouse cDNA fragments studied, metallothionein (Mt)-1 and Mt2 emerged as candidate genes possibly involved in MDMA-induced toxicity to DA neurons. Northern blot analysis confirmed the microarray findings and revealed a dynamic upregulation of Mt1 and Mt2 mRNA in the ventral midbrain within 4-12 hr after MDMA treatment. Western blot analysis showed a similar increase in MT protein levels, with peak times occurring subsequent to increases in mRNA levels. Mt1-2 double knock-out mice were more vulnerable to MDMA-induced toxicity to DA neurons than corresponding wild-type mice. Stimulation of endogenous expression of MT protein with zinc acetate conferred complete protection against MDMA-induced toxicity to DA neurons, and administration of exogenous MT protein afforded partial protection. Collectively, these results indicate that MDMA-induced toxicity to DA neurons is associated with increased Mt1 and Mt2 gene transcription and translation, possibly as part of a neuroprotective mechanism. The present findings may have therapeutic implications for neuropathological conditions involving DA neurons.