Norepinephrine: the next therapeutics frontier for Parkinson's disease

Successful treatment of Parkinson's disease (PD) with neurotransmitter replacement has placed dopamine "center stage" for understanding the pathophysiology of this disorder. The seminal research of Arvid Carlsson and other investigators in the 1950s elevated dopamine's role from that of a mere metabolic intermediate to the "star of the show" in PD and other brain disorders. Neglected by the attention given to dopamine, however, was the significance of another important CNS neurotransmitter, norepinephrine (NE). In nerve terminals containing the rate-limiting enzyme dopamine-β-hydroxylase, NE is formed in the next step in catecholamine synthesis beyond dopamine. Like dopamine, NE is involved in a wide range of cognitive, motor, and autonomic functions of the brain. Beyond its roles as a neurotransmitter, the actions of NE are involved in one or more mechanisms linked to neurodegeneration in the PD brain [1]. There has been only limited pharmacological experience exploring the clinical significance of modulating NE neurotransmission. This review will cover the highlights of this therapeutic research experience.In PD, NE synthesis is greatly decreased throughout the brain. In several regions, NE content is reduced to less than half of its usual tissue concentration [2]. CSF concentration of dopamine-β-hydroxylase (the rate limiting enzyme for NE synthesis) is also diminished [3]. The loss of NErgic innervation is attributable to the prominent pathology found in the locus coeruleus (LC) [4]. From these paired brainstem structures, ascending projections arise that are distributed widely to the cerebral cortex and deeper structures [5]. Long before the significance of decreased dopaminergic innervation was understood as a key feature of PD, neuropathologists recognized that changes in the LC were as extensive as those affecting neurons in the substantia nigra pars compacta (SNpc) [6]. Beyond the dropout of NErgic neurons in the LC, the remaining pigmented neurons tend to