Delta opioid peptide [D-Ala2, D-Leu5]enkephalin causes a near complete blockade of the neuronal damage caused by a single high dose of methamphetamine: examining the role of p53.
The delta opioid peptide [D-Ala2, D-Leu5]enkephalin (DADLE) has been reported to block the neurotoxicity induced by multiple administrations of a moderate dose of methamphetamine (METH). We examined in this study if DADLE might block the neurotoxicity caused by a single high dose of METH in CD-1 mice. The levels of dopamine transporter (DAT), tyrosine hydroxylase (TH), major biogenic amines including DA, 5-hydroxytryptamine (5-HT), and their metabolites were examined. In addition, since the tumor suppressor p53 has been implicated in the neurotoxicity of METH, this study also examined the levels of p53 mRNA and protein affected by METH and DADLE. METH (25 mg/kg, i.p.) caused significant losses of DAT, TH, DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-HT in the striatum within 72 h. The administration of a single dose of DADLE (20 mg/kg, i.p., 30 min before METH) caused a complete blockade of all losses induced by METH except for that of the DA content (a approximately 50% blockade). DADLE did not affect the changes of rectal temperature induced by the administration of the high dose of METH. METH increased p53 mRNA in the striatum and the hippocampus of CD-1 mouse. DADLE abolished the p53 mRNA increase caused by METH. METH tended to increase the p53 protein level at earlier time points. However, METH significantly decreased the p53 protein level by about 30% at the 72-h time point. DADLE blocked both the increase of p53 mRNA and the decrease of p53 protein caused by METH. These results demonstrate a neuroprotective effect of DADLE against the neuronal damage and the alteration of p53 gene expression caused by a single high dose of METH. The results also indicate an apparent discordance between the protein level of p53 and the neurotoxicity caused by a high dose of METH. Synapse 39:305-312, 2001. Published 2001 Wiley-Liss, Inc.
Hayashi
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Molecular Neuropsychiatry Section, Intramural Research Program, National Institute on Drug Abuse/NIH, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Hirata
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Asanuma
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Ladenheim
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Tsao
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Cadet
J L
JL
Su
T P
TP
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D016308:Enkephalin, Leucine-2-Alanine / Q000627:therapeutic use*; D007700:Kinetics; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D012701:Serotonin / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C493215:Slc6a3 protein, mouse; D016159:Tumor Suppressor Protein p53; D012701:Serotonin; D008694:Methamphetamine; D016308:Enkephalin, Leucine-2-Alanine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine