The origin of motor fluctuations in Parkinson’s disease

Abstract

The severity of dopamine depletion and the consequent pathophysiologic changes that occur in basal ganglia circuits determine the severity of parkinsonian signs. Restoring the dopamine deficit or the downstream physiologic abnormalities improves Parkinson's Disease (PD) main motor features and as a result, attenuates the short-duration response (SDR). Therefore, both the magnitude and duration of the motor response are a function of the degree of motor severity, which is primarily governed by the loss of tonic dopaminergic activity and disruption of basal ganglia homeostatic mechanisms among which the STN-GPe/GPi circuits play a fundamental role. As neurodegeneration advances, standard levodopa administration give rises to wider oscillations in striatal dopamine availability and "pulsatile" stimulation of striatal dopamine receptors becomes predominant. This induces molecular and physiologic changes that further accentuate and aggravate the SDR that sustains motor fluctuations. Treatments capable of providing and restoring more tonic and physiologic dopaminergic stimulation may avoid many of these abnormalities and lead to better clinical outcomes.

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

“…These pathways are considered to have competing effects on striatal outputs (DeLong, 1990;Obeso et al, 2004). In fact, both the cataleptic and the antipsychotic-like effects of haloperidol, a D 2 -receptor antagonist, were canceled by co-administration of the D 1 agonist SKF82958 (P ⩽ 0.05; Figure 2a).…”

“…These results suggest that off-rates from PDE10A characterize the pharmacological profile of PDE10A inhibitors. PDE10A inhibitors are known to activate both direct and indirect pathways (Grauer et al, 2009), which are thought to have competing effects on striatal outputs (Figure 2) (DeLong, 1990;Obeso et al, 2004). Although TAK-063 and MP-10 activated the indirect pathway to a similar extent, at ⩾ 85% occupancy, MP-10 induced greater activation of the direct pathway than did TAK-063 (Figure 2).…”

Pharmacological validation of a mouse model of l-DOPA-induced dyskinesia

“…Although the 6-OHDA injection is made in the striatum, the ensuing DA-denervation extends also to extrastriatal structures that are believed to play an important role in the pathophysiology of dyskinesia (Obeso et al, 2004). Indeed, rodents do not exhibit an absolute segregation between striatal and extrastriatal DA projections within the basal ganglia motor circuitry.…”

Revisión crítica de la estimulación subtalámica en la enfermedad de Parkinson

“…La estimulación cerebral profunda tanto en el NST como en el GPi mejora los signos capitales motores de la condición parkinsoniana y reduce las complicaciones inducidas por la medicación 7,14,42,49,65 . Ambas estructuras anatómicas de los ganglios basales, NST y GPi, están hiperactivas en la EP y su inhibición o bloqueo con la estimulación a alta frecuencia induce un claro beneficio motor.…”

“…Este factor es capital sobre todo en los pacientes que presentan problemas motores (disquinesias) y no motores (complicaciones de tipo psiquiátrico) relacionados con la medicación a la hora de elegir una diana sobre la otra 24,60 . En el artículo se revisan comparativamente los resultados de la estimulación del NST y del GPi que han sido publicados por el mismo grupo de trabajo para una mejor evaluación y comprensión de los resultados clínicos, así como valorar los pros y contras entre ambas dianas quirúr-gicas 3,34,35,38,39,42,50 .…”