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Inhibitors of cytochrome c release with therapeutic potential for Huntington's disease

Xin Wang1, Shan Zhu, Zhijuan Pei

  • 1Neuroapoptosis Laboratory and Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|September 19, 2008
PubMed

Insights

Researchers screened drugs to find inhibitors of cytochrome c release, a key factor in Huntington's disease (HD) cell death. This approach identified potential treatments for HD, with some drugs already FDA-approved and able to cross the blood-brain barrier.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Pharmacology

Background:

  • Mitochondrial cytochrome c release is implicated in neurodegenerative diseases.
  • The role of cytochrome c release in Huntington's disease (HD) remains unclear.
  • Identifying therapeutic targets for neuroprotection in HD is crucial.

Purpose of the Study:

  • To investigate the functional role of cytochrome c release in Huntington's disease.
  • To screen for novel inhibitors of mitochondrial cytochrome c release.
  • To evaluate the therapeutic potential of identified inhibitors in HD models.

Main Methods:

  • Screening of a drug library to identify inhibitors of cytochrome c release from isolated mitochondria.
  • Evaluation of effective compounds in a cellular HD model.
  • In-depth in vitro and in vivo assessment using a transgenic mouse model of HD.

Main Results:

  • Successful identification of compounds that inhibit cytochrome c release at the mitochondrial level.
  • Demonstrated the utility of mitochondrial screening for discovering cell death inhibitors.
  • Provided evidence for the functional significance of cytochrome c release in HD pathogenesis.
  • Identified drug candidates that are FDA-approved and blood-brain barrier penetrant.

Conclusions:

  • Mitochondrial screening is a viable strategy for identifying neuroprotective agents.
  • Cytochrome c release plays a significant functional role in Huntington's disease.
  • FDA-approved, blood-brain barrier-penetrant drugs identified may offer a pathway for clinical trials in HD patients.

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