The anticholinergic drug orphenadrine is used in the treatment of Parkinson
's disease. In this study we evaluate the neuroprotective effects of orphen
adrine on excitotoxicity in vivo and in vitro. Orphenadrine prevented the m
itochondrial and the cytoplasmic membrane potential decrease evoked by NMDA
(100 mu M) in rat dissociated cerebellar granule cells showing an IC50 val
ue of 11.6 +/- 4.7 mu M (mean +/- SEM, n = 5) and 13.5 +/- 2.3 mu M (n = 3)
, respectively. Orphenadrine was able to protect cerebellar granule cell cu
ltures from glutamate-induced neurotoxicity. Kainic acid (KA, 10 mg/kg)-ind
uced excitotoxicity was evaluated in vivo using the microglial marker perip
heral-type benzodiazepine receptor (PBR) and heat shock protein 72 (HSP72)
expression in the hippocampus. The B-max of PER for control tissues was 589
.1 +/- 40.0 fmol/mg protein (n = 4), increasing to 1692.5 +/- 51.6 fmol/mg
protein (n = 5) after the KA treatment. Pretreatment with orphenadrine (10
mg/kg) blocked the KA-induced increase in PER density. As expected, KA-admi
nistration induced the expression of HSP72 that was blocked in the orphenad
rine + KA-treated rats. We demonstrate that orphenadrine, interacting at th
e NMDA receptor, is able to prevent the neurotoxicity mediated by activatio
n at glutamate ionotropic receptors. (C) 1999 Elsevier Science Ltd. All rig
hts reserved.