Prevention by eliprodil (SL 82.0715) of traumatic brain damage in the rat. Existence of a large (18 h) therapeutic window.
The neuroprotective potential of eliprodil (SL 82.0715), an N-methyl-D-aspartate (NMDA) receptor antagonist acting at the polyamine modulatory site, in brain trauma was examined in a rat model of lateral fluid-percussion brain injury. The volume of the lesion was assessed histologically by measuring, at 7 days post-injury, the area of brain damage at 10 coronal planes. Eliprodil (10 mg/kg i.p.) when given 15 min, 6 h and 24 h after fluid percussion (1.6 atm) and then b.i.d. for the following 6 days, reduced by 60% the volume of cortical damage. A similar neuroprotection was obtained when the first administration of eliprodil was delayed by up to 12 h after the brain insult. Moreover, when the treatment with this compound was started at 18 h post-injury, cortical damage was still significantly reduced by 33%. Autoradiographic studies showed that eliprodil treatment (10 mg/kg, i.p.), initiated 15 min after the trauma, also caused a marked reduction of the loss of the neuronal marker omega 1-2 (central benzodiazepine) binding sites and of the increase in the glial/macrophage marker peripheral type benzodiazepine binding sites in the cerebral cortex. In contrast, dizocilpine (a blocker of the cationic channel coupled to the NMDA receptor) when administered 6 h and 24 h after fluid percussion and then b.i.d. for the following 6 days induced a non significant reduction of the volume of the lesion at the highest tolerated dose (0.6 mg/kg i.p.). These results demonstrate the neuroprotective activity of eliprodil in experimental brain trauma using neuropathology as an endpoint and indicate that there is a very large time window for therapeutic intervention, consistent with the delayed nature of the neuronal loss, in this condition.
Toulmond
S
S
Synthélabo Recherche (LERS), Biology Department, Bagneux, France.
Serrano
A
A
Benavides
J
J
Scatton
B
B
D000818:Animals; D001345:Autoradiography; D001569:Benzodiazepines / Q000378:metabolism; D001665:Binding Sites; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy*; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D004334:Drug Administration Schedule; D008297:Male; D010880:Piperidines / Q000008:administration & dosage* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013997:Time Factors
D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D001569:Benzodiazepines; D016291:Dizocilpine Maleate; C058083:eliprodil