According to the catecholaldehyde hypothesis, 3,4-dihydroxyphenylacetaldehyde (DOPAL), the immediate product of enzymatic oxidation of cytosolic dopamine by monoamine oxidase (MAO), challenges neuronal homeostasis throughout the lifespan of monoaminergic neurons and eventually contributes to induction of lethal positive feedback loops. The catecholaldehyde hypothesis predicts that MAO inhibition should attenuate or prevent autotoxic death of catecholamine neurons (Goldstein DS, Sharabi Y, Kopin IJ. Catecholamine autotoxicity: Implications for pharmacology and therapeutics of Parkinson disease and related disorders. Pharmacol Ther 2014;144:268-282). A disease modification clinical trial could test this prediction. By the time a PD patient evinces motor signs, the loss of striatal dopaminergic terminals is already advanced. On the other hand, cardiac sympathetic denervation in PD occurs independently of the movement disorder, progresses in a stereotypical dying back fashion involving the left ventricular free wall and apex first and anterobasal septum last, and once it begins progresses rapidly over a few years (Goldstein DS. Dysautonomia in Parkinson disease. Compr Physiol 2014;4:805-826). In PD patients identified as having partial cardiac denervation, trends over time in myocardial noradrenergic innervation as assessed by serial 18F-dopamine PET scanning could be the primary outcome measure in a proof of principle study testing the catecholaldehyde hypothesis. We have found preliminarily that at concentrations that effectively decrease endogenous DOPAL production MAO inhibitors secondarily increase DA auto-oxidation as indicated by cysteinyl-dopamine (Cys-DA) in PC12 cells. We have begun to explore antioxidant catechols that might mitigate this potentially deleterious downstream effect. Hydroxytyrosol (synonymous with 3,4-dihydroxyphenylethanol (DOPET)), a potent antioxidant catechol, is the main antioxidant in olives and is thought to be a determinant of the health benefits of the Mediterranean diet. In PC12 cells we have found preliminarily that combined treatment with the MAO inhibitor selegiline and DOPET results in a dramatic decrease in endogenous DOPAL production without a net change in Cys-DA production. Under an Amendment to NIH Clinical Protocol 06-N-0047, we have found preliminarily that eating olives results in large-magnitude increases in plasma levels of 3,4-dihydroxyphenylacetic acid (DOPAC) but only very small increases in levels of DOPET. DOPAC is not present in olives, and so we hypothesize that the high DOPAC levels probably reflect conversion of DOPET to DOPAC in the liver. We are considering a new protocol involving DOPET administration by intravenous infusion, as this would bypass hepatic metabolism, and measuring effects on CSF levels of catechols such as DOPET, DOPAC, and Cys-DA. Researchers have long suspected that levodopa therapy may accelerate catecholaminergic neurodegeneration in PD, but the data have been controversial and inconsistent. In pre-clinical studies, levodopa-related cytotoxicity occurs at least partly by enzymatic oxidation of cytoplasmic DA catalyzed by MAO. Theoretically, deuterated levodopa might offer a less toxic PD treatment, because of the deuterium isotope effect. Deuterium substitution at the alpha-carbon of levodopa stabilizes the carbon-nitrogen bond of the amine residue. As a result, deuterated DA derived from deuterated levodopa might be less susceptible to conversion to DOPAL. Courtney Holmes and David S. Goldstein are Co-Inventors on a pending patent for deuterated levodopa. We plan to compare non-deuterated levodopa with deuterated levodopa in terms of the extent of generation of DOPAL.

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Haddad, Marie Reine; Choi, Eun-Young; Zerfas, Patricia M et al. (2018) Cerebrospinal Fluid-Directed rAAV9-rsATP7A Plus Subcutaneous Copper Histidinate Advance Survival and Outcomes in a Menkes Disease Mouse Model. Mol Ther Methods Clin Dev 10:165-178
Goldstein, David S; Holmes, Courtney; Cherup, Jamie et al. (2018) Plasma Catechols After Eating Olives. Clin Transl Sci 11:32-37
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