Seizures and brain injury in neonatal rats induced by 1S,3R-ACPD, a metabotropic glutamate receptor agonist.
The role of metabotropic excitatory amino acid receptors in seizures and brain injury was examined using the selective metabotropic agonist 1S,3R-ACPD [(1S,3R)-1-aminocyclopentane-1-3-dicarboxylic acid] in 7-d-old neonatal rats. Systemic administration of 1S,3R-ACPD produced dose-dependent convulsions (ED50 = 16 mg/kg, i.p.) that were stereoselective for the active metabotropic ACPD isomer, since 1R,3S-ACPD was less potent (ED50 = 93 mg/kg, i.p.). 1S,3R-ACPD-induced seizures were antagonized by systemic administration of dantrolene, an inhibitor of intracellular calcium mobilization, but not by the ionotropic glutamate antagonists MK-801 or GYKI-52466. As indexed by hemispheric brain weight differences 5 d postinjection, unilateral intrastriatal injection of 1S,3R-ACPD (0.1-2.0 mumol/microliters), but not 1R,3S-ACPD, produced dose-dependent brain injury (maximal effect of 3.4 +/- 0.5% damage). 1S,3R-ACPD brain injury occurred in the absence of prominent behavioral convulsions. Histologic and ultrastructural examination of 1S,3R-ACPD-injected rat brains revealed swelling and degeneration of select neurons at 4 hr postinjection, but little evidence of injured neurons 5 d later. 1S,3R-ACPD-mediated brain injury was not attenuated by systemic administration of the NMDA antagonist MK-801 or the AMPA antagonist GYKI-52466. However, cointrastriatal injection of dantrolene reduced the severity of 1S,3R-ACPD injury by 88 +/- 7%. These studies indicate that seizures and neuronal injury can be elicited by the selective activation of metabotropic glutamate receptors in perinatal rats, and these effects of 1S,3R-ACPD involve the mobilization of intracellular calcium stores.
McDonald
J W
JW
CNS Research Division, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Fix
A S
AS
Tizzano
J P
JP
Schoepp
D D
DD
D000818:Animals; D000831:Animals, Newborn; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines / Q000494:pharmacology; D001930:Brain Injuries / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D003515:Cycloleucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D003620:Dantrolene / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008854:Microscopy, Electron; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D013238:Stereotaxic Techniques
D014151:Anti-Anxiety Agents; D009498:Neurotoxins; D017470:Receptors, Glutamate; D003515:Cycloleucine; C061950:GYKI 52466; C036361:1-amino-1,3-dicarboxycyclopentane; D001569:Benzodiazepines; D016291:Dizocilpine Maleate; D003620:Dantrolene