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-alpha-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 mu mole/1 mu l) in the cerebral cortex. Results showed that acute L-Glu increased ROS (P < 0.001), LPO (P < 0.001), Ca2+ (P < 0.001), TNF-alpha (P < 0.001), IFN-gamma (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 (Psi Delta m) were decreased (P < 0.05), while ALCAR pretreatment prevented these effects by significantly inhibiting ROS (P < 0.001), LPO (P < 0.001), Ca2+ (P < 0.05), TNF-alpha (P < 0.05), IFN-gamma (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 Psi Delta 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), Psi Delta m (P < 0.05) and additional decreases in ROS (P < 0.001), LPO (P < 0.05), Ca2+ (P < 0.05), TNF-alpha (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.