Article date: February 2001
By: David Pubill, Ester Verdaguer, Anna Ma Canudas, Francesc Xavier Sureda, Elena Escubedo, Jordi Camarasa, Merce Pallàs, Antoni Camins in Volume 132, Issue 3, pages 693-702
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.
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.
For rats, two indirect markers of neuronal damage were used: the binding of [3H]‐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 [3H]‐PK 11195 binding, and expression of HSP27.
Both the increase in [3H]‐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.
We propose that orphenadrine or orphenadrine‐like drugs could be used to treat neurodegenerative disorders mediated by overactivation of NMDA receptors.
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.
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.
For rats, two indirect markers of neuronal damage were used: the binding of [3H]‐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 [3H]‐PK 11195 binding, and expression of HSP27.
Both the increase in [3H]‐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.
We propose that orphenadrine or orphenadrine‐like drugs could be used to treat neurodegenerative disorders mediated by overactivation of NMDA receptors.
British Journal of Pharmacology (2001) 132, 693–702; doi:10.1038/sj.bjp.0703869
DOI: 10.1038/sj.bjp.0703869
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