Clonidine is a currently available FDA-approved drug traditionally used to treat high blood pressure by decreasing heart rate and relaxing blood vessels, allowing for blood to flow more easily through the body. The drug has also been discovered to modulate autophagy, a process used by neurons to dispose of unwanted proteins and damaged cellular components. If this process is disturbed as it is in Huntington's disease (HD) and other neurodegenerative disorders then cellular "trash" can accumulate and harm brain cells. Clonidine can increase autophagy, opening the door for its use as a therapeutic for neurodegenerative diseases such as HD where hallmarks of the disorder involve the formation of protein aggregates. To learn more about the role of protein aggregates in HD, click here.
Clonidine can act through multiple pathways to alter autophagy. Clonidine can bind to both α2-adrenergic (α2-AR) and type I imidazoline (I1R) receptors, which initiates signaling cascades that causes reductions in levels of the cell signaling molecule cyclic adenosine monophosphate (cAMP). cAMP can in turn trigger another signaling pathway that inhibits autophagy. Thus, decreasing cAMP with clonidine has the potential to increase autophagy. To test this hypothesis, experiments that either increased or decreased cAMP activity were conducted.
To look at the effects of increased cAMP signaling on autophagy, researchers used a rat-derived neuronal cell line engineered to express huntingtin aggregates. An analog of cAMP was used to increase the amount of cAMP signaling. As was expected, increased cAMP signaling led to a decrease in the amount of autophagy and an increase in aggregation. Clonidine was shown to have neuroprotective effects when administered to cells—there was an increase in autophagy and a decrease in the formation of huntingtin aggregates. The formation of huntingtin aggregates may disrupt crucial functions within the cell and lead to cell apoptosis. To learn more about aggregate formation and its role in HD, click here.
Clonidine has been tested in several animal models of HD and has been indicated to have some neuroprotective effects.
In the zebrafish model of HD, mutant huntingtin aggregates form in the eyes and the optic nerve. In one study, HD zebrafish that were treated with clonidine had a lower amount of aggregate formation, less degeneration, and less cell death in the eyes when compared to untreated animals.
In the fruit fly HD model, normal development of the eyes is disrupted in cells expressing mutant huntingtin aggregates, resulting in the degeneration of photoreceptors. When clonidine was administered to mutant flies in one study, it resulted in a reduced amount of degeneration in the eyes.
Although numerous experiments testing the effectiveness of clonidine in treating HD in different models have been completed, there is much work to be done before it is administered to human HD patients. However, the early studies have indicated a great deal of potential in clonidine as a treatment, and more research is ongoing.
-A. Pipathsouk
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Sarkar S., et al. "Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies." Cell Death and Differentiation advance online publication, 18 July 2008; doi:10.1038/cdd.2008.110.
This review paper explained the relationship between aggregate formation in several neurological diseases and the role in autophagy in protecting against these diseases. It also explained several animal models of HD.
Williams et al. "Novel targets for Huntington’s Disease in an mTOR-independent autophagy pathway." 2008 May;5(4):295-305
This paper explained the testing of a number of potential HD drugs though targeting the autophagy mechanisms within cells.
Last Modified: 10/26/2009
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