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Possible Treatment of Parkinson's Disease with Intrathecal Medication in the MPTP Model
Author(s) -
HOOD TERRY W.,
DOMINO EDWARD F.,
GREENBERG HARRY S.
Publication year - 1988
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1988.tb31828.x
Subject(s) - neurosurgery , neurology , medicine , medical school , section (typography) , psychiatry , medical education , advertising , business
Parkinson’s disease is a neurological syndrome secondary to diminished levels of dopamine in the corpus striatum of the cerebrum.’ This disease is manifested by the classic clinical constellation of bradykinesia, rigidity, tremor and postural changes. The treatment of Parkinson’s disease was significantly advanced with the introduction of levodopa, a metabolic precursor of dopamine. However, after five years of levodopa therapy, 50% of patients develop fluctuating motor responses, the “on-off” phenomenon, to drug treatment which can be disabling and in many cases poorly controlled by conservative therapy.2 These fluctuations range from excessive involuntary dyskinetic movements to akinesia. Since plasma levels of levodopa are high during periods of mobility with dyskinesias and low during episodes of immobility, a constant drug infusion may provide stable plasma drug levels and control this clinical problem.’ Several investigators have used a constant intravenous infusion of levodopa to control the “on-off” phenomenon in Parkinson’s disease patient^.^ Recently continuous subcutaneous infusion of the dopaminergic agonist lisuride has been reported to control fluctuations of motor performance in clinical trials.’ In an animal model of Parkinson’s disease the direct infusion into the corpus striatum of dopamine has been reported to reduce apomorphine induced rotation in rats with unilateral substantia nigra lesions from 6-hydro~ydopamine.~ Initially the intraventricular application of dopamine was attempted in our laboratory to reverse the symptoms of bradykinesia in the 1-methyl-Cphenyl1,2,5,6 tetrahydropyridine (MPTP) model of Parkinson’s disease in the rhesus monkey. MPTP is a byproduct of improper meperidine synthesis and causes a permanent parkinsonism syndrome in intravenous drug abusers.’ Subsequently this compound has been used extensively in primates to effect the best animal model of Parkinson’s disease, both symptomatically and pathologically, developed to date.* However, the use of dopamine caused many undesirable behavioral side effects which caused us to look for a better agent. Since levodopa is relatively insoluble, we decided to look at other possible precursors of dopamine. For the past two years our laboratory has concentrated on the intraventricular administration of levodopa methyl ester (LDME) to reverse the symptoms of bradykinesia induced by MPTP. Additionally, we have investigated the regional advantage of the intraventricular route over intravenous administration. This report will detail our preliminary experience with this model and discuss the potential treatment advantages of intraventricular perfusion in the treatment of “on-off” phenomenon of Parkinson’s disease patients.