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Targeting the dopaminergic pathway in PD

PD affects about 1 in 800 people, with an average age of onset of around 65–70 years (3). The disease typically presents with a resting tremor, bradykinesia, and rigidity. The core pathology underlying these motor symptoms and signs is the progressive degeneration of the nigrostriatal dopaminergic pathway. However, it is now well recognized that the disease is much more than this, and patients are frequently also troubled by an array of nonmotor symptoms (e.g., depression, cognitive decline, constipation, and pain), and pathological intraneuronal protein aggregates called Lewy bodies and Lewy neurites also develop in a wide range of brain areas as the disease progresses (4).

Since targeting the dopaminergic pathway pharmacologically is of significant benefit to patients, there has been great interest in trying to restore this system in the form of dopamine cell replacement (5), delivery of neurotrophic factors (6, 7), or neuroprotective drug treatment (7, 8). Because exenatide has been shown to reduce neurodegeneration in several different neurotoxic lesion rodent models of PD (such as those induced by MPTP, lipopolysaccharide, N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine [DSP-4], parachloroampetamine [pCA], and 6-hydroxydopamine), this agent has promise in an area of great unmet need (9–11). As with other studies of neuroprotective agents in animal models of PD, exenatide has been administered in close association with the toxin, and the treatment has been found to reduce neuronal loss. Exactly how it mediates this effect is still unresolved, but it might involve direct protective effects on different monoaminergic neurons (2, 9–11), increased cell proliferation in the adult brain (12), or indirect actions on inflammation (2, 9).

In a clinical setting, it is difficult to assess whether an agent has truly rescued dopamine neurons or simply provided symptomatic benefit. In clinical trials with neurotrophic factors and other potentially neuroprotective treatments, this problem has been tackled by imaging the nigrostriatal dopamine pathway and using long follow-up periods, both of which bring substantial cost. In the case of drug therapies, the use of delayed-start trials has been advocated. In this approach, there is a delay in the introduction of the active agent in one arm of the study, with the aim of determining whether subjects on the treatment for a long period reach the same end point as those on it for a shorter time. If the drug provides solely symptomatic benefit, all patients would be expected to reach the same end point regardless of when the drug was started. As an alternative to this approach, patients may be reassessed after a defined washout period for the active agent at the end of the trial, with the aim of washing away any symptomatic effects of the drug to see whether there are any true underlying, neuroprotective effects (13–15).


Date: 2014-12-21; view: 1596


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