SK Channel Openers as Therapeutics for Cerebellar Ataxia

Summary

Principal Investigator: Heike Wulff
Affiliation: University of California
Country: USA
Abstract: Cerebellar ataxia is a lethal neurological disease, which afflicts about 150,000 people in the US. There are currently no known preventive, neuroprotective or symptomatic treatments for this devastating disease. Using a transgenic mouse model we recently identified a novel mechanism of initiation of cerebellar ataxia through hyperexcitability of the deep cerebellar neurons (DCN), the sole output pathway of the cerebellum. Small conductance Ca -activated K+ (SK) channels, key regulators of firing frequency in the DCN, were silenced in DCN neurons of Tg mice with a naturally occurring dominant-inhibitory SK isoform (SK3-1B) that suppresses the entire SK channel family. Tg mice developed severe cerebellar ataxia by the 12th day of life characterized by motor incoordination, intention tremor and gait abnormalities in the absence of neurodegeneration. This model, together with findings from other animal models for cerebellar ataxia, strongly suggests that increased DCN excitability may be an important step in the causation of this disorder. Pharmacological reduction of DCN excitability may provide a novel therapeutic approach for cerebellar ataxia. Since SK channels are critical in regulating the firing frequency of DCN neurons and their blockade causes enhanced firing, an opener of SK channels should slow down DCN firing and ameliorate the symptoms of cerebellar ataxia. Riluzole, a FDA approved drug for the therapy of amyotrophic lateral sclerosis, has been reported to be a potent SK channel opener. In a preliminary study in a Tg mouse model for human spinocerebellar ataxia type 2 (SCA2), we found that riluzole produced a dramatic improvement in motor performance after only 4 days of treatment. We plan to extend these exciting preliminary findings by pursuing 3 specific aims: Aim 1: Evaluation of riluzole in 2 animal models of ataxia; Aim 2: Design of a more potent and selective SK opener that unlike riluzole does not block slowly inactivating sodium channels; Aim 3: Evaluation of our new SK opener in 2 animal models of ataxia. Taken together these important proof-of-concept studies will help to determine whether SK channel openers constitute a new therapeutic approach to improve motor performance in dominant cerebellar ataxias.
Funding Period: 2005-07-15 - 2009-04-30
more information: NIH RePORT

Top Publications

  1. ncbi Modulators of small- and intermediate-conductance calcium-activated potassium channels and their therapeutic indications
    Heike Wulff
    Department of Medical Pharmacology and Toxicology, University of California, Davis, CA 95616, USA
    Curr Med Chem 14:1437-57. 2007
  2. ncbi Naphtho[1,2-d]thiazol-2-ylamine (SKA-31), a new activator of KCa2 and KCa3.1 potassium channels, potentiates the endothelium-derived hyperpolarizing factor response and lowers blood pressure
    Ananthakrishnan Sankaranarayanan
    Department of Pharmacology, University of California, Davis, California 95616, USA
    Mol Pharmacol 75:281-95. 2009
  3. ncbi Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived hyperpolarizing factor vasodilator pathway and causes hypertension
    Sebastian Brähler
    Department of Internal Medicine Nephrology, Philipps University, Marburg, Germany
    Circulation 119:2323-32. 2009

Scientific Experts

  • Heike Wulff
  • Christoph Busch
  • Ananthakrishnan Sankaranarayanan
  • Joachim Hoyer
  • Sebastian Brähler
  • Ralf Köhler
  • Volker J Schmidt
  • Tim Schultz
  • Pavel I Zimin
  • Han Si
  • Anuradha Kaistha
  • Brajesh P Kaistha
  • Stephanie E Wölfle
  • Chris T Bond
  • Girija Raman
  • Cor de Wit
  • Anna Lena Hasenau
  • Michael Kacik
  • John P Adelman
  • Ivica Grgic

Detail Information

Publications3

  1. ncbi Modulators of small- and intermediate-conductance calcium-activated potassium channels and their therapeutic indications
    Heike Wulff
    Department of Medical Pharmacology and Toxicology, University of California, Davis, CA 95616, USA
    Curr Med Chem 14:1437-57. 2007
    ..1 as a target for the treatment of traumatic and possibly ischemic brain injury. Taken together KCa2 and KCa3.1 channels constitute attractive new targets for several diseases that currently have no effective therapies...
  2. ncbi Naphtho[1,2-d]thiazol-2-ylamine (SKA-31), a new activator of KCa2 and KCa3.1 potassium channels, potentiates the endothelium-derived hyperpolarizing factor response and lowers blood pressure
    Ananthakrishnan Sankaranarayanan
    Department of Pharmacology, University of California, Davis, California 95616, USA
    Mol Pharmacol 75:281-95. 2009
    ..The blood pressure-lowering effect of SKA-31 suggests KCa3.1 channel activation as a new therapeutic principle for the treatment of hypertension...
  3. ncbi Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived hyperpolarizing factor vasodilator pathway and causes hypertension
    Sebastian Brähler
    Department of Internal Medicine Nephrology, Philipps University, Marburg, Germany
    Circulation 119:2323-32. 2009
    ..To clarify the roles of SK3 and IK1 channels in the EDHF dilator response and their contribution to blood pressure control in vivo, we generated mice deficient for both channels...