Pathogenesis And Treatment Of Neurodegenerative Disease

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Improving the translation of recent findings from basic laboratory research to better therapies for neurologic disease constitutes a major challenge for the neurosciences as well as a critical goal for Branch research. ETB recent contributions to the development of several treatments for Parkinson?s disease (PD) illustrate approaches to some of the relevant issues. Building on our previous findings in rodent and primate models of PD, our clinical studies have discovered the potential therapeutic benefit of various drugs, including our recently completed trials involving non-dopaminergic treatments that target selected striatal transmitter receptors, such as adenosine A2a, serotonin 5HT1A and alpha-2 adrenergic autoreceptors. We have demonstrated that drugs of these types can modulate striatal dopaminergic function and may be useful as adjuvant in the treatment of this disorder. These works exemplify a strategy for successfully bridging a novel approach to PD therapy from an evolving research concept to pivotal clinical trials. During the past year we conducted additional translational proof-of principle studies aimed at advancing the treatment of motor complications in PD. These trials evaluated the effects of serotonin 5HT2 A/C blockade and continuous transdermal dopaminergic stimulation on parkinsonian symptoms and on motor complications in advanced PD, including motor fluctuations and levodopa-induced dyskinesias. In addition to these investigations on PD, our branch also completed last year two research projects on the pathophysiology of the restless legs syndrome (RLS). In the first study, the role of dopaminergic mechanisms in spinal flexor reflex circuitry was investigated in a double blind randomized trial of ropinirole versus placebo in patients with RLS. The second study evaluated the potential contribution of sensorimotor gating abnormalities in the pathophysiology of this condition. These studies are important to understand the possible mechanisms underlying this frequent neurological disorder.