L-threo-dihydroxyphenylserine corrects neurochemical abnormalities in a Menkes disease mouse model.
Abstract | OBJECTIVE: METHODS: At 8, 10, and 12 days of age, wild-type and mo-br mice received intraperitoneal injections of 200μg/g body weight of L-DOPS, or mock solution. Five hours after the final injection, the mice were euthanized, and brains were removed. We measured catecholamine metabolites affected by DBH via high-performance liquid chromatography with electrochemical detection, and assessed brain histopathology. RESULTS: Compared to mock-treated controls, mo-br mice that received intraperitoneal L-DOPS showed significant increases in brain norepinephrine (p < 0.001) and its deaminated metabolite, dihydroxyphenylglycol (p < 0.05). The ratio of a non-beta-hydroxylated metabolite in the catecholamine biosynthetic pathway, dihydroxyphenylacetic acid, to the beta-hydroxylated metabolite, dihydroxyphenylglycol, improved equivalently to results obtained previously with brain-directed ATP7A gene therapy (p < 0.01). However, L-DOPS treatment did not arrest global brain pathology or improve somatic growth, as gene therapy had. INTERPRETATION: We conclude that (1) L-DOPS crosses the blood-brain barrier in mo-br mice and corrects brain neurochemical abnormalities, (2) norepinephrine deficiency is not the cause of neurodegeneration in mo-br mice, and (3) L-DOPS treatment may ameliorate noradrenergic hypofunction in Menkes disease.
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Authors | Anthony Donsante, Patricia Sullivan, David S Goldstein, Lauren R Brinster, Stephen G Kaler |
Journal | Annals of neurology
(Ann Neurol)
Vol. 73
Issue 2
Pg. 259-65
(Feb 2013)
ISSN: 1531-8249 [Electronic] United States |
PMID | 23224983
(Publication Type: Journal Article, Research Support, N.I.H., Intramural)
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Copyright | Copyright © 2012 American Neurological Association. |
Chemical References |
- Antiparkinson Agents
- Atp7a protein, mouse
- Cation Transport Proteins
- 3,4-Dihydroxyphenylacetic Acid
- Copper
- Dopamine beta-Hydroxylase
- Adenosine Triphosphatases
- Copper-Transporting ATPases
- Droxidopa
- Dopamine
- Norepinephrine
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Topics |
- 3,4-Dihydroxyphenylacetic Acid
(metabolism)
- Adenosine Triphosphatases
(genetics, metabolism)
- Animals
- Antiparkinson Agents
(pharmacokinetics, pharmacology)
- Blood-Brain Barrier
(metabolism)
- Brain
(drug effects, metabolism, pathology)
- Brain Chemistry
(drug effects, physiology)
- Cation Transport Proteins
(genetics, metabolism)
- Copper
(metabolism)
- Copper-Transporting ATPases
- Disease Models, Animal
- Dopamine
(biosynthesis, metabolism)
- Dopamine beta-Hydroxylase
(metabolism)
- Droxidopa
(pharmacokinetics, pharmacology)
- Female
- Male
- Menkes Kinky Hair Syndrome
(drug therapy, metabolism, pathology)
- Mice
- Mice, Inbred C57BL
- Mice, Neurologic Mutants
- Nerve Degeneration
(drug therapy, metabolism, pathology)
- Norepinephrine
(biosynthesis, deficiency, metabolism)
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