Neuronal damage and MAP2 changes induced by the glutamate transport inhibitor dihydrokainate and by kainate in rat hippocampus in vivo.
Neurotoxicity mediated by glutamate is thought to play a role in neurodegenerative disorders, and alterations in cytoskeletal proteins are possibly involved in the mechanisms of neuronal death occurring in Alzheimer's disease. In the present work we studied the neurotoxic effects of the intrahippocampal injections of the glutamate transport inhibitor dihydrokainate as compared to those of kainate, as well as the concomitant changes in the microtubule-associated protein MAP2. Neuronal alterations were assessed at 3, 12, 24, and 48 h by Nissl staining and immunocytochemistry of MAP2. At 3 h, both compounds induced neuronal damage that was correlated with loss of dendritic MAP2 immunoreactivity. Neuronal damage was more evident at 12 h and 24 h after drug injection, and at these times an accumulation of MAP2 in the somata of pyramidal neurons was observed. The effects of dihydrokainate were restricted to the CA1 region and totally prevented by the N-methyl-D-aspartate receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), but not by the non-NMDA receptor antagonist 2,3-dihydro-6-nitro-7-sulphamoyl-benzo(f)-quinoxaline (NBQX). In contrast, kainate-induced alterations included CA1, CA3, and CA4 subfields, and the changes in CA1 were prevented by NBQX, while MK-801 was ineffective. These results suggest that early MAP2 disruption may be a marker of the excitotoxicity due to activation of different glutamate receptors located in discrete hippocampal regions.
Arias
C
C
Departamento de Neurociencias, Universidad Nacional Autónoma de México, D.F., México.
Arrieta
I
I
Massieu
L
L
Tapia
R
R
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000493:pharmacokinetics*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D018691:Excitatory Amino Acid Antagonists; D008869:Microtubule-Associated Proteins; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D018698:Glutamic Acid; C020889:dihydrokainic acid; D016291:Dizocilpine Maleate; D007608:Kainic Acid