Somatic delivery of catecholamines in the striatum attenuate parkinsonian symptoms and widen the therapeutic window of oral sinemet in rats.
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.
Lindner
M D
MD
Cyto Therapeutics Inc., Providence, Rhode Island 02906, USA. mlindner@cyto.com
Plone
M A
MA
Mullins
T D
TD
Winn
S R
SR
Chandonait
S E
SE
Stott
J A
JA
Blaney
T J
TJ
Sherman
S S
SS
Emerich
D F
DF
D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001058:Apomorphine; D001522:Behavior, Animal / Q000187:drug effects; D002230:Carbidopa / Q000494:pharmacology*; D017690:Cell Transplantation / Q000379:methods; D004195:Disease Models, Animal; D004298:Dopamine / Q000494:pharmacology*; D004338:Drug Combinations; D004357:Drug Synergism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D009069:Movement Disorders / Q000188:drug therapy / Q000209:etiology; D017072:Neostriatum / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells / Q000637:transplantation*; D010302:Parkinson Disease, Secondary / Q000150:complications / Q000188:drug therapy* / Q000601:surgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D012399:Rotation
D000978:Antiparkinson Agents; D004338:Drug Combinations; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D002230:Carbidopa; D001058:Apomorphine; D004298:Dopamine