Guidelines for clinical
transplantation studies for
Parkinson's disease emphasize that transplants should be considered as an adjunct to systemic
L-DOPA, yet few preclinical studies have specifically assessed the potential of transplants as an adjunct to the clinical gold standard treatment. The objectives of the present study were to determine if encapsulated PC12 cells implanted in rats with severe unilateral
dopamine depletions: (i) have a direct
therapeutic effect on measures of parkinsonian symptoms; and/or (ii) increase the therapeutic window of oral
sinemet in this model. Rats with severe unilateral
dopamine depletions received striatal implants of encapsulated PC12 cells producing
dopamine and
L-DOPA. These rats were tested on a battery of behavioral measures of parkinsonian symptoms, at a range of doses of oral
sinemet (0, 12, 24, and 36 mg/kg). Stereotypies/
dyskinesias were also quantified after high doses of oral
sinemet (36 and 50 mg/kg). The results confirm that parkinsonian symptoms can be quantified in rats with severe
dopamine depletions, and the validity and clinical relevance of these measures are supported by the fact that the clinical gold standard treatment, oral
sinemet, attenuates these parkinsonian symptoms. Somatic delivery of
dopamine and
L-DOPA, directly to the
dopamine-depleted striatum, also attenuates parkinsonian symptoms. In fact, the magnitude of the
therapeutic effect produced by continuous, site-specific, somatic delivery of
dopamine and
L-DOPA was larger than the effect produced by acute, systemic, oral
sinemet. The beneficial effects of oral
sinemet and striatal implants of
catecholamine-producing devices were additive, but there were no adverse effects related to striatal
catecholamine-producing devices, and these devices did not increase the adverse effects related to oral
sinemet. Therefore, striatal implants of
catecholamine-producing devices have direct
therapeutic effects which are fairly robust, and they widen the therapeutic window of oral
sinemet.