The effect of groups II and III metabotropic glutamate receptor activation on neuronal injury in a rodent model of traumatic brain injury.
OBJECTIVE
The role of metabotropic glutamate receptor activation after traumatic brain injury (TBI) is not well understood. In vitro studies suggest that activation of Groups II and III metabotropic glutamate receptors may provide some degree of neuroprotection and may be potential targets for the development of therapeutic strategies. Thus, we examined the effects of Group II and Group III selective agonists on neuronal degeneration after in vivo TBI.


METHODS
Fifty male Sprague-Dawley rats were subjected to lateral fluid percussion brain injury immediately followed by an intracranial injection of 2-(2',3')-dicarboxycyclopropylglycine (DCG-IV) (Group II) or (R,S)-4-phosphonophenylglycine (Group III) in the CA2 and CA3 areas of the hippocampus. DCG-IV was injected at doses of 20 fmol, 100 fmol, and 500 fmol, and (R,S)-4-phosphonophenylglycine was injected at 8 nmol, 40 nmol, and 200 nmol. Vehicle injection control groups were used for comparison with each drug group. All animals were killed 24 hours after TBI was induced. Four 50-microm brain sections were obtained from each animal and stained for degenerating neurons with the fluorochrome Fluoro-Jade. Two independent, blinded investigators counted the number of degenerating (Fluoro-Jade-positive) neurons in the CA2 and CA3 areas of the hippocampus of each brain section.


RESULTS
Compared with vehicle, the 500-fmol dose of DCG-IV significantly reduced the number of Fluoro-Jade-positive degenerating neurons (P < 0.001). Lower doses of DCG-IV were associated with a decreased but not statistically significant number of Fluoro-Jade-positive neurons. In contrast, (R,S)-4-phosphonophenylglycine had no significant effect on the number of degenerating neurons.


CONCLUSIONS
Administration of selective Group II metabotropic glutamate receptor agonists protects neurons against in vivo TBI. These receptors may thus be a promising target for future neuroprotective drugs.
Zwienenberg
M
M
Department of Neurological Surgery, University of California at Davis, 95616, USA.
Gong
Q Z
QZ
Berman
R F
RF
Muizelaar
J P
JP
Lyeth
B G
BG
D000818:Animals; D001930:Brain Injuries / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D003521:Cyclopropanes / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes; D005998:Glycine / Q000031:analogs & derivatives / Q000627:therapeutic use; D008297:Male; D008856:Microscopy, Fluorescence; D009410:Nerve Degeneration / Q000175:diagnosis / Q000517:prevention & control; D009474:Neurons / Q000473:pathology*; D018696:Neuroprotective Agents / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015599:Trauma Severity Indices
C119327:4-phosphonophenylglycine; D003521:Cyclopropanes; D005456:Fluorescent Dyes; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D005998:Glycine