Rescue of cell death and inflammation of a mouse model of complex 1-mediated vision loss by repurposed drug molecules

Alfred K. Yu, Sandipan Datta, Marissa Z. McMackin, Gino A Cortopassi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Inherited mitochondrial optic neuropathies, such as Leber's hereditary optic neuropathy (LHON) and Autosomal dominant optic atrophy (ADOA) are caused by mutant mitochondrial proteins that lead to defects in mitochondrial complex 1-driven ATP synthesis, and cause specific retinal ganglion cell (RGC) loss. Complex 1 defects also occur in patients with primary open angle glaucoma (POAG), in which there is specific RGC loss. The treatment of mitochondrial optic neuropathy in the US is only supportive. The Ndufs4 knockout (Ndufs4 KO) mouse is a mitochondrial complex 1-deficient model that leads to RGC loss and rapid vision loss and allows for streamlined testing of potential therapeutics. Preceding RGC loss in the Ndufs4 KO is the loss of starburst amacrine cells, which may be an important target in the mechanism of complex 1-deficient vision loss. Papaverine and zolpidemwere recently shown to be protective of bioenergetic loss in cell models of optic neuropathy. Treatment of Ndufs4 KO mice with papaverine, zolpidem, and rapamycin-suppressed inflammation, prevented cell death, and protected from vision loss. Thus, in the Ndufs4 KO mouse model of mitochondrial optic neuropathy, papaverine and zolpidem provided significant protection from multiple pathophysiological features, and as approved drugs in wide human use could be considered for the novel indication of human optic neuropathy.

Original languageEnglish (US)
Pages (from-to)4929-4936
Number of pages8
JournalHuman Molecular Genetics
Volume26
Issue number24
DOIs
StatePublished - Dec 1 2017

Fingerprint

Drug Repositioning
Optic Nerve Diseases
Retinal Ganglion Cells
Cell Death
Papaverine
Inflammation
Knockout Mice
Autosomal Dominant Optic Atrophy
Leber's Hereditary Optic Atrophy
Amacrine Cells
Mitochondrial Proteins
Mutant Proteins
Sirolimus
Energy Metabolism
Therapeutics
Adenosine Triphosphate
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Rescue of cell death and inflammation of a mouse model of complex 1-mediated vision loss by repurposed drug molecules. / Yu, Alfred K.; Datta, Sandipan; McMackin, Marissa Z.; Cortopassi, Gino A.

In: Human Molecular Genetics, Vol. 26, No. 24, 01.12.2017, p. 4929-4936.

Research output: Contribution to journalArticle

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