Reversal of Agerelated Learning Deficits and Brain Oxidative Stress in Mice with Superoxide Dismutas

1
Reversal of Age-related Learning Deficits and
Brain Oxidative Stress in Mice with Superoxide
Dismutase/catalase Mimetics

• Liu, Liu, Bi, Thompson

2
Background

• Loss of learning and memory function from 8-11
  months in aging mice is associated with increases
  in markers of brain oxidative stress.
• Contextual fear learning and levels of protein
  oxidation in brain show strong negative
  correlation.

3
Hypothesis

• Clinical application of synthetic catalytic
  scavengers of ROS are beneficial in reversing
  age-related learning deficits.

4
Treat mice with SOD mimetics

• SOD mimetics from Eukarion EUK-189 and EUK-207.
• Female mice at 8 months old randomly assigned to
  6 groups (16-18 per group)
• control
• untreated control
• low dose EUK-189
• high dose EUK-189
• low dose EUK-207
• high doseEUK-207

5

• Minipumps implanted in anesthetized mice.
• drug delivered for 28 days
• low rate 9nmol/day
• high rate 0.09 ?mol/day
• Pumps replaced twice of over 3 months of
  treatment.

6
Behavioral testing after 3 months

• Plexiglass cages.
• Videocam to record freezing behaviour (index of
  fear conditioning).
• Computer to control events.
• Mice placed alone in clean chamber.

7

• Day 1 3 minutes elapse, 3 tones sound,
  footshock, 1 minute later mouse removed.
• Day 2 testing for conditioning to context, no
  sound, no footshock, 8 minutes later mouse
  removed
• Day 3 testing for conditioning to tone, mice
  placed in different chamber,1 minute elapses, 1
  tone sounds, 7 minutes later mouse removed

8
Behavioral Analysis

• Fear conditioning measured as of time mice
  exhibited a freezing response (absence of all
  movement except breathing)
• Measured for auditory (startle threshold) and
  visual functions.
• Measured for nociception ( onset latency to tail
  flick at 51C hotplate)

9
Effects of SOD/catalase mimetic on fear
conditioning learning

• control mice show low levels of freezing for both
  tone and context (indicates impaired learning and
  memory at middle age)
• SOD mimetic mice show increased tone and context
  freezing at both doses
• Compared EUK-207 mice at 11 months old to control
  mice at 8 months old drug appears to reverse
  impairment of older mice

10
Effects of SOD/catalase mimetic on brain
oxidative stress

• Mimetics decreased age-related free-radical
  damage
• decreased lipid peroxidation
• decreased protein oxidation