The role of D1 stimulation in the therapy of movement disorders, and particularly PD, has been debated for years. Bromocriptine is a D1 antagonist, pergolide a D1 agonist, while ropinirole and pramipexole do not interact with D1 receptors at all. Since all these DAAs have similar efficacy in PD, the role of D1 receptors in PD therapy is questionable. However recent,

reports suggest that the specific Drstimulating drug, ABT-431, is also effective in PD.31 Thus, there arc several remaining Inhibitors,research,lifescience,medical Natural Product Library issues in DAA therapy (Table III). Table III. Remaining issues in dopamine agonist (DAA) therapy. Other drugs The efficacy of selegiline in the treatment, of PD is based on the assumption that inhibition of the monoamine oxidase B (MAOB) enzyme may prevent. DA neurotoxicity.32,33 The extensive DATATOP (Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism) study demonstrated the safety and beneficial Inhibitors,research,lifescience,medical symptomatic effects of selegiline in early PD,but not necessarily its neuroprotective effect.34 It is possible that at higher therapeutic doses, MAOB inhibitors will not only ameliorate disease symptoms, but. could also provide neuroprotection, which has been demonstrated in vitro with

equivalent drug concentrations. Several MAOB inhibitors are at various stages Inhibitors,research,lifescience,medical of development. A new formulation of selegiline dissolves instantly in the mouth, eliminating the first-pass effect, in the Inhibitors,research,lifescience,medical liver, so that therapeutic levels are reached at an eighth of the daily regular dose of selegiline. TMs reduces the concentrations of amphetamine, the unwanted metabolite of selegiline, which otherwise limits the maximal tolerated dose. Rasagiline, another MAOB inhibitor, is presently being

evaluated in clinical trials in the USA, Europe, and Israel. Inhibitors,research,lifescience,medical At. doses up to 2 mg/day, rasagiline shows good safety and tolerability.32 It has a similar pharmacological profile to selegiline, but without amphetamine as a metabolite. Amantadine has been used for the treatment of PD for several decades, even though its mechanism of action is obscure.35,36 Recently, it was shown to function by inhibiting N-methyl-D-aspartate (NMDA) receptors and found to be effective in reducing dyskinesias.37,38 Mcmantinc, a related also drug, also functions as a neuroprotective agent through this mechanism. Memantine is used in Germany as an antispastic drug and also to treat dementia, and is presently being evaluated for its effectiveness in PD, on the basis of preliminary results.39 The antiglutamatergic effect of amantadine and memantine also suggests a neuroprotective action, and memantine is now actively promoted in AD. Treatment of nonparkinsonian symptoms Although motor symptoms are the cardinal features of PD, most if not all patients will also manifest symptoms in other spheres. Depression is particularly common and frequently antedates the motor disorder.