Srdjan vlajkovic lecture 2
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Cochlear Homeostasis in
Stress and Injury
Srdjan Vlajkovic
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Abnormal Cochlear Homeostasis
• Noise-induced hearing loss
• Age-related hearing loss (presbyacusis)
• Ototoxicity
• Meniere’s disease
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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
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Problem?
• People working in construction or military
• Accidental exposure
Cellular bases of NIHL: prophylactic and
therapeutic drugs
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Effects of noise on the cochlea
IHC
OHC
S
L
Pillar cells
noise
SGN
SV
SL
SL
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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
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Disturbances of ionic balance in the cochlea due to the
loss of Type II and Type IV fibrocytes in the spiral
ligament. This can disrupt K+ cycling.
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Inflammation
Hirose et al.
(2005)
CD45+ Inflammatory Cells
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Damage to sensory hair cells by noise
Acute trauma
http://www.iurc.montp.inserm.fr/cric/audition/english/ear/fear.htm
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Glutamate excitotoxicity
http://www.iurc.montp.inserm.fr/cric/audition/english/ear/fear.htm
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OHC are the most prominent target for noise
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Oxidative stress and hair cell death
What 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.
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Free radical formation
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During noise exposure, the electron transport chain of the mitochondria
uses 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.
How are ROS/free radicals formed as a result of
noise?
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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).
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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.
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Damage to the cochlea by ROS
Green fluorescence: dichlorofluorescein (DCF)
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Apoptosis and necrosis in the noise-exposed cochlea
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The mechanisms of NIHL
Noise
Overdriving the
mitochondriaExcitotoxicity Ischemia/reperfusion Inflammation
Free radicals
Lipid peroxidation DNA
damage
Protein
damage
Apoptotic and necrotic cell death
Hearing loss Adapted from Henderson et al., 2006
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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
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ROS/Antioxidant Balance
Antioxidants 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
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Sound conditioning
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Sound conditioning and antioxidants
glutathione reductase -glutamyl cysteine synthetase catalase
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Antioxidants in prevention of NIHL
Local application (RWM):
• glutathione monoethyl ester (GSS): a precursor molecule to glutathione
Systemically 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.
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Prevention of NIHL by antioxidants
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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.
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Post-noise treatments
D-methionine (Campbell et al. 2007)
L-NAC and salicylate (Kopke et al. 2000)
Trolox and salicylate (Yamashita et al, 2005)
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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
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Post-exposure (24 h) treatment of NIHL with a
selective A1 adenosine receptor agonist ADAC
• 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
Vlajkovic et al., 2010
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Post-exposure (6 h) treatment of NIHL with ADAC
****** *** *** *** *** ***
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HAIR CELL SURVIVAL
Multiple ADAC injections
Multiple vehicle
injections
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Lipid peroxidation
A 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
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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.
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Cochlear blood flow and NIHL
A third point of intervention against NIHL may be prevention of the cochlear ischemia/reperfusionassociated 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
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Apoptotic cell death
The 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
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Inhibition of Src activity by KX1-004
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Inhibition of ROS formation by KX1-004
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Apoptotic pathways
In 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.
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Oxidative stress and acquired hearing loss
There 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.
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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.