Verapamil is a currently available FDA-approved drug traditionally used to treat irregular heartbeats (arrhythmias) and high blood pressure by relaxing blood vessels. It has been discovered that verapamil can also modulate autophagy, a process by which cells gets rid of unwanted proteins and damaged cellular components. If this process is disrupted as it is in Huntington’s Disease (HD) and other neurodegenerative disorders then cellular “trash” can accumulate and harm brain cells. Thus, Verapamil’s effects on autophagy opens the door for its use in treating HD where the formation of protein aggregates is characteristic. To learn more about autophagy, click here. To learn more about the role of protein aggregates in HD, click here.
Verapamil was one of five L-type Ca+2 channel antagonists initially screened to test for its efficacy in modulating autophagy. L-type Ca+2 channels are specialized high-voltage ion channels found on the dendritic spines of cortical neurons. For more information about the different parts of the brain, see the brain tutorial here. Verapamil and other calcium channel inhibitors may regulate autophagy by limiting the amount of calcium that can enter the cell. High levels of intracellular Ca+2 can up-regulate autophagy by activating calpains, which are enzymes that aid in protein breakdown. Interestingly, some studies have found that calpain activity is increased in HD cells and can chop the mutant huntingtin protein into smaller fragments which allows it to enter the nucleus of neurons leading to toxicity.
Verapamil may block this toxicity by preventing calcium from entering the neuron. This lower concentration of calcium can reduce calpain activity, which can in turn increase autophagy. In HD, more autophagy means that more of the mutant huntingtin protein is cleared and fewer aggregates formed. To learn more about aggregate formation and its role in HD, click here.
The Promise of Verapamil in treating HD
Verapamil was tested for its ability to induce autophagy in several HD cellular and mouse models. To learn more about mouse models, click here. The first, and simplest model used was the cell model. Rat-derived neuronal cells were engineered to express huntingtin aggregates and some were treated with verapamil. Cells exposed to the drug showed a greater degree of aggregate clearance than cells that were not.
The next model used to explore the effects of verapamil on HD was the fruit fly, a commonly used model for many experiments. The development of the eyes in flies expressing the mutant huntingtin protein is altered, which causes the photorecetors to become disorganized and to degenerate. Flies given verapamil had less severe degeneration, than control flies did.
The next animal model of HD tested was the zebrafish. Zebrafish expressing mutant huntingtin form aggregates in their eyes and optic nerve. As in human HD, cells that form aggregates are more likely to die. Zebrafish administered verapamil had fewer aggregates.
Despite all of these experiments indicating a neuroprotective role for verapamil, the process for approving the use of verapamil in treating HD is still in very early stages. Although the results of preliminary studies are very promising, many more trials and more research needs to be done before using verapamil in HD treatments.
Gafni J., and L. Ellerby. “Calpain Activation in Huntington’s Disease.” Journal of Neuroscience. 2002 June; 22(12):4842-4849.
This technical paper explained how calpain activation breaks huntingtin protein into pieces small enough to enter the nucleus and lead to toxicity in HD cells.
- 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.” Nature Chemical Biology. 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.
A. Pipathsouk, 5/21/2009