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Norepinephrine Deficiency in Parkinson Disease
124
THEME E Neurology
2. Adams JR, van Netten H, Schulzer M, Mak E, McKenzie J, Strongosky A, et al. PET in LRRK2 mutations: comparison to sporadic Parkinson’s disease and evidence for presymptomatic compensation. Brain : a journal of neurology. 2005; 128: 2777 85. 3. Sossi V, de la Fuente-Fernandez R, Nandhagopal R, Schulzer M, McKenzie J, Ruth TJ, et al. Dopamine turnover increases in asymptomatic LRRK2 mutations carriers. Movement disorders : official journal of the Movement Disorder Society. 2010; 25(16): 2717 23.
Norepinephrine Deficiency in Parkinson Disease Horacio Kaufmann New York University School of Medicine, USA
Parkinson disease is defined biochemically as a deficiency of dopamine in the striatum due to degeneration of dopamine neurons in the pars compacta of the substantia nigra. However, in addition to the reduction of dopamine levels there is extensive pathological, biochemical, and recent imaging evidence indicating reduced levels of norepinephrine both in the brain and in the peripheral autonomic nervous system of patients with Parkinson disease. Interestingly, the norepinephrine deficiency was recognized before the finding of the dopamine deficiency in the brain of patients with Parkinson disease. Experimental evidence indicates that loss of norepinephrine is crucial for both the onset and progression of Parkinson disease. Indeed, data suggest that degeneration of norepinephrine containing neurons in the locus ceruleus in the pontine tegmentum precede degeneration of dopamine neurons in the substantia nigra and that deficiency of norepinephrine hastens the subsequent degeneration of dopamine containing neurons. Moreover, indirect but compelling evidence suggests that norepinephrine might have a neuroprotective effect in the parkinsonian brain. Clinical signs and symptoms attributable to norepinephrine deficiency in patients with Parkinson disease include depression, cognitive impairment and orthostatic hypotension. Pharmacological strategies to reverse norepinephrine depletion might provide symptomatic and potential neuroprotective benefits in patients with Parkinson disease. Pharmacological strategies that can ameliorate or reverse norepinephrine deficiency include norepinephrine transporter inhibitors to increase norepinephrine in the synaptic cleft; presynaptic α-2 adrenergic blockade to increase norepinephrine release in remaining noradrenergic neurons; and the artificial amino acid L-dihydroxyphenylserine (L-DOPS, Droxidopa) that is converted to norepinephrine by decarboxylation. Recently completed large phase III clinical trials of droxidopa showed significant improvement of orthostatic hypotension in patients with Parkinson disease and other neurodegenerative disorders.
THEME E Neurology
2. Adams JR, van Netten H, Schulzer M, Mak E, McKenzie J, Strongosky A, et al. PET in LRRK2 mutations: comparison to sporadic Parkinson’s disease and evidence for presymptomatic compensation. Brain : a journal of neurology. 2005; 128: 2777 85. 3. Sossi V, de la Fuente-Fernandez R, Nandhagopal R, Schulzer M, McKenzie J, Ruth TJ, et al. Dopamine turnover increases in asymptomatic LRRK2 mutations carriers. Movement disorders : official journal of the Movement Disorder Society. 2010; 25(16): 2717 23.
Norepinephrine Deficiency in Parkinson Disease Horacio Kaufmann New York University School of Medicine, USA
Parkinson disease is defined biochemically as a deficiency of dopamine in the striatum due to degeneration of dopamine neurons in the pars compacta of the substantia nigra. However, in addition to the reduction of dopamine levels there is extensive pathological, biochemical, and recent imaging evidence indicating reduced levels of norepinephrine both in the brain and in the peripheral autonomic nervous system of patients with Parkinson disease. Interestingly, the norepinephrine deficiency was recognized before the finding of the dopamine deficiency in the brain of patients with Parkinson disease. Experimental evidence indicates that loss of norepinephrine is crucial for both the onset and progression of Parkinson disease. Indeed, data suggest that degeneration of norepinephrine containing neurons in the locus ceruleus in the pontine tegmentum precede degeneration of dopamine neurons in the substantia nigra and that deficiency of norepinephrine hastens the subsequent degeneration of dopamine containing neurons. Moreover, indirect but compelling evidence suggests that norepinephrine might have a neuroprotective effect in the parkinsonian brain. Clinical signs and symptoms attributable to norepinephrine deficiency in patients with Parkinson disease include depression, cognitive impairment and orthostatic hypotension. Pharmacological strategies to reverse norepinephrine depletion might provide symptomatic and potential neuroprotective benefits in patients with Parkinson disease. Pharmacological strategies that can ameliorate or reverse norepinephrine deficiency include norepinephrine transporter inhibitors to increase norepinephrine in the synaptic cleft; presynaptic α-2 adrenergic blockade to increase norepinephrine release in remaining noradrenergic neurons; and the artificial amino acid L-dihydroxyphenylserine (L-DOPS, Droxidopa) that is converted to norepinephrine by decarboxylation. Recently completed large phase III clinical trials of droxidopa showed significant improvement of orthostatic hypotension in patients with Parkinson disease and other neurodegenerative disorders.