Evaluation of an a6ßy2 GABA Receptor-Specific Drug as Potential Therapy

IETF Funded Research

Here’s an overview of a research study which received a 2019 research grant from the IETF:

Principal Investigator: Adrian Handforth, M.D.
Veterans Affairs Greater Los Angeles Healthcare System

Behind the cerebral hemispheres lies the cerebellum, a structure involved in precise motor control. Brain imaging studies performed on ET patients over 20 years ago showed that the cerebellum has a higher metabolic rate than normal, suggesting that brain cells here are abnormally active in ET. It has been found that low oral doses of alcohol that suppress tremor reduce this high metabolic rate in cerebellum down towards normal, suggesting that alcohol suppresses tremor by inhibiting cerebellar brain cells. The most abundant type of brain cell in the cerebellum is the granule cell. The ability of these cells to excite cerebellar outflow pathways is limited by the neurotransmitter GABA that is released by local brain cells.

GABA is the brain’s main inhibitory neurotransmitter, and it works by activating GABA receptors. Brain GABA receptors are not uniform but differ according to their subunit composition. They all contain 2 alpha subunits, of which there are 6 types, 2 beta (3 types), and either a delta (only 1 type) or a gamma (3 types) subunit. Cerebellar granule cells contain most of the brain’s alpha6-beta-delta receptors. This is interesting, because if a drug can be found that is specific in activating these receptors, it might be an effective and well-tolerated treatment for ET. Dr. Adrian Handforth and colleagues at VA Greater Los Angeles Healthcare System previously found that a GABA delta-receptor-specific drug, gaboxadol, reduced tremor in the harmaline mouse model of ET (mice who were injected with the drug harmaline to induce tremor). But, it did not work if the mice lacked the GABA receptor alpha6 or delta subunit. While this finding suggests this approach is on the right track, a problem is that gaboxadol at higher doses will also activate alpha4-beta-delta receptors in the rest of the brain, causing off-target side effects such as sleepiness. To date, there are no drugs that activate only alpha6-beta-delta receptors, and thereby act on cerebellar granule cells selectively. However, these cells are also special in possessing most of the brain’s alpha6-beta-gamma2 GABA receptors. As it happens, drugs have been created that are specific for these receptors. This creates an opportunity to find out whether a drug that inhibits cerebellar granule cells relatively selectively will suppress tremor effectively in doses that are well tolerated.

The drug known as Compound 6 selectively activates only alpha6-beta-gamma2 receptors and has already been shown to affect cerebellar granule cell function when injected systemically but has not been tested on tremor. In initial experiments, Dr. Handforth’s team will find out what dose levels are associated with psychomotor impairment in mice. Only doses at which all mice pass will be used in subsequent tremor experiments. Tremor will be induced in normal (wild-type) mice with the drug harmaline. Tremor in the harmaline model has similar tremor circuitry to ET and responds to medications used to treat ET. Compound 6 dose levels that suppress tremor will be determined and compared with dosages needed to cause psychomotor impairment. Mice lacking the GABA receptor alpha6 subunit will also be tested.

It is anticipated that Compound 6 will be found to suppress harmaline-induced tremor in wild-type mice, but not in mice lacking alpha6 GABA receptor subunits, indicating that Compound 6 is likely suppressing tremor by inhibiting cerebellar granule cells, where most brain alpha6-containing GABAA receptors are located.  More importantly, because Compound 6 was devised to activate alpha6-beta-gamma2 GABA receptors with exquisite selectivity, receptors located almost only on cerebellar granule cells, it is anticipated that Compound 6 will suppress tremor in doses much less than those that cause impairment. Full safety and toxicology testing of Compound 6 has not been done, so that it is not yet known whether it could be given to humans. Nonetheless, Dr. Handforth believes that this work will provide proof-of-concept evidence that an alpha6-beta-gamma2 GABA receptor-selective medication might be highly effective and well-tolerated for ET.