ANTIPARKINSONIAN EFFECTS OF REMACEMIDE HYDROCHLORIDE, A GLUTAMATE ANTAGONIST, IN RODENT AND PRIMATE MODELS OF PARKINSONS-DISEASE

Loss of dopaminergic innervation of the striatum results in overactivi ty of the glutamatergic pathways from the subthalamic nucleus to the i nternal segment of the globus pallidus and the substantia nigra pars r eticulata, the output nuclei of the basal ganglia. Previous work has s hown that local blockade of glutamate receptors in the internal segmen t 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 antipa rkinsonian effects in rodent and primate models of Parkinson's disease . Remacemide hydrochloride is an anticonvulsant, neuroprotective compo und with antagonist activity at the N-methyl-D-aspartate receptor ion channel. In normal rats and monoamine-depleted rats, remacemide hydroc hloride did not cause locomotor hyperactivity, unlike MK-801. When mon oamine-depleted rats were treated with a subthreshold dose of levodopa methylester, remacemide hydrochloride (5-40 mg/kg, orally) caused a d ose-dependent increase in locomotor activity. Moreover, remacemide hyd rochloride (10 mg/kg, orally) potentiated the effects of each suprathr eshold dose of levodopa methylester tested (100-200 mg/kg, intraperito neally). Parkinsonian rhesus monkeys were tested with oral doses of ve hicle plus vehicle, vehicle plus levodopa-carbidopa, and remacemide hy drochloride (5 mg/kg) plus levodopa-carbidopa. Blinded clinical scorin g of videotapes revealed that treatment with remacemide hydrochloride plus levodopa-carbidopa was substantially better than levodopa-carbido pa plus vehicle or vehicle plus vehicle. The effects of remacemide hyd rochloride 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 hydrochlori de in patients with Parkinson's disease may be warranted.