Drugs Tested on T-type Calcium Channel

A study by Dr. Adrian Handforth and Dr. Arnulfo Quesada has yielded notable results with a  potential focus for essential tremor (ET) drug treatment. Funded by a grant from the IETF, the study concerns the impact of five drugs in blocking T-type calcium channels and suppressing tremor in two different models when tested on mice. Drawing from their IETF-supported work, the scientists produced three papers, one of which was published in 2008 in Drug Metabolism and Disposition and another published in 2010 in Neuropharmacology. The third paper has been accepted for publication in the European Journal of Pharmacology.

ET is a common disorder that lacks molecular targets for therapeutic development. In a search for targets, some researchers have focused on the rhythmic connection between T-type calcium channel activation and the olivo-cerebellar system that is implicated in essential tremor. The olivo-cerebellar system, one of the key neuronal circuits in the brain, plays an important role in the organization of vertebrate motor control.

The Handforth-Quesada study built on previous research (Sinton et al., 1989) predicting 20 years ago that T-type calcium antagonists may effectively suppress tremor. This new study tested whether five compounds were effective in suppressing tremor in harmaline and GABA receptor alpha 1 animal models of tremor.

Harmaline produces a postural/kinetic tremor, evident in animals, that shares several similarities with ET including suppression by anti-ET drugs such as 1-octanol. Harmaline-induced tremor is the most-studied ET model. Tremor in the GABA receptor alpha 1 model is also postural/kinetic in nature and responds to anti-ET drugs. Use of these two animal models of tremor offers a strategy to better understand and develop new treatments for ET.

“Our paper in Neuropharmacology reported that five drugs that block T-type calcium channels suppress tremor in both the harmaline and the GABAA alpha1 genetic models of tremor in mice,” says Dr. Handforth. “Importantly, this work supported the idea that drugs of this class might be therapeutic for essential tremor.”

Further, a recent report from yet another study (Park et al., 2010) “complements this theme” using the harmaline model of tremor. T-type calcium channels are subdivided into three types, of which the one called Cav3.1 is most common in the cerebellum and inferior olive. The Park et al. team found that mice lacking the Cav3.1 T-type calcium channel had well-preserved motor  functioning, but were much less able to have tremor in response to harmaline. The same finding  occurred when the expression of the Cav3.1 channel was selectively suppressed in the inferior olive. These findings based on genetic approaches are consistent with inferences from the
pharmacological studies of Handforth/Quesada, but further suggest that the Cav3.1 subtype of T-type calcium channels is specifically involved in tremor expression.

Dr. Handforth elaborates, “These papers together suggest that a viable therapeutic target for treating ET is the T-type calcium channel, particularly the Cav3.1 subtype.”

Dr. Adrian Handforth – Neurology Service, Veterans Affairs, Greater Los Angeles Healthcare System, Los Angeles, CA.

Dr. Arnulfo Quesada is with the Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA; and Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, CA.

Study update:
Dr. Handforth explains how the aim of research is to narrow down exactly which combination of delta, alpha, and beta subunits forms the receptor capable of suppressing tremor when activated. He believes that the identification of this receptor could lead to the development of drugs that specifically suppress tremor, yet might be well tolerated.

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