Neurotoxicity of glutamate uptake inhibition in vivo: correlation with succinate dehydrogenase activity and prevention by energy substrates
Section snippets
Animal treatment
Male Wistar rats (250–290 g) were used throughout the study. They were handled according to the Rules for Research in Health Matters (Mexico) and the local Animal Care Committee approved all animal treatments. All efforts were made to minimize the number of animals used and their suffering. All animals received a single i.p. injection of 3-NP (20 mg/kg) dissolved in 10 mM phosphate buffer (pH adjusted to 7.0–7.5 with 1 M NaOH) and 4, 24 or 48 h later they received an intrastriatal
Correlation between neurotoxicity of PDC and SDH activity
The time course of SDH activity after a single i.p. administration of 3-NP (20 mg/kg) was determined histochemically as described in the Experimental procedures. According to this analysis SDH activity was maximally inhibited 2–4 h after 3-NP injection while no inhibition was found at 1 h. Enzyme activity was almost completely recovered at 48 h (Fig. 1A). According to the statistical analysis no difference was found between the 1 h and the 48 h groups while differences were found between the 1
Discussion
Previous in vivo microdialysis experiments indicate that intrastriatal administration of the substrate inhibitor of glutamate transporters, PDC, leads to substantial elevation of the extracellular levels of excitatory amino acids, reaching aspartate and glutamate concentrations higher than 50 and 100 μM, respectively (considering 6–7% membrane recovery for these amino acids (Massieu et al., 1995, Sánchez-Carbente and Massieu, 1999)). PDC-induced glutamate release in vivo probably occurs through
Conclusion
The present study shows that induction of the reverse action of glutamate transporters by PDC leads to neuronal death in the rat striatum in vivo when mitochondrial energy metabolism is partially and transiently inhibited. The present results also suggest the potential of energy substrates such as creatine, pyruvate and acetoacetate as neuroprotective agents against ischemic neuronal damage.
Acknowledgements
The authors thank Mr. Federico Jandete for his help in histological work. This work was supported by CONACYT 27970N and UNAM (DGAPA IN203400).
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