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 agonist of the N-methyl-D-aspartate (NMDA) complex receptor, to analyse the protective effect of a systemic bolus of MgSO4, a non-competitive antagonist of the NMDA ionophore-complex receptor. MgSO4 did not prevent microgyia, induced by ibotenate when injected at P0 immediately after the post-migratory settlement of layer V, but did prevent ulegyrias, porencephalic cysts, and other cortical and cortical-subcortical hypoxic-like lesions arising after completion of the neocortical cyto-architectonic development at P5. Protection was optimal in 80 per cent of mice at 600mg/kg, with no mortality due to MgSO4; thereafter mortality increased with dosage. The protective effect appears after the developmental acquisition of two properties of the excitotoxic cascade, namely the coupling of the massive calcium influx with NMDA-receptor overstimulation and the predominance of magnesium-obliterable calcium channels. This animal model supports the clinical intervention studies with magnesium in hypoxias/perfusion failures and has implications for their design. If maturation of the excitotoxic cascade follows the same sequence in humans, protection is probably low before 26 weeks of gestational age.
Marret
S
S
Service de Neurologie Pédiatrique, University of Louvain Medical School at Brussels, Belgium.
Gressens
P
P
Gadisseux
J F
JF
Evrard
P
P
D000818:Animals; D001926:Brain Death; D002560:Cerebrovascular Circulation / Q000187:drug effects; D002985:Clinical Protocols; D005260:Female; D000860:Hypoxia / Q000139:chemically induced* / Q000150:complications; D007051:Ibotenic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008274:Magnesium / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D009474:Neurons / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
D016194:Receptors, N-Methyl-D-Aspartate; D007051:Ibotenic Acid; D016202:N-Methylaspartate; D008274:Magnesium