TY - JOUR
T1 - Antiparkinsonian effects of remacemide hydrochloride, a glutamate antagonist, in rodent and primate models of Parkinson's disease
AU - Greenamyre, J. Timothy
AU - Eller, Robert V.
AU - Zhang, Zhiming
AU - Ovadia, Aliza
AU - Kurlan, Roger
AU - Gash, Don M.
PY - 1994/6
Y1 - 1994/6
N2 - Loss of dopaminergic innervation of the striatum results in overactivity of the glutamatergic pathways from the subthalamic nucleus to the internal segment of the globus pallidus and the substantia nigra pars reticulata, the output nuclei of the basal ganglia. Previous work has shown that local blockade of glutamate receptors in the internal segment of the globus pallidus or substantia nigra pars reticulata leads to marked suppression of parkinsonian signs. We have now examined whether systemic administration of a glutamate receptor antagonist has antiparkinsonian effects in rodent and primate models of Parkinson's disease. Remacemide hydrochloride is an anticonvulsant, neuroprotective compound with antagonist activity at the N‐methyl‐D‐aspartate receptor ion channel. In normal rats and monoaminedepleted rats, remacemide hydrochloride did not cause locomotor hyperactivity, unlike MK‐801. When monoaminedepleted rats were treated with a subthreshold dose of levodopa methylester, remacemide hydrochloride (5–40mg/kg, orally) caused a dose‐dependent increase in locomotor activity. Moreover, remacemide hydrochloride (10 mg/kg, orally) potentiated the effects of each suprathreshold dose of levodopa methylester tested (100–200 mg/kg, intraperitoneally). Parkinsonian rhesus monkeys were tested with oral doses of vehicle plus vehicle, vehicle plus levodopa‐carbidopa, and remacemide hydrochloride (5 mg/kg) plus levodopa‐carbidopa. Blinded clinical scoring of videotapes revealed that treatment with remacemide hydrochloride plus levodopa‐carbidopa was substantially better than levodopa‐carbidopa plus vehicle or vehicle plus vehicle. The effects of remacemide hydrochloride lasted at least 5 hours. We conclude that certain N‐methyl‐D‐aspartate receptor antagonists have antiparkinsonian actions and low potential for side effects. Clinical trials of remacemide hydrochloride in patients with Parkinson's disease may be warranted.
AB - Loss of dopaminergic innervation of the striatum results in overactivity of the glutamatergic pathways from the subthalamic nucleus to the internal segment of the globus pallidus and the substantia nigra pars reticulata, the output nuclei of the basal ganglia. Previous work has shown that local blockade of glutamate receptors in the internal segment of the globus pallidus or substantia nigra pars reticulata leads to marked suppression of parkinsonian signs. We have now examined whether systemic administration of a glutamate receptor antagonist has antiparkinsonian effects in rodent and primate models of Parkinson's disease. Remacemide hydrochloride is an anticonvulsant, neuroprotective compound with antagonist activity at the N‐methyl‐D‐aspartate receptor ion channel. In normal rats and monoaminedepleted rats, remacemide hydrochloride did not cause locomotor hyperactivity, unlike MK‐801. When monoaminedepleted rats were treated with a subthreshold dose of levodopa methylester, remacemide hydrochloride (5–40mg/kg, orally) caused a dose‐dependent increase in locomotor activity. Moreover, remacemide hydrochloride (10 mg/kg, orally) potentiated the effects of each suprathreshold dose of levodopa methylester tested (100–200 mg/kg, intraperitoneally). Parkinsonian rhesus monkeys were tested with oral doses of vehicle plus vehicle, vehicle plus levodopa‐carbidopa, and remacemide hydrochloride (5 mg/kg) plus levodopa‐carbidopa. Blinded clinical scoring of videotapes revealed that treatment with remacemide hydrochloride plus levodopa‐carbidopa was substantially better than levodopa‐carbidopa plus vehicle or vehicle plus vehicle. The effects of remacemide hydrochloride lasted at least 5 hours. We conclude that certain N‐methyl‐D‐aspartate receptor antagonists have antiparkinsonian actions and low potential for side effects. Clinical trials of remacemide hydrochloride in patients with Parkinson's disease may be warranted.
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U2 - 10.1002/ana.410350605
DO - 10.1002/ana.410350605
M3 - Article
C2 - 8210221
AN - SCOPUS:0028232327
SN - 0364-5134
VL - 35
SP - 655
EP - 661
JO - Annals of Neurology
JF - Annals of Neurology
IS - 6
ER -