Orphenadrine prevents 3-nitropropionic acid-induced neurotoxicity in vitroand in vivo

Citation
D. Pubill et al., Orphenadrine prevents 3-nitropropionic acid-induced neurotoxicity in vitroand in vivo, BR J PHARM, 132(3), 2001, pp. 693-702
Citations number
53
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BRITISH JOURNAL OF PHARMACOLOGY
ISSN journal
00071188 → ACNP
Volume
132
Issue
3
Year of publication
2001
Pages
693 - 702
Database
ISI
SICI code
0007-1188(200102)132:3<693:OP3ANI>2.0.ZU;2-E
Abstract
1 Previous studies indicate that 3-nitropropionic acid (3-NPA) neurotoxicit y involves the excitotoxic activation of N-methyl-D-aspartate (NMDA) recept ors. Thus, we examined the effect of orphenadrine (an anticholinergic drug with NMDA receptor antagonist properties) on 3-NPA neurotoxicity in both cu ltured rat cerebellar granule cells (CGCs) and in rats. 2 Orphenadrine protected CGCs from 3-NPA-induced mortality, as assessed by both the neutral red viability assay and laser scanning cytometry, using pr opidium iodide staining. 3 For rats, two indirect markers of neuronal damage were used: the binding of [H-3]-PK 11195 to the peripheral-type benzodiazepine receptor (PBR), a m icroglial marker, and expression of the 27 kD heat-shock protein (HSP27), a marker of activated astroglia. Systemic administration of 3-NPA (30 mg kg( -1) per day for 3 days) induced a 170% increase in [H-3]-PK 11195 binding, and expression of HSP27. 4 Both the increase in [H-3]-PK 11195 and HSP 27 expression were prevented by previous administration of 30 mg kg-l per day of orphenadrine for 3 days . Lower doses (10 and 20 mg kg(-1)) had no protective effect. Orphenadrine also reduced 3-NPA-induced mortality in a dose-dependent manner. 5 We propose that orphenadrine or orphenadrine-like drugs could neurodegene rative disorders mediated by overactivation of NMDA receptors.