Neuroprotective actions in vivo and electrophysiological actions in vitro of 202W92

Citation
L. Caputi et al., Neuroprotective actions in vivo and electrophysiological actions in vitro of 202W92, BRAIN RES, 919(2), 2001, pp. 259-268
Citations number
47
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Neurosciences & Behavoir
Journal title
BRAIN RESEARCH
ISSN journal
0006-8993 → ACNP
Volume
919
Issue
2
Year of publication
2001
Pages
259 - 268
Database
ISI
SICI code
0006-8993(20011123)919:2<259:NAIVAE>2.0.ZU;2-J
Abstract
202W92 (R-(-)-2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)pyrimidi ne) is a novel compound in the same chemical series as the antiepileptic dr ug lamotrigine and the neuroprotective sipatrigine. Here 202W92 was quantit atively assessed as a neuroprotective agent in focal cerebral ischaemia, an d as an inhibitor of sodium and calcium channels and of synaptic transmissi on. In the rat permanent middle cerebral artery occlusion (MCAO) model of a cute focal ischaemia, 202W92 reduced infarct. volume by 75% in cortex and b y 80% in basal ganglia, with ED50 approximately 2 mg/kg (single i.v. dose, 10 min post-occlusion). In whole-cell current recordings from single cells, 202W92 completely and reversibly inhibited voltage gated sodium channels ( IC50 3x10(-6) M) in rat freshly-isolated cortical neurons and in the GH, pi tuitary cell line. 202W92 also inhibited a nifedipine-sensitive fraction (a pproximately 35%) of native high-voltage-activated (HVA) calcium current in rat cortical neurons (IC50 15x10(-6) M) and weakly inhibited low-voltage-a ctivated (LVA) calcium currents of the recombinant alpha 1I-mediated T-type (IC50> 100x10(-6) M). The drug inhibited the amplitude and frequency of 4- aminopyridine-evoked glutamatergic excitatory post-synaptic currents (EPSCs ). In conclusion, 202W92 is an effective neuroprotective agent when adminis tered post-ischaemia and a potent sodium channel inhibitor in vitro. (C) 20 01 Elsevier Science B.V. All rights reserved.