Neuroprotective Therapies for Parkinson’s Disease

Source: From Medscape Pharmacists

Conference Report

Neuroprotection in Parkinson’s Disease

American College of Clinical Pharmacy Annual Meeting; November 2-5, 2003; Atlanta, Georgia

Posted 01/20/2004

Jack J. Chen, PharmD, BCPS, CGP

The currently available therapies for PD are symptomatic and become less effective over time due to progression of the underlying disease process. Therefore, a crucial need for therapies that slow or arrest disease progression has been identified. It is important to note that experts within the area of neuroprotection agree that all human neuroprotective studies to date are characterized by study design and technical methodology limitations that prevent definitive statements of successful neuroprotection and that the design of future neuroprotective trials is a complex process.

Nevertheless, in order to identify potential neuroprotective agents available for testing, the Committee to Identify Neuroprotective Agents in Parkinson’s (CINAPS), supported by the National Institute of Neurologic Disorders and Stroke (NINDS), conducted a systematic assessment of currently available pharmacologic agents. From a list of 59 potential neuroprotective agents, the Committee identified 12 agents that are currently available and should be considered priority agents for further investigation in PD (Table).


Several epidemiologic studies have demonstrated that high intake of caffeine (ie, coffee, tea) is associated with an inverse risk of developing PD, and animal experiments support protective effects of caffeine. Caffeine is an adenosine receptor antagonist, and the compound KW-6002, a specific adenosine 2A receptor antagonist, has demonstrated neuroprotective effects in animal models of PD.

Coenzyme Q10

Also referred to as “CoQ10,” this compound is a dietary supplement that is widely available. In a recent phase 2 study, high doses of CoQ10 (1200 mg per day) demonstrated symptomatic benefits in patients with early PD.[1] The putative neuroprotective activity of CoQ10 may be due to its antioxidant properties and enhancement of the mitochondrial complex I activity (which may be defective in PD). Of note, the CoQ10 product used in the study also contained significant amounts of vitamin E, another known antioxidant. The possible influence of vitamin E on the results of this study was not evaluated. However, in a previous clinical study (DATATOP), high-dose vitamin E (up to 2000 IU per day) was not associated with clinical symptomatic or neuroprotective benefits.[2]

Dopamine Agonists

Although dopamine agonists have been used to provide symptomatic relief in PD for many years, attention is now focused on putative neuroprotective effects of these agents. In vivo experiments have demonstrated that the ergot (eg, bromocriptine, pergolide) and nonergot (eg, pramipexole, ropinirole) dopamine agonists protect cultured cells from death due to oxidative damage. Recently published clinical data in patients with early PD provide intriguing neuroimaging results suggesting a putative neuroprotective effect.

The Parkinson Study Group used single-photon emission computed tomography (SPECT) to compare the effects of pramipexole vs levodopa on PD progression. The imaging ligand [123I] beta-CIT was used as a marker of dopamine transporter density. Results of the 46-month study demonstrated that pramipexole-treated patients had reduced loss of striatal dopamine uptake compared with levodopa-treated patients.[3] The Requip as Early Therapy versus L-dopa PET (REAL-PET) study used serial positron emission tomography (PET) scans to assess PD progression in patients receiving ropinirole vs levodopa.[4] The ligand 18F-dopa was used as a marker of the functional integrity of dopamine terminals. After 2 years, ropinirole-treated patients demonstrated a significantly slower loss of putamen dopamine storage capacity compared with levodopa-treated patients. It is important to note that neither study contained a placebo arm.

Therefore, it is unknown whether the dopamine agonist was acting as a neuroprotectant and slowing the rate of neuronal loss or whether levodopa was increasing the rate of neuronal loss. Additionally, the variable sensitivity of functional imaging data to clinical changes and the effects of dopamine agonists on altering dopamine transporters and receptors have made the neuroimaging data difficult to interpret in terms of neuroprotection. Therefore, definitive neuroprotection cannot be confirmed on the basis of these studies.


Rasagiline is a selective monoamine oxidase type B inhibitor that has demonstrated antioxidant and antiapoptotic activity in preclinical experimental models. Clinically, rasagiline has demonstrated symptomatic benefits in patients with early and advanced PD. In the 26-week, randomized, placebo-controlled TEMPO study, patients with early PD benefitted from rasagiline treatment.[5] However, the study was not designed to detect neuroprotective benefits. Rasagiline is anticipated to be available in the United States in late 2004.

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