Stimulation of N-methyl-D-aspartate receptors induces apoptosis in rat brain

Brain Res. 1996 Jul 1;725(2):166-76. doi: 10.1016/0006-8993(96)00200-4.


To evaluate the contribution of apoptotic mechanisms to excitotoxin-induced neurodegeneration as well as to characterize the glutamate receptor subtypes involved, biochemical and morphological effects of intrastriatally administered NMDA receptor agonist N-methyl-D-aspartate (NMDA) or quinolinic acid (QA) were studied. Receptor autoradiography showed that NMDA (75-300 nmol) caused a loss of 18-68% of striatal D1 dopamine (DA) and 10-43% of NMDA receptors 7 days after drug administration. Treatment with QA (60-240 nmol) also led to a loss of 60-73% of D1 DA and 37-44% of NMDA receptors in the ipsilateral striatum. Agarose gel electrophoresis revealed that both NMDA and QA induced internucleosomal DNA fragmentation in the striatum 12 to 48 h after drug administration. NMDA- and QA-induced internucleosomal DNA fragmentation was attenuated by the protein synthesis inhibitor cycloheximide in a dose-dependent manner. Terminal transferase-mediated deoxyuridine triphosphate (d-UTP)-digoxigenin nick end labeling (TUNEL)-positive nuclei were found in the ipsilateral striatum in response to NMDA or QA treatment. In addition, many fragmented nuclei were observed in the NMDA or QA-treated striatum and propidium iodide staining showed profound nuclear condensation in the NMDA or QA-treated striatum. NMDA- and QA-induced internucleosomal DNA fragmentation and TUNEL-positive nuclei as well as nuclear condensation were abolished by the NMDA receptor antagonist MK-801, but not by the AMPA/KA receptor antagonist NBQX. MK-801, but not NBQX, also prevented NMDA or QA-induced striatal cell death. These results suggest that apoptotic mechanisms are involved in excitotoxin-induced striatal cell death. The initiation of an apoptotic cascade by NMDA or QA appears to be mediated by stimulation of NMDA but not AMPA/KA receptors.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Autoradiography
  • DNA Fragmentation
  • DNA Nucleotidylexotransferase / metabolism
  • Deoxyuracil Nucleotides / chemistry
  • Dizocilpine Maleate / pharmacology*
  • Excitatory Amino Acid Agonists / pharmacology*
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Genetic Techniques
  • Male
  • Nucleic Acid Hybridization
  • Quinoxalines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / agonists*
  • Stimulation, Chemical


  • Deoxyuracil Nucleotides
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Quinoxalines
  • Receptors, N-Methyl-D-Aspartate
  • 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
  • Dizocilpine Maleate
  • DNA Nucleotidylexotransferase