Is there room for non-dopaminergic treatment in Parkinson disease?
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- Lieberman, A. & Krishnamurthi, N. J Neural Transm (2013) 120: 347. doi:10.1007/s00702-012-0946-0
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Although levodopa and dopaminergic drugs remain the mainstay of therapy for the motor symptoms of Parkinson disease (PD), they fail to address many of the non-motor symptoms of PD including orthostatic hypotension, freezing of gait (FOG) and difficulty with balance, drug-induced paranoia and hallucinations, and drug-induced dyskinesias. Droxidopa, a drug that increases norepinephrine, treats orthostatic hypotension, cholinomimetic drugs sometimes help with FOG and difficulty with balance, pimavanserin, a drug that blocks serotonin receptors, treats paranoia and hallucinations, and anti-glutaminergic drugs treat dyskinesias. Thus, there are ample opportunities for non-dopaminergic drugs in PD.
KeywordsParkinson diseaseLevodopaNon-dopaminergic drugsNon-motor symptoms
The introduction of levodopa in 1967 revolutionized the treatment of Parkinson Disease (PD). Levodopa combined with carbidopa to block levodopa’s metabolism in the periphery and drive more levodopa into the brain, or levodopa/carbidopa combined with entacapone or tolcapone to drive even more levodopa into the brain, or levodopa/carbidopa combined with rasagiline or selegiline to prolong the duration of the dopamine formed from levodopa, or the use of synthetic dopamine analogues, dopamine agonists, are variations on the theme of levodopa as a treatment for PD. While levodopa and its iterations (decarboxylase inhibitors, catechol-O-methyl transferase inhibitors, monoamine B-oxidase inhibitors, and dopamine agonists) have improved PD, it has not cured PD, and many unmet needs remain. These include intractable tremor, balance difficulty, falls, freezing of gait (FOG), cognitive impairment, memory loss, levodopa-induced dyskinesias and dystonias, levodopa induced psychoses, hallucinations, agitation, delusions and paranoia, autonomic nervous system insufficiency, especially orthostatic hypotension, apathy, akinesia and sleep disturbances. Although it is simplistic to think that alterations in a single or in several neurotransmitters will restore damaged or impaired circuits nonetheless alterations in cholinergic, serotonergic, glutaminergic, and noradrenergic activity have, indeed, met or shown promise of meeting many of the unmet needs.
Prior to the introduction of levodopa, central acting anti-cholinergic drugs were a mainstay of treatment relieving, in part, tremor and PD-induced dystonia. The drugs are thought to block “excessive” cholinergic activity in the putamen. Since the introduction of levodopa, cholinomimetic drugs that block the breakdown of acetylcholine in the cortex, have gained a real but limited role in improving cognition and memory loss. And, recently, cholinomimetic drugs, have gained another real but limited role in improving balance, FOG, and decreasing falls (Bohnen et al. 2009; McFarland et al. 2011; Yarnall et al. 2011; Chung et al. 2010). Presumably these effects are achieved by increasing cholinomimetic transmission in the pedunculopontine nucleus (PPN), a cholinergic nucleus in the brain-stem.
Serotonin, 5-hydroxytryptamine (5-HT), like dopamine, is a major neurotransmitter in the brain. Drugs that block the re-uptake of serotonin have played a prominent role in the treatment of anxiety and depression in PD. In addition to a role in emotion, serotonin has a role in behavior. Serotonin receptors, 5-HT3 and 5-HT2A receptors in cortical and subcortical regions are involved in behavior. Lysergic acid diethylamide, a major hallucinogen is an agonist at 5-HT2A receptors. Ondansetron, a 5-HT3 antagonist, an anti-emetic, has a small role in countering hallucinations associated with levodopa (Zoldan et al. 1996). Recently, pimavanserin, a specific 5-HT2A antagonist, has shown promise in countering the delusions, the hallucinations, and the paranoia associated with levodopa (Meltzer et al. 2010).
Glutamate is the major excitatory neurotransmitter in the brain. Excess glutamate or enhanced glutamate sensitivity has been implicated in the involuntary movements, chorea and dystonia, of Huntington Disease. And excess glutamate or enhanced glutamate sensitivity may be implicated in levodopa-induced dyskinesias and dystonias. Amantadine, an antagonist at fast-acting NMDA glutamate receptors and talampanel, an antagonist at fast-acting AMPA glutamate receptors, have demonstrated a limited ability to reduce levodopa induced dyskinesias and dystonias. Recently, a drug that is an allosteric modulator of slow-acting, metabotropic glutamate 5-receptors has shown promise in reducing levodopa-induced dyskinesias and dystonias in rodents and primates, and in, a limited trial, in humans with PD (Sheffler et al. 2011; Dror et al. 2011; Ouattara et al. 2010; Rylander et al. 2010).
Norepinephrine (NE), like dopamine, acetylcholine, serotonin and glutamate is a major neurotransmitter in the brain. In PD, the loss of NE neurons in the locus ceruleus, the main NE nucleus in the brain, is greater and occurs earlier than the loss of dopaminergic neurons in the substantia nigra. The locus ceruleus has major projections to the subcortex, cortex and to the brainstem. The loss of NE neurons and NE tone has been implicated in the apathy, akinesia, and sleep disturbances in PD. The loss of NE neurons and NE tone has also been implicated in the autonomic nervous system (ANS) insufficiency of PD, especially in orthostatic hypotension and supine hypertension. NE re-uptake inhibitors have played a prominent but limited role in the depression of PD, especially the apathetic depression. Dihydroxyphenylserine (DOPS), Droxidopa, Northera-TM is an artificial amino acid and is a precursor of NE. As l-dopa is converted by dopa-decarboxylase into dopamine, droxidopa is converted by dopa-decarboxylase into NE. Inhibitors of dopa-decarboxylase such as carbidopa and benserazide, do not cross the blood-brain barrier, but blocks the conversion of droxidopa to NE in the periphery (Kaufmann 2006, 2008), resulting in an increased entry of NE into the central nervous system (CNS). The increased entry of NE into the CNS may be responsible for the reported improvement in ANS insufficiency, apathy, and akinesia (Birkmayer et al. 1983; Kaufmann 2008; Mathias 2008; Ogawa et al. 1985).
No one denies the benefits of levodopa and dopaminergic therapy in PD; such benefits do not, however, exclude a role for other neurotransmitters including acetyl choline, serotonin, glutamate and norepinephrine.