Chronic pretreatment with acetyl-L-carnitine and ±DL-α-lipoic acid protects against acute glutamate-induced neurotoxicity in rat brain by altering mitochondrial function.
Cellular oxidative stress and energy failure were shown to be involved in Glutamate (L-Glu) neurotoxicity, whereas, acetyl-L-carnitine (ALCAR) and ±DL-α-lipoic acid (LA) are known to be key players in the mitochondrial energy production. To evaluate the effects of the above antioxidants, adult rats were pretreated with ALCAR (100 mg/kg i.p for 21 days) and both ALCAR and LA (100 mg/kg i.p + 50 mg/kg i.p for 21 days), before stereotactically administering L-Glu bolus (1 μmole/1 μl) in the cerebral cortex. Results showed that acute L-Glu increased ROS (P < 0.001), LPO (P < 0.001), Ca(2+) (P < 0.001), TNF-α (P < 0.001), IFN-γ (P < 0.001), NO (P < 0.001) levels and mRNA expression of Caspase-3, Casapase-9, iNOS, and nNOS genes with respect to saline-injected control group. Key antioxidant parameters such as SOD, CAT, GSH, GR along with mitochondrial transmembrane potential (Ψ∆m) were decreased (P < 0.05), while ALCAR pretreatment prevented these effects by significantly inhibiting ROS (P < 0.001), LPO (P < 0.001), Ca(2+) (P < 0.05), TNF-α (P < 0.05), IFN-γ (P < 0.001), NO (P < 0.01) levels and expression of the above genes. This chronic pretreatment of ALCAR also increased SOD, CAT, GSH, GR, and Ψ∆m (P < 0.0.01, P < 0.0.01, P < 0.05, P < 0.05, and P < 0.001, respectively) with respect to L: -Glu group. The addition of LA to ALCAR resulted in further increases in CAT (P < 0.05), GSH (P < 0.01), GR (P < 0.05), Ψ∆m (P < 0.05) and additional decreases in ROS (P < 0.001), LPO (P < 0.05), Ca(2+) (P < 0.05), TNF-α (P < 0.05) and mRNA expression of iNOS and nNOS genes with respect to ALCAR group. Hence, this "one-two punch" of ALCAR + LA may help in ameliorating the deleterious cellular events that occur after L-Glu.
Nagesh Babu
G
G
REQUIMTE, Departamento de química-Fisica, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha, 164, 4099-030 Porto, Portugal. gnageshbabu@yahoo.com
Kumar
Alok
A
Singh
Ram Lakhan
RL
D000108:Acetylcarnitine / Q000008:administration & dosage*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004359:Drug Therapy, Combination; D018698:Glutamic Acid / Q000633:toxicity*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D020258:Neurotoxicity Syndromes / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D008063:Thioctic Acid / Q000008:administration & dosage*; D016896:Treatment Outcome
D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D000108:Acetylcarnitine; D008063:Thioctic Acid