Pathogenesis And Treatment Of Neurodegenerative Disease

Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

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 previus findings in rodent and primate models of PD, our clinical study using a highly selective adenosine A2A antagonist (KW-6002) discovered the ability of A2A receptor blockade to benefit motor dysfunction. These results confirmed that drugs capable of blocking A2A receptors confer therapeutic benefit to parkinsonian patients and exemplify a strategy for successfully bridging a novel approach to PD therapy from an evolving research concept to pivotal clinical trials. Other of our related investigator-initiated, proof-of-concept clinical studies also made important advances relevant to the treatment of PD, including our recently completed trials involving non-dopaminergic treatments that target selected striatal transmitter receptors, such as serotonin 5HT1A and alpha-2 adrenergic autoreceptors. Our two separate studies using sarizotan, a 5HT1A agonist, and fipamezole, an alpha2 adrenergic antagonist, suggested that 5HT1A receptor stimulation and alpha 2-adrenergic receptor blockade in levodopa-treated parkinsonian patients can modulate striatal dopaminergic function and that drugs of these types may be useful as adjuvant in the treatment of this disorder. During the past year we also designed and started the implementation of other translational proof-of principle studies aimed at advancing the treatment of motor complications in PD. These trials evaluate the effects of serotonin 5HT2 A/C blockade, combined AMPA and NMDA receptor-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 conducted last year 2 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 is evaluating 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.