|Ph.D Student||Sader-Mazbar Ola|
|Subject||The Role of Monoamine Oxidase Subtypes in Striatal|
Metabolism of Dopamine Produced from L-DOPA in the
|Department||Department of Medicine||Supervisor||Professor Emeritus John Finberg|
|Full Thesis text|
The MAO-B inhibitor rasagiline is an effective adjunct treatment to L-DOPA in Parkinson's disease (PD). Chronic inhibition of MAO-B produces only a minor increase in striatal dopamine (DA) extracellular levels in intact rats, by contrast to the large increase following selective inhibition of MAO-A. However the precise contribution of each MAO subtype to striatal DA metabolism in the parkinsonian brain is still unclear. Since in advanced PD there is pronounced degeneration of serotonergic (5-HT) as well as dopaminergic neurons, depletion of both 5-HT and DA inputs in the rat striatum may approximate more closely the human parkinsonian striatum.
This is the first study to investigate the effect of chronic MAO-A and -B inhibition on the metabolism of L-DOPA-derived DA in a parkinsonian rat model. Two models were compared: the 6-hydroxydopamine lesion model (single-lesion) and the double-lesion model in which an additional serotonergic toxin (5,7-dihydroxytryptamine) was injected intracerebroventricularly. The double lesion procedure caused a marked gliosis in the striatum, as seen also in parkinsonian brains. MAO-B activity in the double-lesion striatum was significantly increased, while no change was detected in MAO-A activity in either lesion model. These results indicate that most of MAO-A activity is not contained in dopaminergic or serotonergic axon terminals. In support of this biochemical finding, a series of immunofluorescence studies showed MAO-A localization in medium spiny neurons (MSNs).
By collecting striatal microdialysates following a single L-DOPA administration, we showed that chronic rasagiline pretreatment increased maximal microdialysate DA levels in the double lesion more than in the single lesion group and significantly decreased DA oxidative metabolism only in double lesioned rats. On the other hand, clorgyline pretreatment elevated L-DOPA-induced DA levels in both models over 10 fold, with a large decrease in metabolite levels. In double-lesioned rats which received daily injections of L-DOPA for 10 days, chronic rasagiline treatment increased the duration of rotational response to L-DOPA, but did not cause an increase in dyskinetic movements.
In conclusion, the compartmentalization of MAO results in MAO-A playing a dominant role in the metabolism of DA in the rat brain. When both DA and 5-HT terminals are eliminated as in the case of advanced PD, MAO-B enzyme, apparently in the astrocytes, plays a larger part in DA metabolism but MAO-A (in MSNs) remains the major enzyme.
These results have clinical relevance, since they explain the efficacy of MAO-B inhibition in advanced stages of PD.