PREVENTION BY MAGNESIUM OF EXCITOTOXIC NEURONAL DEATH IN THE DEVELOPING BRAIN - AN ANIMAL-MODEL FOR CLINICAL INTERVENTION STUDIES

Excitotoxic disturbances during brain development were studied in the mouse using intracerebral injections of ibotenate, a glutamatergic ago nist of the N-methyl-D-aspartate (NMDA) complex receptor, to analyse t he protective effect of a systemic bolus of MgSO4, a non-competitive a ntagonist of the NMDA ionophore-complex receptor, MgSO4 did not preven t microgyia, induced by ibotenate when injected at PO immediately afte r the post-migratory settlement of layer V, but did prevent ulegyrias, porencephalic cysts, and other cortical and cortical-subcortical hypo xic-like lesions arising after completion of the neocortical cyto-arch itectonic development at P5. Protection was optimal in 80 per cent of mice at 660mg/kg, with no mortality due to MgSO4; thereafter mortality increased with dosage. The protective effect appears after the develo pmental acquisition of two properties of the excitotoxic cascade, name ly the coupling of the massive calcium influx with NMDA-receptor overs timulation and the predominance of magnesium-obliterable calcium chann els. This animal model supports the clinical intervention studies with magnesium in hypoxias/perfusion failures and has implications for the ir design. If maturation of the excitotoxic cascade follows the same s equence in humans, protection is probably low before 26 weeks of gesta tional age.