Catechol- O-Methyltransferase Inhibitors in Preclinical Models as Adjuncts of l-Dopa Treatment

Abstract

Long-term L-dopa treatment is limited by the development of motor complications, such as motor fluctuations and dyskinesias. These motor complications are postulated to arise from a non-physiological intermittent or pulsatile stimulation of striatal dopamine (DA) receptors that normally receive tonic stimulation. The concept of continuous dopaminergic stimulation (CDS) proposes that therapies providing more continuous stimulation of brain dopaminergic receptors are associated with a reduced risk of motor complications. One approach to the CDS is to prolong the half-life of L-dopa inhibiting its degradation by means of the administration of catechol-O-methyltransferase (COMT) inhibitors, as entacapone, a potent, selective, and reversible peripherally acting inhibitor. Animal models of L-dopa-induced motor complications can be obtained in monkeys and rats with severe damage in the nigrostriatal dopaminergic pathway induced by 1-methyl-4-phenyl-1-2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA), respectively. The effect of entacapone on L-dopa-induced motor response and complications has been widely investigated in preclinical models. The administration of entacapone is able to potentiate the long-duration response (LDR) to L-dopa and to attenuate L-dopa-induced motor fluctuations and dyskinesias in these preclinical models. These effects, however, are not related with a normalization of the molecular changes induced by L-dopa in the basal ganglia nuclei.