Abstract
Delta opioid peptide [d-Ala2,d-leu5]enkephalin (DADLE) can prolong organ preservation and increases myocardial tolerance to ischemia. Our study examined the protective property of DADLE against methamphetamine- (METH) induced dopaminergic terminal damage in the central nervous system. Because the neurotoxicity of METH involves reactive oxygen species, we also examined if DADLE might be an antioxidative agent in vitro. DADLE at 2 and 4 mg/kg (i.p.), given 30 min before each METH administration (5 or 10 mg/kg, i.p., four injections in a day at 2-hr intervals), dose-dependently blocked the METH-induced long-term dopamine transporter loss. The opioid antagonist naltrexone blocked this action of DADLE in both aspects of striata but tends not to affect the effects of DADLE in the nucleus accumbens. DADLE did not alter changes in body temperature induced by METH. The reduction of striatal dopaminergic content and tyrosine hydroxylase activity caused by METH, however, were not blocked by DADLE. In vitro, DADLE was approximately equipotent to glutathione in inhibiting both superoxide anion formation induced by xanthine oxidase and hydroxyl radical formation evoked by ferrous/citrate complex. DADLE was only slightly less potent than glutathione in inhibiting the iron/ascorbate-induced brain lipid peroxidation. These results suggest that DADLE can protect the terminal membranes of dopaminergic neurons against METH-induced insult but not the loss of dopaminergic content and tyrosine hydroxylase activity and that this action of DADLE might involve opioid receptors as well as the sequestration of free radical.
Footnotes
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Send reprint requests to: Dr. Tsung-Ping Su, Molecular Neuropsychiatry Section, IRP, NIDA/NIH, P.O. Box 5180, Baltimore, MD 21224.
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1 This work was supported by the Basic Neurobiology and Biological Systems Research Branch, Division of Basic Research, NIDA.
- Abbreviations:
- BPT
- bathophenanthroline disulfonic acid
- CNS
- central nervous system
- DA
- dopamine or dopaminergic
- DADLE
- [d-Ala2,d-leu5]enkephalin
- DAT
- dopamine transporter(s)
- 2
- 3-DHBA and 2,5-DHBA, 2,3- and 2,5-dihydroxybenzoic acid
- DOPAC
- 3,4-dihydroxyphenylacetic acid
- DTT
- dithiothreitol
- GSH
- glutathione
- HPLC-ECD
- high performance liquid chromatography utilizing electrochemical detection
- HVA
- homovanillic acid
- METH
- methamphetamine
- 6-MPH4
- 6-methyl-5,6,7,8-tetrahydropterin
- PTBN
- α-phenyl-N-tert-butyl nitrone
- PD
- Parkinson’s disease
- ROS
- reactive oxygen species
- RTI-121
- 3β-(4-[125I]iodophenyl)tropane-2β-carboxylic acid isopropyl ester
- TBA
- thiobarbituric acid
- TBARS
- thiobarbituric acid reactive substances
- TH
- tyrosine hydroxylase
- ANOVA
- analyses of variance
- Received February 16, 1998.
- Accepted June 1, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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