The most appropriate time for the initiation of dopaminergic symptomatic
therapy in
Parkinson's disease remains debatable. It has been suggested that early correction of basal ganglia pathophysiological abnormalities may have long-term beneficial effects. To test this hypothesis, we investigated the early and delayed actions of
L-dopa and
pramipexole, using a delayed-start protocol of treatment. The effects of early and delayed administration of these drugs on motor response, development of
dyskinesias, neurogenesis and molecular markers in basal ganglia were studied in rats with a unilateral and partial 6-hydroxydopamine-induced nigrostriatal lesion. Ten days after lesioning, rats received treatment with: a)
L-dopa methyl ester (25mg/kg with 6.25mg/kg of
benserazide, i.p., twice a day); b)
pramipexole (0.5mg/kg, sc, twice a day) or c) saline for 4weeks. Four weeks
after treatment initiation, rats from the saline group were distributed in three groups that then received the following treatments: d)
L-dopa, e)
pramipexole or f) saline, for 4weeks more. Three animals in each treatment arm received
5-bromo-2-deoxyuridine injections (200mg/kg) 3days before starting treatment. When compared with delayed-start
L-dopa, early-start
L-dopa treatment induced a lower rotational response (p<0.01), an improvement in limb akinesia (p<0.05), a lower level of
dyskinesia (p<0.01) and a normalization of lesion-induced molecular changes in basal ganglia. When compared with delayed-start
pramipexole, early-start
pramipexole induced a higher rotational response (p<0.01), but did not improve limb akinesia, induce
dyskinesia nor normalize lesion-induced molecular changes. Neither significant modifications of striatal
dopamine D1-D3 receptor heteromerization nor subventricular zone neurogenesis was found after any
L-dopa or
pramipexole treatments. Our data support a possible restoration of basal ganglia physiological mechanisms by early-start
L-dopa therapy.