Seizures and brain injury in neonatal rats induced by 1 S,3A-ACPD, a metabotropic glutamate receptor agonist

Abstract

The role of metabotropic excitatory amino acid receptors inseizures 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. Sys temic administration of 1S,3R-ACPD produced dose-dependent convulsions (ED5O = 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 dantrotene, 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 μmol/μl), 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 de-generation 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.