Verapamil

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

Last Modified: 05/22/2009

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