Neuroprotective effect of L-carnitine in the 3-nitropropionic acid (3-NPA)-evoked neurotoxicity in rats.
A plant and fungal toxin, 3-NPA, acts as an inhibitor of mitochondrial function via irreversible inactivation of the mitochondrial inner membrane enzyme, succinate dehydrogenase (SDH). Inhibition of SDH disturbs electron transport and leads to cellular energy deficits and neuronal injury. We have shown that pretreatment with l-carnitine, while not significantly attenuating SDH inhibition, prevented hypothermia and oxidative stress-associated increased activity of free radical-scavenging enzymes. Here, a neurohistological method was applied to examine the effect of carnitine pretreatment against 3-NPA-induced neurotoxicity. Twenty adult male Sprague-Dawley rats were randomly divided into two groups (n = 10/group). Rats in the first group were injected twice with 3-NPA at 30 mg/kg s.c., 2 days apart, and the second group of animals received l-carnitine pretreatment at 100 mg/kg 30-40 min before 3-NPA administration. Rats in both groups were perfused 7 days later and their brains harvested. Degenerating neurons were identified and localized via the fluorescent marker Fluoro-Jade B. In the three animals that survived 3-NPA dosing, one exhibited no pathology, one exhibited moderate unilateral damage to the striatum, and the third exhibited extensive bilateral neuronal degeneration in multiple forebrain regions. In the seven surviving animals that received l-carnitine prior to 3-NPA insult, six exhibited no lesions, while one exhibited a modest unilateral lesion in the striatum. It appears that l-carnitine is protective against 3-NPA-induced toxicity, as reflected by both reduced mortality and significantly reduced neuronal degeneration.
Division of Neurotoxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079, USA. zbinienda@nctr.fda.gov
Zbigniew
Z
Binienda
Ashraf
A
Virmani
Beata
B
Przybyla-Zawislak
Larry
L
Schmued
D000818:Animals; D002331:Carnitine / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009574:Nitro Compounds; D011422:Propionates / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018696:Neuroprotective Agents; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; C015392:3-nitropropionic acid; D002331:Carnitine