Neuroprotection in mice by NGP1-01 after transient focal brain ischemia.
The effect of the polycyclic cage amine NGP1-01, a dual action antagonist at both L-type calcium channels and NMDA receptors, was measured after transient (1 h) focal cerebral ischemia in the mouse middle cerebral artery occlusion (MCAO) model. Mice were left untreated, or received NGP1-01 (20 mg/kg per dose intraperitoneally), memantine (20 mg/kg per dose intraperitoneally), or vehicle (DMSO) at 15 min, 24 h and 48 h after reperfusion. Sensorimotor function was tested daily for two weeks using the "corner test", a proven paradigm for the assessment of functional integrity in rodents. NGP1-01 significantly reduced sensorimotor deficits over the 2-week period (p<0.001, ANOVA). Although memantine was less effective than NGP1-01 (p<0.05), it still significantly attenuated sensorimotor deficits in the animals. In a separate study, brain damage 3 days after stroke was determined histologically in mice receiving no treatment, DMSO, or NGP1-01 (dosages and dosage schedule same as above). Serial brain sections were stained for nonviable neurons with Fluoro-Jade B and the volume of damaged tissue was estimated. NGP1-01 treated mice had a significantly lower volume of brain damage (13+/-7 mm(3), p<0.01) than both control groups (no treatment: 47+/-4 mm(3), DMSO: 50+/-10 mm(3)). In conclusion, at weight-equivalent doses, NGP1-01 was at least as neuroprotective as the established NMDA receptor antagonist memantine. It may be a promising lead structure for the development of novel multiple-action drugs in treating ischemic stroke and other neurodegenerative diseases with an excitotoxic component.
Hao
Jiukuan
J
Department of Pharmaceutical Sciences and PATOS Stroke Research Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
Mdzinarishvili
Alexander
A
Abbruscato
Thomas J
TJ
Klein
Jochen
J
Geldenhuys
Werner J
WJ
Van der Schyf
Cornelis J
CJ
Bickel
Ulrich
U
D000704:Analysis of Variance; D000818:Animals; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D001952:Bridged-Ring Compounds / Q000627:therapeutic use*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005452:Fluoresceins; D051379:Mice; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009930:Organic Chemicals; D010468:Perceptual Disorders / Q000209:etiology / Q000517:prevention & control; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D013997:Time Factors
D001952:Bridged-Ring Compounds; D005452:Fluoresceins; D018696:Neuroprotective Agents; D009930:Organic Chemicals; C435731:fluoro jade; C049649:NGP 1-01; D010751:Phosphopyruvate Hydratase