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Neurodegenerative Disease Parkinson’s Disease


Calcium Channels as a Potential Target for Neuroprotection in Parkinson’s Disease


Tanya Simuni, MD1 and D James Surmeier, PhD2


1. Associate Professor of Neurology and Director, Parkinson's Disease and Movement Disorders Center; 2. Nathan S Davis Professor and Chairman, Department of Physiology, Feinberg School of Medicine, Northwestern University


Abstract


Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1 % of the population above the age 65. The principal motor symptoms of PD are attributable to the preferential loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Recent studies demonstrate that dopaminergic (DA) neurons in the SNc, as well as many neurons in other regions affected by PD, have a


distinctive physiologic phenotype. They are autonomous L-type Cav1.3 Ca2+ channels pacemakers. Continuous Ca2+ influx results in increased oxidative stress that may explain the selective vulnerability of these neurons. More importantly for PD, blocking these channels with


isradipine, the most potent of the dihydropyridine (DHP) channel antagonists at L-type Ca2+ channels with the Cav1.3 subunit, protects these neurons in in vitro and in vivo models of parkinsonism. Neuroprotective effect is achieved at the serum concentrations that can be achieved with the doses approved for human use. Recent epidemiologic data also points to a reduced risk of PD with chronic use of specifically centrally acting DHP Ca2+ channel antagonists. Isradipine is an approved agent for the treatment of hypertension. Our pilot data demonstrate acceptable dose-dependent tolerability of isradipine in early PD. A pilot Phase II multicenter, double-blind, placebo-controlled, safety, tolerability, and dosage finding study of isradipine in early PD has completed recruitment, with the results of the study to be available in the near future. Results of that study will inform the design of the planned Phase III pivotal efficacy trial of isradipine, as a disease modifying agent in early PD.


Keywords Parkinson’s disease, neuroprotection, isradipine, Ca channels


Disclosure: Tanya Simuni, MD, has received research support from the Michael J Fox Foundation and Northwestern Dixon Foundation for the conduct of the STEADY-PD trial. D James Surmeier, PhD, has a pending application for the use of a patent on dihydropyridine compounds in Parkinson’s disease. Received: November 18, 2011 Accepted: November 28, 2011 Citation: US Neurology, 2011;7(2):109–12 Correspondence: Tanya Simuni, MD, Parkinson's Disease and Movement Disorders Center, Northwestern University Feinberg School of Medicine, 710 North Lake Shore Drive, 1126, Chicago, IL 60611. E: tsimuni@nmff.org


Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1 % of the population above the age 65.1


The incidence


PD is manifested by the combination of primary motor disability (bradykinesia, rigidity, tremor, and gait impairment) as well as a spectrum of non-motor symptoms including cognitive, mood, autonomic, and sleep dysfunction.3


of PD is expected to increase dramatically worldwide with increased life expectancy.2


The cause of cells degeneration in PD remains


unknown. While there is a widespread distribution of neuropathologic changes in the brain responsible for the spectrum of the motor and non-motor manifestations of PD, degeneration of dopamine-producing cells in the substantia nigra pars compacta (SNc) is central to the primary motor signs of the disease.3


Presently, treatment of PD is limited to symptomatic therapy, aimed at mitigating the dopamine deficiency. While treatment can be very effective early in the stages of the disease, it does not impact the progression of the degenerative process. A neuroprotective agent that


© TOUCH BRIEFINGS 2011


could slow the progression of the disease has been the holy grail of research in PD. Several agents have been tried, but none have been shown to be effective. The reasons for this failure are unclear, but are likely to stem from the complexity of pathogenesis and the inability to attack the disease process sufficiently early in its course. Another major limitation in clinical trials currently is lack of reliable, objective biomarkers of disease progression. Until such biomarkers are available, the term that should be used in the discussion of the clinical trials outcomes is disease modification, which implies a positive impact on the clinical course of the disease without specifically linking it to pathogenesis. Ultimately, the choice of an agent for neuroprotection in PD should be based on the solid understanding of etiology.


Parkinson’s Disease Etiology


The etiology of PD remains unknown. The pathologic hallmark of PD is the presence of intracytoplasmic eosinophyllic, proteinaceous inclusions, termed Lewy bodies (LB), in surviving neurons. LBs contain


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