(1) Decreased vesicular uptake: A common theme in catecholaminergic neurodegeneration: Vesicular sequestration limits the buildup of toxic products of enzymatic and spontaneous oxidation of catecholamines. A vesicular storage defect therefore could play a pathogenic role in the death of catecholaminergic neurons in a variety of neurodegenerative diseases. We retrospectively analyzed data from 20 conditions with decreased or intact catecholaminergic innervation, involving different etiologies, pathogenetic mechanisms, and lesion locations. All conditions involving parkinsonism had accelerated loss of putamen 18F-DOPA-derived radioactivity; all conditions involving cardiac sympathetic denervation had accelerated loss of myocardial 18F-dopamine-derived radioactivity; and all conditions involving localized loss of catecholaminergic innervation had evidence for decreased vesicular storage specifically in the denervated regions. Thus, across neurodegenerative diseases, loss of catecholaminergic neurons seems to be associated with decreased vesicular storage in the residual neurons (Goldstein DS, Holmes C, Mash D, Sidransky E, Stefani A, Kopin IJ, Sharabi Y. Deficient vesicular storage: A common theme in catecholaminergic neurodegeneration. Parkinsonism Relat Disord 2015;21:1013-1022). (2) MAO inhibition increases Cys-DA levels while decreasing DOPAL levels in catecholamine-producing cells: We have found that at concentrations that effectively decrease endogenous DOPAL production, MAO inhibitors secondarily increase spontaneous oxidation of dopamine as indicated by Cys-DA levels in PC12 cells (Goldstein DS, Jinsmaa Y, Sullivan P, Kopin IJ, Sharabi Y. Comparison of monoamine oxidase inhibitors in decreasing endogenous production of the autotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) in PC12 cells. J Pharmacol Exp Ther 2016;356:484-493). (3) Hydroxytyrosol (DOPET) mitigates the increase in spontaneous oxidation of dopamine during MAO inhibition: Inhibiting MAO diverts the fate of cytoplasmic dopamine toward potentially harmful spontaneous oxidation products, indicated by increased Cys-DA levels. DOPET is an abundant anti-oxidant phenol in constituents of the Mediterranean diet. Whether DOPET alters enzymatic or spontaneous oxidation of DA has been unknown. Rat pheochromocytoma PC12 cells were incubated with DOPET alone or with the MAO-A inhibitor clorgyline or the MAO-B inhibitors rasagiline or selegiline. Co-incubation with DOPET prevented the increases in Cys-DA levels seen with all 3 MAO inhibitors. DOPET therefore inhibits both enzymatic and spontaneous oxidation of endogenous DA and mitigates the increase in spontaneous oxidation of DA during MAO inhibition (Goldstein DS, Jinsmaa Y, Sullivan P, Kopin IJ, Sharabi Y. 3,4-Dihydroxyphenylethanol (hydroxytyrosol) mitigates the increase in spontaneous oxidation of dopamine during monoamine oxidase inhibition in PC12 cells. Neurochem Res 2016;41:2173-2178). (4) Poor plasma bioavailability of hydroxytyrosol in ingested olives: We estimated the plasma bioavailability of dietary DOPET after olives ingestion. Healthy volunteers ate 10 Kalamata olives. Arm venous blood was sampled at baseline and at 15, 30, 45, 60, 120, 180, and 240 minutes. Ingesting olives increased plasma DOPET to 18.5 times baseline at 30 minutes; however, the plasma bioavailability of DOPET in olives was estimated to be only 0.17%. Because of poor plasma bioavailability, it seems unlikely that dietary intake of olives would exert anti-oxidant effects in catecholaminergic neurons (Goldstein et al., unpublished observations). (5) Combining MAO inhibition with an anti-oxidant to slow the disease process in PD: We are planning a new clinical trial to test whether combining an MAO inhibitor with an anti-oxidant slows the loss of catecholaminergic neurons in PD. We envision the protocol involving three studies. The first study is to assess whether MAO inhibition increases CSF Cys-DA levels (a measure of spontaneous oxidation of DA) while decreasing DOPAC levels (a measure of enzymatic oxidation of DA) and whether an anti-oxidant attenuates the increment in CSF Cys-DA without affecting the decrease in DOPAC levels in healthy volunteers. The second study is to determine whether combining an MAO inhibitor with an anti-oxidant slows the loss of cardiac sympathetic neurons in PD patients with partial cardiac sympathetic denervation. The third study is to examine whether combining an MAO inhibitor with an anti-oxidant prevents or increases the time to development of symptomatic disease in individuals who have multiple risk factors for PD and have positive biomarkers of loss of central dopaminergic or cardiac catecholamine neurons. Key dependent measures for these studies would be cardiac noradrenergic innervation assessed by 18F-DA PET scanning, putamen dopaminergic innervation assessed by 18F-DOPA scanning, CSF fluid levels of catechols including DOPAC and Cys-DA, and noradrenergic innervation and alpha-synuclein visualized by immunofluorescence confocal microscopy in skin biopsy specimens. Our laboratory is uniquely capable of carrying out these measurements.
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