Chronic Pretreatment with Acetyl-l-Carnitine and ±DL-α-Lipoic Acid Protects Against Acute Glutamate-Induced Neurotoxicity in Rat Brain by Altering Mitochondrial Function

Abstract

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 (1μmole/1 μl) in the cerebral cortex. Results showed that acute l-Glu increased ROS (P < 0.001), LPO (P < 0.001), Ca2+ (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), Ca2+ (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), Ca2+ (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.

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Acknowledgments

We acknowledge the financial support from Council of Scientific and Industrial Research to Alok Kumar in the form of a senior research fellowship.

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Correspondence to G. Nagesh Babu.

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Nagesh Babu, G., Kumar, A. & Singh, R.L. Chronic Pretreatment with Acetyl-l-Carnitine and ±DL-α-Lipoic Acid Protects Against Acute Glutamate-Induced Neurotoxicity in Rat Brain by Altering Mitochondrial Function. Neurotox Res 19, 319–329 (2011). https://doi.org/10.1007/s12640-010-9165-3

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Keywords

  • Caspases
  • Nitric oxide
  • iNOS
  • nNOS
  • Mitochondrial transmembrane potential
  • Intracellular calcium