Srdjan VlajkovicCochlear Homeostasis in   Stress and Injury
Abnormal Cochlear Homeostasis•   Noise-induced hearing loss•   Age-related hearing loss (presbyacusis)•   Ototoxicity•   M...
Noise-induced hearing loss (NIHL)A significant source of hearing loss in industrial  societies.Focus on prevention:  - hea...
Problem?• People working in construction or military• Accidental exposureCellular bases of NIHL: prophylactic and therapeu...
Effects of noise on the cochlea                                       SL                                       S          ...
The effect of noise on the stria vascularis and                 blood vessels• High level noise - acute swelling of the st...
Disturbances of ionic balance in the cochlea due to theloss of Type II and Type IV fibrocytes in the spiralligament. This ...
InflammationCD45+ Inflammatory Cells                       Hirose et al.                          (2005)
Damage to sensory hair cells by noise                  Acute traumahttp://www.iurc.montp.inserm.fr/cric/audition/english/e...
Glutamate excitotoxicityhttp://www.iurc.montp.inserm.fr/cric/audition/english/ear/fear.htm
OHC are the most prominent target for noise
Oxidative stress and hair cell deathWhat active mechanisms at the cellular level are triggering hair cell death?• A number...
Free radical formation
How are ROS/free radicals formed as a result of                   noise?During noise exposure, the electron transport chai...
Reactive oxygen species (ROS)• Oxygen-based molecules that act as free radicals:  - superoxide (O2-)  - hydroxyl radical (...
What are the mechanisms of ROS-induced loss of sensory cells?• ROS and free radicals are capable of damaging DNA, breaking...
Damage to the cochlea by ROSGreen fluorescence: dichlorofluorescein (DCF)
Apoptosis and necrosis in the noise-exposed                 cochlea
The mechanisms of NIHL                                NoiseOverdriving the     Excitotoxicity   Ischemia/reperfusion      ...
Pharmacological interventions to reduce                hearing loss(1) restoring the normal balance of free radicals with ...
ROS/Antioxidant BalanceAntioxidants are molecules that scavenge ROS and convert  them to less dangerous molecules.Increasi...
Sound conditioning
Sound conditioning and antioxidantsglutathione reductase   -glutamyl cysteine synthetase   catalase
Antioxidants in prevention of NIHLLocal application (RWM):• glutathione monoethyl ester (GSS): a precursor molecule to  gl...
Prevention of NIHL by antioxidants
Treatment after noise exposure              (rescue phenomenon)• Prophylactic agents: administered before and  usually dur...
Post-noise treatmentsL-NAC and salicylate (Kopke et al. 2000)                                           Trolox and salicyl...
Adenosine in Tissue Protection and Regeneration • Boost antioxidant defences • Improve blood flow and oxygen supply • Inhi...
Post-exposure (24 h) treatment of NIHL with aselective A1 adenosine receptor agonist ADAC                                 ...
Post-exposure (6 h) treatment of NIHL with ADAC ***   ***   ***   ***   ***   ***   ***
HAIR CELL SURVIVAL                        Multiple ADAC injections     Multiple vehicle           injections
Lipid peroxidationA process through which ROS and free radicals break down lipid molecules.   It is a self-perpetuating pr...
Inhibition of lipid peroxidation• Pharmacological inhibition of lipid peroxidation may be a  method for rescue of hearing ...
Cochlear blood flow and NIHLA third point of intervention against NIHL may be  prevention of the cochlear ischemia/reperfu...
Apoptotic cell deathThe final point of intervention is at the level of the  cellular signals responsible for apoptotic cel...
Inhibition of Src activity by KX1-004
Inhibition of ROS formation by KX1-004
Apoptotic pathwaysIn addition to the Src and JNK signaling pathways,   numerous other pathways are involved in the inducti...
Oxidative stress and acquired hearing lossThere is growing evidence that oxidative stress in the  cochlea may be a common ...
Recommended reading:• Henderson et al. (2006) The role of oxidative stress in  noise-induced hearing loss. Ear & Hearing 2...
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Srdjan vlajkovic lecture 2

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Srdjan vlajkovic lecture 2

  1. 1. Srdjan VlajkovicCochlear Homeostasis in Stress and Injury
  2. 2. Abnormal Cochlear Homeostasis• Noise-induced hearing loss• Age-related hearing loss (presbyacusis)• Ototoxicity• Meniere’s disease
  3. 3. Noise-induced hearing loss (NIHL)A significant source of hearing loss in industrial societies.Focus on prevention: - hearing conservation programs - use of protection devices - frequent screening - education on the causes and ways to prevent it
  4. 4. Problem?• People working in construction or military• Accidental exposureCellular bases of NIHL: prophylactic and therapeutic drugs
  5. 5. Effects of noise on the cochlea SL S L OHC SVSGN SL IHC noise Pillar cells
  6. 6. The effect of noise on the stria vascularis and blood vessels• High level noise - acute swelling of the stria vascularis• Loss of intermedate cells (permanent)• Stria shrinks as a long-term result• Reduction in cochlear blood flow (CBF) heavily influenced by the length and intensity of the noise exposure• Consequence: elevated auditory thresholds and damage to the vital cochlear tissues
  7. 7. Disturbances of ionic balance in the cochlea due to theloss of Type II and Type IV fibrocytes in the spiralligament. This can disrupt K+ cycling.
  8. 8. InflammationCD45+ Inflammatory Cells Hirose et al. (2005)
  9. 9. Damage to sensory hair cells by noise Acute traumahttp://www.iurc.montp.inserm.fr/cric/audition/english/ear/fear.htm
  10. 10. Glutamate excitotoxicityhttp://www.iurc.montp.inserm.fr/cric/audition/english/ear/fear.htm
  11. 11. OHC are the most prominent target for noise
  12. 12. Oxidative stress and hair cell deathWhat active mechanisms at the cellular level are triggering hair cell death?• A number of studies emerged showing increased reactive oxygen species (ROS) and free radicals during and after noise exposure.• Free radicals are molecules with an unpaired electron capable of altering the electron arrangements in stable molecules.
  13. 13. Free radical formation
  14. 14. How are ROS/free radicals formed as a result of noise?During noise exposure, the electron transport chain of the mitochondriauses large amounts of oxygen, which can then create large amounts of superoxide as an unwanted byproduct. The increased superoxide can then react with other molecules to generate higher levels of other ROS in the cochlea.
  15. 15. Reactive oxygen species (ROS)• Oxygen-based molecules that act as free radicals: - superoxide (O2-) - hydroxyl radical (OH-) - peroxynitrite radical (ONOO ·1-)• Readily capable of generating free radicals: - hydrogen peroxide (H2O2) - ozone (O3).
  16. 16. What are the mechanisms of ROS-induced loss of sensory cells?• ROS and free radicals are capable of damaging DNA, breaking down lipid and protein molecules, and triggering cell death, all of which can contribute to the loss of function seen after noise• Lipid peroxidation: a series of reactions through which free radicals and ROS can break down lipid molecules.
  17. 17. Damage to the cochlea by ROSGreen fluorescence: dichlorofluorescein (DCF)
  18. 18. Apoptosis and necrosis in the noise-exposed cochlea
  19. 19. The mechanisms of NIHL NoiseOverdriving the Excitotoxicity Ischemia/reperfusion Inflammation mitochondria Free radicals Lipid peroxidation DNA Protein damage damage Apoptotic and necrotic cell death Hearing loss Adapted from Henderson et al., 2006
  20. 20. Pharmacological interventions to reduce hearing loss(1) restoring the normal balance of free radicals with antioxidants(2) reducing glutamate excitotoxicity with NMDA receptor antagonists(3) maintaining adequate cochlear blood flow during and after noise(4) reducing inflammation(5) inhibiting pathways to apoptotic cell death to preserve hair cells
  21. 21. ROS/Antioxidant BalanceAntioxidants are molecules that scavenge ROS and convert them to less dangerous molecules.Increasing cochlear antioxidant supplies can substantially prevent HC damage and hearing loss.Antioxidant levels can be increased in two ways:• application of exogenous antioxidant molecules directly into the cochlea or systemically into the body;• endogenously by using sound conditioning
  22. 22. Sound conditioning
  23. 23. Sound conditioning and antioxidantsglutathione reductase -glutamyl cysteine synthetase catalase
  24. 24. Antioxidants in prevention of NIHLLocal application (RWM):• glutathione monoethyl ester (GSS): a precursor molecule to glutathioneSystemically injected:• Allopurinol (an inhibitor of ROS production)• Superoxide dismutase (ROS scavenger)• Mannitol (a scavenger of the hydroxyl (OH-) radical)• GSS• LNAC (n-l-acetylcysteine): antioxidant properties and increases levels of glutathione.• Salicylate (can scavenge the hydroxyl radical)• Acetyl-l carnitine (ALCAR) improves mitochondrial respiration efficiency, leading to decreased ROS production during noise.• DMET (d-methionine) increases the levels of available cochlear glutathione. ALCAR and DMET provided nearly 100% protection against noise-induced PTS, OHC and IHC loss.
  25. 25. Prevention of NIHL by antioxidants
  26. 26. Treatment after noise exposure (rescue phenomenon)• Prophylactic agents: administered before and usually during and after noise exposure• Rescue agents: first administered after noise exposure but before permanent NIHL has occurred• Regeneration of hair cells for permanent NIHL is a different research area• Rescue Phenomenon: Continued free radical formation in the cochlea for 7-10 days after noise exposure• First 24 hrs after noise exposure could be a critical period for antioxidant intervention.
  27. 27. Post-noise treatmentsL-NAC and salicylate (Kopke et al. 2000) Trolox and salicylate (Yamashita et al, 2005) D-methionine (Campbell et al. 2007)
  28. 28. Adenosine in Tissue Protection and Regeneration • Boost antioxidant defences • Improve blood flow and oxygen supply • Inhibit the release of neurotransmitters • Stabilise cells by stimulating K+ and inhibiting Ca2+ channels • Suppress inflammation • Promote anti-apoptotic pathways • Promote angiogenesis
  29. 29. Post-exposure (24 h) treatment of NIHL with aselective A1 adenosine receptor agonist ADAC Vlajkovic et al., 2010• Noise exposure: 110 dB SPL (8-12 kHz) for 24 hours• ADAC administration 6 or 24 hrs after noise• Single or multiple i.p. injections
  30. 30. Post-exposure (6 h) treatment of NIHL with ADAC *** *** *** *** *** *** ***
  31. 31. HAIR CELL SURVIVAL Multiple ADAC injections Multiple vehicle injections
  32. 32. Lipid peroxidationA process through which ROS and free radicals break down lipid molecules. It is a self-perpetuating process that may be contributing to the expansion of the HC death lesion after noise. 0 days 2 days 4 days
  33. 33. Inhibition of lipid peroxidation• Pharmacological inhibition of lipid peroxidation may be a method for rescue of hearing after noise exposure.• A series of drugs that reduce lipid peroxidation effects in the organ of Corti (e.g. Lazaroid) were also found to limit noise-induced threshold shift.
  34. 34. Cochlear blood flow and NIHLA third point of intervention against NIHL may be prevention of the cochlear ischemia/reperfusion associated with noise exposure.• Drugs that promote blood flow: - Cardiac output can be increased, - Cochlear blood vessels can be dilated, - Blood can be thinned by expanding the plasma content.• Inhibition of angiotensin II receptors by Sarthran leads to maintenance of normal blood vessel diameter during noise, and reduction of TTS• Inhibition of the receptors for norepinephrine, increase CBF and reduce noise-induced TTS
  35. 35. Apoptotic cell deathThe final point of intervention is at the level of the cellular signals responsible for apoptotic cell death.• CEP-1347, a selective c-Jun-N-terminal (JNK) inhibitor• KX1-004, a potent inhibitor of Src activity• Riluzole, a neuroprotective agent that restricts excitotoxicity and apoptotic and necrotic cell death
  36. 36. Inhibition of Src activity by KX1-004
  37. 37. Inhibition of ROS formation by KX1-004
  38. 38. Apoptotic pathwaysIn addition to the Src and JNK signaling pathways, numerous other pathways are involved in the induction of apoptosis.• The caspases enzyme cascade plays a key role in the execution of apoptotic cell death in the HC.• The calpain enzyme pathway, a series of calcium- dependent enzymes involved in breaking down cells during apoptosis, has also been targeted. Leupeptin, a calpain inhibitor, protected chinchilla HC and reduced TTS.
  39. 39. Oxidative stress and acquired hearing lossThere is growing evidence that oxidative stress in the cochlea may be a common factor for hearing loss from aminoglycoside antibiotics, ototoxic anticancer drugs and aging.
  40. 40. Recommended reading:• Henderson et al. (2006) The role of oxidative stress in noise-induced hearing loss. Ear & Hearing 27:1-19.• Le Prell et al. (2007) Mechanisms of noise-induced hearing loss indicate multiple methods of prevention Hearing Research 226:22-43.

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