A New Use for Old Drugs

Written by Dr. Amy Smith-Dijak Edited by Logan Morrison

Basic biology helps identify a new treatment for ataxia

Drug design doesn’t always have to start with a blank slate. Sometimes understanding how existing drugs work can help researchers to design new ones, or even to recombine old drugs in new and more effective ways. That’s what the researchers behind this paper did. They investigated the basic biology of three existing drugs: chlorzoxazone, baclofen, and SKA-31.

Two of these – chlorzoxazone and baclofen – are already FDA-approved for use as muscle relaxants, and chlorzoxazone had previously been found to have a positive effect on eye movements in spinocerebellar ataxia type 6. Looking at the results of their experiments, they realized that a combination of chlorzoxazone and baclofen would probably be an effective treatment for ataxia over a long period. They offered this drug combination to patients, who had few adverse effects and showed improvement in their diseasesymptoms. Based on these findings, the researchers recommended that larger trials of this drug combination should be conducted and that people trying to design new drugs to treat ataxia should try to interact with the same targets as chlorzoxazone.

mutliple types of drugs in pill form scattered ac
Can old drugs have potential for new types of treatment? Photo by Anna Shvets on Pexels.com.

When this paper’s authors started their research, they wanted to know more about how ataxia changes the way that brain cells communicate with each other. Brain cells do this using a code made up of pulses of electricity. They create these pulses by controlling the movement of electrically charged atoms known as ions. The main ions that brain cells use are potassium, sodium, calcium and chloride. Cells control their movement through proteins on their surface called ion channels which allow specific types of ions to travel into or out of the cell at specific times. Different types of cells use different combinations of ion channels, which causes different types of ions to move into and out of the cell more or less easily and under different conditions. This affects how these cells communicate with each other.

For example, a cell’s “excitability” is a measure of how easy it is for that cell to send out electrical pulses. Creating these pulses depends on the right ions entering and exiting the cell at the right time in order to create one of these pulses. Multiple types of spinocerebellar ataxia seem to make it difficult for Purkinje cells, which send information out of the cerebellum, to properly control the pattern of electrical signals that they send out. This would interfere with the cerebellum’s ability to communicate with the rest of the brain. The cerebellum plays an important roll in balance, posture and general motor coordination, so miscommunication between it and the rest of the brain would account for many of the symptoms of spinocerebellar ataxias.

Earlier research had found a link between this disrupted communication and a decrease in the amount of some types of ion channels that let potassium ions into Purkinje cells. Thus, this paper’s authors wanted to see if drugs that made the remaining potassium channels work better would improve Purkinje cell communication.

The authors’ first step was to look for baseline differences in the electrical signalling of healthy and ataxic Purkinje cells. To simplify their experiments, the authors decided to use a mouse model of just one type of spinocerebellar ataxia. They chose a mouse model of spinocerebellar ataxia type 1. They recorded the electrical signals from the model mice’s Purkinje cells and compared them to the signals from healthy Purkinje cells.

Healthy Purkinje cells send out a constant string of large electrical pulses known as “spikes”. However, many of the ataxic Purkinje cells did not send out spikes. The authors also wanted to test how easy it was for the Purkinje cells to send out a spike. To do this, they treated the Purkinje cells with drugs that stopped them from naturally sending out spikes and then ran a small electrical current through them. They increased the amount of current until the Purkinje cell sent out a spike. The smaller the amount of current needed to make the Purkinje cell send out a spike, the easier it is for the Purkinje cell to create its own spikes. Although many of the Purkinje cells in the ataxic mice didn’t send out spikes, it was easier for the authors to produce spikes in these cells than in the healthy cells.

This decrease in the amount of current needed to produce a spike is known as “hyperexcitability”. It is a symptom of many neurological diseases, most prominently epilepsy, and can lead to levels of activity in the brain that are so high that they damage brain cells. Both the lack of spikes and the hyperexcitability that the researchers saw probably are probably related to the symptoms of spinocerebellar ataxia.

Once the authors had established these baseline differences between ataxic and healthy Purkinje cells, they wanted to see what effect potassium channel-enhancing medications would have on them. Potassium ions exit brain cells at the end of each electrical pulse. This temporarily decreases brain cells’ excitability after each pulse and allows them send their electrical pulses at the right rate. Thus, making it easier for potassium channels to leave the cell could reduce hyperexcitability. They chose three medications to test: chlorzoxazone, SKA-31, and baclofen. Neither chlorzoxazone nor SKA-31 alone had any effect on the number of cells sending out spikes, but when they were given together with baclofen both increased the number of spiking cells. However, only chlorzoxazone and baclofen together reduced cells’ hyperexcitability. In light of these results, the researchers would use chlorzoxazone and SKA-31 in combination with baclofen for their future experiments.

After figuring out which combinations of medications improved Purkinje cell signalling, the researchers wanted to see if they would improve the symptoms of ataxia. First, they tested this in their model mice using a task called the rotarod assay. This involves putting the mice onto a rod that is rotating at a constant rate. Not falling off requires the mouse to adjust its position to match its rotation, so the better the mouse’s motor control the longer it will be able to stay on the rod. After being treated with a combination of either chlorzoxazone and baclofen or SKA-31 and baclofen for one to two weeks, the mice were indeed able to stay on the rod longer. To check whether this improvement would last over the long term, the researchers then continued treating the mice for a total of 10 weeks. When the researchers re-tested the mice, only those treated with chlorzoxazone and baclofen stayed on the rod longer than ataxic mice of the same age. This means that while increasing the number of Purkinje cells sending out spikes improves motor control in the short term (something that SKA-31 and baclofen can do), long-term improvement depends on the reduced hyperexcitability that only chlorzoxazone and baclofen provided.

Having found that a combination of chlorzoxazone and baclofen could improve mice’s motor control over the long term, the authors decided to try these medications in human ataxia patients. They offered this drug combination to patients at the University of Michigan Ataxia Clinic. Ultimately 17 people with spinocerebellar ataxia type 1, 2, 6, 8, or 13 received this drug combination. Over treatment periods of between 12 and 39 months, most of these patients showed a decrease in their ataxia symptoms, as scored using the SARA scale. It should be noted that this study did not include a control group, and neither the doctors prescribing the drugs nor patients taking them were blinded to their treatment, so this is not the equivalent of a clinical trial. However, as only four of the 17 patients had to stop treatment due to side effects, it does seem to demonstrate that this drug combination can be used safely. Overall, these results suggest that a combination of chlorzoxazone and baclofen should be the focus of a more systematic clinical study in the future.

In addition to providing evidence that a combination of chlorzoxazone and baclofen could be used as a therapy for spinocerebellar ataxia, this research also makes some larger points about treating these diseases. Firstly, it shows that not all medications that improve disease symptoms in the short term will continue to do so in the long term. Secondly, it suggests that other drugs that interact with the same type of potassium channels as chlorzoxazone might also work as treatments for spinocerebellar ataxia. Following these leads could lead to the discovery or development of even more effective treatments for spinocerebellar ataxia.

Key Terms

Ion: An atom that has too many or too few electrons, and so has an electrical charge

Ion Channel: A protein on the outside of the cell that lets ions into or out a cell

Purkinje Cell: A type of brain cell that sends information out of the cerebellum to other parts of the brain.

Spike: A large pulse of electricity that Purkinje cells use to communicate with other types of brain cells

Conflict of Interest Statement

Dr. David D. Bushart, who completed the work described in the summary, is a contributor to SCAsource. Dr. Bushart did not have any contribution to the writing or editing of this summary. Logan Morrison, who edited this article, currently works in the lab that did this research. This paper was published before he joined the lab. Amy Smith-Dijak declares no conflict of interest.

Citation of Article Reviewed

Bushart, D.D., et al., Targeting potassium channels to treat cerebellar ataxia. Annals of Clinical and Translational Medicine, 2018. 5(3): p. 297-314. (https://www.ncbi.nlm.nih.gov/pubmed/29560375)