NADPH Oxidase Inhibitors as a Treatment for Amyotrophic Lateral Sclerosis

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NADPH Oxidase Inhibitors as a Treatment for
Amyotrophic Lateral Sclerosis

• By Thomas Lew
• Mentor Dr. Joe Beckman
• Linus Pauling Institute

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Amyotrophic Lateral Sclerosis

• Results from the death
• of motor neurons
• Muscle degeneration
• Paralysis
• Death

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Amyotrophic Lateral Sclerosis

• Majority of ALS cases are sporadic but some
  inherit mutant SOD1 gene
• SOD1 gene codes for copper-zinc superoxide
  dismutase (SOD)
• SOD scavenges superoxide

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SOD Mutations and ALS

• Over 100 different ALS causing mutations have
  been discovered dispersed throughout the SOD1
  gene
• Transgenic mouse model SOD1G93A

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NADPH Oxidase (Nox)

• Nox catalyzes the reduction of oxygen to
  superoxide
• Starts cascade of motor neuron destruction

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Superoxide Generation
Outside of cell or lumen of phagosome
Bedard, K. et al. Physiol Rev 2007, 87, 245
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NADPH Oxidase

• Nox catalyzes the reduction of oxygen to
  superoxide
• Starts cascade of motor neuron destruction
• NADPH oxidase (Nox) KO mutants delayed onset
  (Engelhardt et al.)

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Engelhardt Results
Marden, J. et al J.
Clin. Invest. 2007, 117, 2913


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Apocynin

• Plant-derived Picrorhiza kurroa
• Nox-inhibitor

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Diapocynin

• Apocynin is thought to be metabolically active as
  a dimer

Peroxidase oxidation
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Objective

• Test if the Engelhardt results are reproducible
• Compare the efficacy of apocynin and diapocynin
  as a treatment for ALS

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Hypothesis

• Nox is an important initial catalyst for
  oxidative damage in ALS patients and thus by
  inhibiting this pathway of free radical
  generation, motor neuron death resulting from ALS
  will be delayed

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Salicylamine

• Pyridoxamine lipophilic analogue
• Lipid peroxidation inhibitor
• Protective against isoketal toxicity

NH2
OH
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Methods

• Synthesize apocynin, diapocynin, and salicyl-
  amine treatments
• Treat ALS (G93A) mice over lifetime
• Measure onset of disease via
• Weight loss
• Hang test
• Stride test

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Hang Test
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Stride Test
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Results
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Implications

• Know much about mechanism, but still no treatment
• Nox looks like a promising new therapeutic target
• If animal models successful, move to clinical
  trials

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Acknowledgements

• Howard Hughes Medical Institute
• Dr. Kevin Ahern
• Dr. Joe Beckman
• Dr. Kari Trumbull
• The Beckman Lab