Norepinephrine deficiency in Parkinson's disease: The case for noradrenergic enhancement
Alberto J. Espay MD, MSc
Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA
Search for more papers by this authorPeter A. LeWitt MD, MMedSc
Departments of Neurology, Henry Ford Hospital and Wayne State University School of Medicine, West Bloomfield, Michigan, USA
Search for more papers by this authorCorresponding Author
Horacio Kaufmann MD
Dysautonomia Center, Department of Neurology, NYU School of Medicine, New York, New York, USA
Correspondence to: Dr. Horacio Kaufmann, Dysautonomia Center, NYU School of Medicine, 530 First Avenue, 9Q, New York, NY 10016, USA; [email protected]Search for more papers by this authorAlberto J. Espay MD, MSc
Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA
Search for more papers by this authorPeter A. LeWitt MD, MMedSc
Departments of Neurology, Henry Ford Hospital and Wayne State University School of Medicine, West Bloomfield, Michigan, USA
Search for more papers by this authorCorresponding Author
Horacio Kaufmann MD
Dysautonomia Center, Department of Neurology, NYU School of Medicine, New York, New York, USA
Correspondence to: Dr. Horacio Kaufmann, Dysautonomia Center, NYU School of Medicine, 530 First Avenue, 9Q, New York, NY 10016, USA; [email protected]Search for more papers by this authorRelevant conflicts of interest/financial disclosures: The authors participated as consultants/scientific advisory board members for Chelsea, and were investigators in the Chelsea-sponsored clinical trials leading to the approval of droxidopa for the treatment of orthostatic hypotension.
Full financial disclosures and author roles may be found in the online version of this article.
ABSTRACT
The dramatic response of most motor and some nonmotor symptoms to dopaminergic therapies has contributed to maintaining the long-established identity of Parkinson's disease (PD) as primarily a nigrostriatal dopamine (DA) deficiency syndrome. However, DA neurotransmission may be neither the first nor the major neurotransmitter casualty in the neurodegenerative sequence of PD. Growing evidence supports earlier norepinephrine (NE) deficiency resulting from selective degeneration of neurons of the locus coeruleus and sympathetic ganglia. Dopaminergic replacement therapy therefore would seem to neglect some of the motor, behavioral, cognitive, and autonomic impairments that are directly or indirectly associated with the marked deficiency of NE in the brain and elsewhere. Therapeutic strategies to enhance NE neurotransmission have undergone only limited pharmacological testing. Currently, these approaches include selective NE reuptake inhibition, presynaptic α2-adrenergic receptor blockade, and an NE prodrug, the artificial amino acid L-threo-3,4-dihydroxyphenylserine. In addition to reducing the consequences of deficient noradrenergic signaling, enhancement strate gies have the potential for augmenting the effects of dopaminergic therapies in PD. Furthermore, early recognition of the various clinical manifestations associated with NE deficiency, which may precede development of motor symptoms, could provide a window of opportunity for neuroprotective interventions. © 2014 International Parkinson and Movement Disorder Society
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