An evaluation of l-ephedrine neurotoxicity with respect to hyperthermia and caudate/putamen microdialysate levels of ephedrine, dopamine, serotonin, and glutamate.
l-Ephedrine is an active ingredient in several herbal formulations with a mechanism of action similar to amphetamine and methamphetamine. However, its potential to damage dopaminergic terminals in the caudate/putamen (CPu) has yet to be fully evaluated. The studies here used in vivo brain microdialysis experiments to determine the systemic doses and extracellular brain levels of l-ephedrine necessary to produce similar increases in CPu extracellular dopamine and marked hyperthermia that were previously shown necessary for amphetamine-induced neurotoxicity in male Sprague-Dawley rats. At an environmental temperature of 23 degrees C, a single 40 mg/kg intraperitoneal (ip) dose of l-ephedrine produced marked hyperthermia (>/= 40 degrees C), peak microdialysate ephedrine levels of 7.3 +/- 1.2 microM, and a 20-fold increase in microdialysate dopamine levels. Twenty-five mg/kg produced a lesser degree of hyperthermia, peak microdialysate ephedrine levels of 2.6 +/- 0.4 microM, and a 10-fold increase in dopamine levels. Three doses of 40 mg/kg given at 3-h intervals or 4 doses of 25 mg/kg l-ephedrine given at 2-h intervals were compared with 4 doses of 5 mg/kg d-amphetamine given at 2-h intervals. Multiple doses of either ephedrine or amphetamine caused severe hyperthermia (>/= 41.3 degrees C) but striatal tissue levels of dopamine 7 days after dosing were reduced only 25% or less by ephedrine compared to the 75% reductions produced by amphetamine. The increases in CPu microdialysate levels of serotonin produced by either 4 x 25 mg/kg l-ephedrine or 4 x 5 mg/kg d-amphetamine did not significantly differ, but elevation of dopamine levels by d-amphetamine were over 2-fold times the level caused by l-ephedrine. Microdialysate glutamate levels were elevated to the same extent by either 25 mg/kg l-ephedrine or 4 x 5 mg/kg d-amphetamine. l-Ephedrine may not be as neurotoxic to dopaminergic terminals as d-amphetamine, because non-lethal doses of l-ephedrine do not sufficiently increase the CPu dopamine levels within nerve terminals or the extracellular space to those necessary for a more pronounced long-term dopamine depletion.
Bowyer
J F
JF
Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA. jbowyer@nctr.fda.gov
Newport
G D
GD
Slikker
W
W
Gough
B
B
Ferguson
S A
SA
Tor-Agbidye
J
J
D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000378:metabolism / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D003913:Dextroamphetamine / Q000633:toxicity; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity; D004809:Ephedrine / Q000378:metabolism / Q000633:toxicity*; D005334:Fever / Q000139:chemically induced* / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism; D007536:Isomerism; D008297:Male; D017551:Microdialysis; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D011699:Putamen / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism
D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; D009498:Neurotoxins; D012701:Serotonin; D018698:Glutamic Acid; D004809:Ephedrine; D003913:Dextroamphetamine; D004298:Dopamine