Nicotine reduces levodopa‐induced dyskinesias in lesioned monkeys

Quik, Maryka; Cox, Heather; Parameswaran, Neeraja; O’Leary, Kathryn; Langston, J. William; Monte, Donato A. Di

doi:10.1002/ana.21203

Cited by 125 publications

(152 citation statements)

References 51 publications

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“…Accordingly, microvascular responses ought to be considered when evaluating the effects of either anti-or pro-dyskinetic treatments with unknown mechanisms of action. Intriguingly, some vasoactive substances, such as a 2 -adrenergic receptor antagonists (Zou and Cowley, 2000), nicotine (Hawkins et al, 2002), and nitric oxide synthase inhibitors (Faraci and Brian, 1994) exert strong anti-dyskinetic effects in animal models of PD (Fox et al, 2001;Padovan-Neto et al, 2009;Quik et al, 2007Quik et al, , 2008. Elucidating the effects of these treatments on microvascular physiology and angiogenesis in the brain will be an exciting task for future studies.…”

Section: Discussionmentioning

confidence: 99%

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

Lindgren

Ohlin

Cenci

2009

Neuropsychopharmacol

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Angiogenesis occurs in the brains of Parkinson's disease patients, but the effects of dopamine replacement therapy on this process have not been examined. Using rats with 6-hydroxydopamine lesions, we have compared angiogenic responses induced in the basal ganglia by chronic treatment with either L-DOPA, or bromocriptine, or a selective D1 receptor agonist (SKF38393). Moreover, we have asked whether L-DOPA-induced angiogenesis can be blocked by co-treatment with either a D1-or a D2 receptor antagonist (SCH23390 and eticlopride, respectively), or by an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK1/2) (SL327). L-DOPA, but not bromocriptine, induced dyskinesia, which was associated with endothelial proliferation, upregulation of immature endothelial markers (nestin) and downregulation of endothelial barrier antigen in the striatum and its output structures. At a dose inducing dyskinesia (1.5 mg/kg/day), SKF38393 elicited angiogenic changes similar to L-DOPA. Antagonism of D1-but not D2 class receptors completely suppressed both the development of dyskinesia and the upregulation of angiogenesis markers. In fact, L-DOPA-induced endothelial proliferation was markedly exacerbated by low-dose D2 antagonism (0.01 mg/kg eticlopride). Inhibition of ERK1/2 by SL327 attenuated L-DOPA-induced dyskinesia and completely inhibited all markers of angiogenesis. These results highlight the specific link between treatment-induced dyskinesias and microvascular remodeling in the dopamine-denervated brain. L-DOPA-induced angiogenesis requires stimulation of D1 receptors and activation of ERK1/2, whereas the stimulation of D2 receptors seems to oppose this response.

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Section: Discussionmentioning

confidence: 99%

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

Lindgren

Ohlin

Cenci

2009

Neuropsychopharmacol

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“…457 In an experimental study in MPTP monkeys, nicotine pretreatment markedly reduced peak and total levodopa-induced dyskinesias. 1028 This suggests that either nicotine or nicotine agonists may have a role in the prevention of levodopa dyskinesia.…”

Section: Treatment Of Dyskinesias and Motor Fluctuationsmentioning

confidence: 99%

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Olanow¹,

Stern²,

Sethi³

2009

Neurology

744

658

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Parkinson disease (PD) is an age-related neurodegenerative disorder that affects as many as 1-2% of persons aged 60 years and older. With the aging of the population, the frequency of PD is expected to increase dramatically in the coming decades. Current therapy is largely based on a dopamine replacement strategy, primarily using the dopamine precursor levodopa. However, chronic treatment is associated with the development of motor complications, and the disease is inexorably progressive. Further, advancing disease is associated with the emergence of features such as freezing, falling, and dementia which are not adequately controlled with dopaminergic therapies. Indeed, it is now appreciated that these nondopaminergic features are common and the major source of disability for patients with advanced disease. Many different therapeutic agents and treatment strategies have been evaluated over the past several years to try and address these unmet medical needs, and many promising approaches are currently being tested in the laboratory and in the clinic. As a result, there are now many new therapies and strategic approaches available for the treatment of the different stages of PD, with which the treating physician must be familiar in order to provide patients with optimal care. This monograph provides an overview of the management of PD patients, with an emphasis on pathophysiology, and the results of recent clinical trials. It is intended to provide physicians with an understanding of the different treatment options that are available for managing the different stages of the disease and the scientific rationale of the different approaches. 1 PD is the second most common neurodegenerative disorder, with an average age at onset of about 60 years. An estimated 5 million people throughout the world have PD, with 1 million individuals each in the United States and in Europe with the disorder. PD affects approximately 0.3% of the population and 1% to 2% of those older than 60 years.2 With the aging of the population and the substantial increase in the number of at-risk individuals older than 60 years, it is anticipated that the prevalence of PD will increase dramatically in the coming decades.

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“…Nicotine, a component of cigarette smoke, has been shown in a Parkinsonian model to prevent the loss of dopaminergic markers and preserve neuronal plasticity (Quik et al, 2006a,b). It also reduces, and maintains the reduction in, the dyskinetic side effects of levodopa (Quik et al, 2007). Chronic nicotine treatment induces brain CYPs in rats (Howard et al, 2003;Yue et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment

et al. 2008

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Cytochrome P450 (CYP) 2D6, an enzyme found in the liver and the brain, is involved in the metabolism of numerous centrally acting drugs (e.g. antidepressants, neuroleptics, opiates), endogenous neurochemicals (e.g. catecholamines) and in the inactivation of neurotoxins (e.g. pesticides, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)). Although CYP2D6 is essentially an uninducible enzyme in the liver, we show that smokers have higher CYP2D6 in the brain, especially in the basal ganglia. In order to determine whether nicotine, a component of cigarette smoke, could increase brain CYP2D, African Green monkeys were treated chronically with nicotine (0.05 mg/kg for 2 days, then 0.15 mg/kg for 2 days followed by 0.3 mg/kg for 18 days s.c., b.i.d.). Monkeys treated with nicotine showed significant induction of CYP2D in brain when compared to saline-treated animals as detected by western blotting and immunocytochemistry. No changes in liver CYP2D were observed in nicotine-treated monkeys. Induction was observed in various brain regions including those affected in Parkinson's disease (PD) such as substantia nigra (3-fold, p = 0.01), putamen (2.1-fold, p = 0.001) and brainstem (2.4-fold, p = 0.001), with the caudate nucleus approaching significance (1.6-fold, p = 0.07).Immunocytochemistry revealed that the expression of CYP2D in both saline-and nicotine-treated monkeys is cell-specific particularly in the cerebellum, frontal cortex and hippocampus. These results suggest that monkey brain expresses CYP2D, which is induced in specific cells and brain regions upon chronic nicotine treatment. Smokers, or those using nicotine treatment, may have higher levels of brain CYP2D6 that may result in altered localized CNS drug metabolism and inactivation of neurotoxins.

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Nicotine reduces levodopa‐induced dyskinesias in lesioned monkeys

Abstract: These data suggest that nicotine or selective nicotinic agonists may represent a useful treatment strategy to reduce levodopa-induced dyskinesias.

Cited by 125 publications

References 51 publications

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment

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