Energy substrates protect hippocampus against endogenous glutamate-mediated neurodegeneration in awake rats.
Excitotoxicity due to excessive glutamatergic neurotransmission is a well-studied phenomenon that has been related to the mechanisms of neuronal death occurring in some disorders of the CNS. We have previously shown that the intrahippocampal perfusion by microdialysis of 4-aminopyridine (4-AP) in rats stimulates endogenous glutamate release from nerve endings and this results in excitotoxic effects such as immediate seizures and delayed neuronal death, due to the overactivation of N-methyl-D-aspartate (NMDA) receptors. To study whether mitochondrial energy dysfunction and oxidative stress could be involved in this 4-AP-induced excitotoxicity, we evaluated in awake rats the protective effect of several energy substrates and antioxidant compounds, using microdialysis, electroencephalographic (EEG) recording and histological analysis. The 4-AP-induced behavioral and EEG seizures, which progressed to status epilepticus in about 30 min, were prevented by the NMDA receptor antagonist MK-801, whereas acetoacetate, DL- and L-β-hydroxybutyrate did not protect against seizures but increased the latency to the onset of status epilepticus; pyruvate, α-ketoglutarate and glutathione ethyl ester did not show any protective effect. 4-AP also produced nearly complete loss of pyramidal neurons in CA1 and CA3 regions of the ipsilateral hippocampus 24 h after the experiment. MK-801 totally prevented this neuronal death and the energy substrates tested protected by about 50%, whereas the antioxidants showed only a weak protection. We conclude that ketone bodies possess weak anticonvulsant effects and that energy metabolism impairment plays a more important role than oxidative stress in the delayed hippocampal neurodegeneration resulting from the excitotoxic action of 4-AP mediated by endogenous glutamate.
División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, AP 70-253, 04510, Mexico, DF, Mexico.
Citlalli
C
Netzahualcoyotzi
Ricardo
R
Tapia
D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology / Q000627:therapeutic use*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D016291:Dizocilpine Maleate