Orphenadrine prevents 3-nitropropionic acid-induced neurotoxicity in vitro and in vivo.
1. Previous studies indicate that 3-nitropropionic acid (3-NPA) neurotoxicity involves the excitotoxic activation of N-methyl-D-aspartate (NMDA) receptors. Thus, we examined the effect of orphenadrine (an anticholinergic drug with NMDA receptor antagonist properties) on 3-NPA neurotoxicity in both cultured 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 propidium iodide staining. 3. For rats, two indirect markers of neuronal damage were used: the binding of [(3)H]-PK 11195 to the peripheral-type benzodiazepine receptor (PBR), a microglial 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 [(3)H]-PK 11195 binding, and expression of HSP27. 4. Both the increase in [(3)H]-PK 11195 and HSP 27 expression were prevented by previous administration of 30 mg kg(-1) 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 be used to treat neurodegenerative disorders mediated by overactivation of NMDA receptors.
Pubill
D
D
Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Nucli Universitari de Pedralbes, 08028 Barcelona, Spain.
Verdaguer
E
E
Canudas
A M
AM
Sureda
F X
FX
Escubedo
E
E
Camarasa
J
J
Pallàs
M
M
Camins
A
A
D000818:Animals; D000959:Antihypertensive Agents / Q000633:toxicity; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009026:Mortality; D018727:Muscarinic Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000517:prevention & control; D009574:Nitro Compounds; D009966:Orphenadrine / Q000494:pharmacology* / Q000627:therapeutic use; D011422:Propionates / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium
D000959:Antihypertensive Agents; D007546:Isoquinolines; D018727:Muscarinic Antagonists; D009574:Nitro Compounds; D011422:Propionates; D014316:Tritium; D009966:Orphenadrine; C015392:3-nitropropionic acid; C037850:PK 11195