Editors' ChoiceNeurology

Illuminating Drug Action in the Parkinsonian Brain

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Science Translational Medicine  22 Dec 2010:
Vol. 2, Issue 63, pp. 63ec199
DOI: 10.1126/scitranslmed.3002060

Although there are drugs available to treat the neurodegenerative disorder Parkinson’s disease, such drugs only ameliorate symptoms and do not stem the loss of dopaminergic neurons in the substantia nigra, which underlies this debilitating movement disorder. Thus, improved drugs and treatments are badly needed. Sophisticated imaging technologies can help in the development of new treatments by providing a window into the brain that illuminates both disease pathogenesis and drug action. Such an approach is yielding dividends, as shown by the recent study of Black and colleagues. These investigators use a form of functional MRI called pulsed arterial spin labeling, which directly measures cerebral blood flow, to evaluate the pharmacodynamic effects of a new drug in Parkinson’s disease patients. The new drug, SYN115, is an adenosine A2a receptor antagonist. Such antagonists are known to alleviate the symptoms of Parkinson’s disease by modulating the basal ganglia, part of the thalamic system that controls movement.

Using their imaging system in Parkinson’s patients given SYN115, the authors correlated drug pharmacodynamics with decreased cerebral blood flow in the thalamus and in several other brain regions associated with movement and alertness. Decreased blood flow in response to SYN115 treatment was particularly strong in the thalamus, which is part of the so-called “indirect” pathway of movement control. The regionally specific pattern of drug effects on cerebral blood flow in the brain suggested alterations in neuronal activity rather than vascular changes. These effects were distinct from those observed in healthy individuals given caffeine, which blocks all adenosine receptor subtypes and causes diffuse changes in blood flow across the whole brain. This imaging study takes a step toward characterizing the effects of a new drug on neural pathways implicated in Parkinson’s disease. Furthermore, it shows how noninvasive functional neuroimaging can provide unique insights into how drugs work in the brain, thus providing valuable information for developing therapeutics for treating intractable diseases of the central nervous system.

K. J. Black et al., Quantification of indirect pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson disease. J. Neurosci. 30, 16284–16292 (2010). [Abstract]

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