Compensatory mechanisms in degenerative neurologic diseases. Insights from parkinsonism
D. B. Calne and M. J. Zigmond
Department of Medicine, University of British Columbia, University Hospital, Vancouver, Canada.
In animal models of parkinsonism, the ability to lose a substantial
proportion of dopaminergic neurons without behavioral deficits does not
derive from other systems taking over function of the dopaminergic pathway.
The surviving nigrostriatal projection increases both the rate of synthesis
and the release of dopamine, as compensatory adjustments. This capacity
allows at least a fivefold rise in dopamine delivery per neuron, and this
enhancement is potentiated further by receptor up-regulation. Decreased
reuptake, due to loss of nerve endings, may also lead to augmented
occupancy of dopamine receptors, and so constitute yet another compensatory
mechanism. In humans, positron emission tomography has revealed subclinical
impairment of the dopaminergic nigrostriatal pathway in subjects at risk
for parkinsonism caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and
Lytico-Bodig (the amyotrophic lateral sclerosis-parkinsonism dementia
complex of Guam). However, the separation of patients with clinically overt
idiopathic parkinsonism from controls is less marked in vivo (by positron
emission tomography) than in postmortem analysis (by neurochemical assay).
This disparity may be attributable to the reduction in the number of
nigrostriatal nerve endings, leading, in vivo, to a relative increase of
extracellular dopamine because active reuptake into the nerve endings is an
important mechanism for removing dopamine from the synaptic cleft. In
contrast, in a postmortem setting, dopamine that is not sequestered in the
storage vesicles of nerve endings is readily available for biochemical
degradation during the interval between death and brain analysis. Finally,
it is also possible that differences may derive, in part, from dissimilar
kinetic systems for handling exogenous and endogenous levodopa.
