Hearing IED 1

1. ROS

   Nota:

   • FREE RADICALS - superoxide (02-) - hydroxyl radical (OH-) - peroxynitrite radical (ONOO-1-) GENERATE FREE RADICALS - h2o2 - ozone (O3)-
2. CAUSE

   Nota:

   • WHAT THEY CAUSE - common factor for hearing loss from noise, aminoglycoslide antibiotics, ototoxic anti cancer drugs, and raging
3. ACTIONS

   Nota:

   • WHAT THEY DO - ROS --> breakdown lipids and proteins in the membrane, damage DNA, 
4. HOW FORMED

   Nota:

   • HOW ARE THEY FORMED- noise --> electron transport chain of the mitochon uses a lot of O2 (lots of aerobic respiration) --> lots of SUPEROXIDE (unwanted by prod) is formed. superoxide goes and reacts with other stuff that generates more ROS

1. OHCS are affected and replaced by scars from supporting cells
2. Spiral gang neurons degenerate
3. Initial loss of basal cells and high frequencies

1. stereocilia damage

   Nota:

   • highest impact is on stereocilia of the hair cells → mechanical damage → high amp movement of basilar memb, → stereocilia bent and distorted - prolonged exposure → cells will undergo apoptosis and die 
2. Glutamate excitotoxicity

   Nota:

   • -->huge depol of cells and excessive release of Glutamate that acts on NMDA and AMPA receptors  --> swelling and destruction of post synp gang  --> this can recover, but prolonged exposure then  --> Ca entry to the synapse will eventually activate pro-apop pathways  --> loss of spiral gang neurons       
3. Inflammation

   Nota:

   • there are many different inflame cells and these can cause damage to the delicate structure of the inner ear  --> diagram shows infiltration happening at spiral ligament
4. Apoptosis and Necrosis

   Nota:

   • 1. apoptosis – process by which damaged cells are removed, diff cause, not well regulated, swelling of cells that will burst and spill their contents in ext cell space -> cause inflammation in the cochlea + organ of corti damaged in only one specific area --> many HCs are missing, many cells undergoing diff stages of apoptosis of necrosis 2. Necrosis – swelling of nuclei     
   • 1. apoptosis – process by which damaged cells are removed, diff cause, not well regulated, swelling of cells that will burst and spill their contents in ext cell space -> cause inflammation in the cochlea + organ of corti damaged in only one specific area --> many HCs are missing, many cells undergoing diff stages of apoptosis of necrosis 2. Necrosis – swelling of nuclei     

1. Epidemiology

   Nota:

   • - Onset: 45 - 54 - 44% by 69 - 66% by 79  - >90% over age of 80
2. OVERVIEW

   Nota:

   • - Env (trauma, aud stresses, otological diseases) + genetic factors (intrinsic, genetically controlled AGEING PROCESS) - loss begins at HIGHEST FREQs - social isolation, depression, loss of self- esteem  - reduced hearing sensitivity  - reduced speech understanding in NOISY ENVs  - slowed central processing or acoustic info  - impaired localisation.  SUMMARY - env+gene + red sensitivity + localisation + speech, slowed central processing + depression,social isolation. (6)
3. Pathology

   Nota:

   • - damage to SV --> stria atrophy  - loss of OHCs  - loss of spiral gang neutrons - degenerative processes in central aud pathways 
4. Classification

   Nota:

   • 1. sensory (Ohcs) --> ENV NOISE TOX 2. neural (neuronal cell loss) 3. metabolic (strial atrophy) --> HEREDITARY 3. mixed and indeterminate 
5. mechanisms

   Nota:

   • - reduction of vascularisation in the SV - oxidative stress (MITO damage APOP pathways)  - apoptosis  - collagen damage (fibrocytes 2 and 4 --> K+ cycling disruption and therefore EP) - accumulative noise exposure (accumulative OX STRESS)

1. whats been done

   Nota:

   • - degene of SV - loss of Na/K therefore reduced K secretion  - decline in EP (cant have transduction) dead battery hypothesis 
2. Animal examples

   Nota:

   • C57BL/6 - early onset hearing loss- ARHL (ahl) locus of the chrom 10 - carrying specific mutation in cadherin 23 imp for encoding component for hair cell tip link  CBA/CaJ- late onset hearing loss- ahl - resistance geneFisher (344 albino rat)- sensory ARHLMongolian gerbil - strial ARHL 
3. Changes in coch BVs

   Nota:

   • at 3months gerbils have very dense network of capillaries and are WIDE as they grow older --> capillary network much less dense + narrower + loss of connections with each other --> loss of vasculature --> atrophy of network at 18 months 

Nota:

• cause  - aminoglycoside ABs - platinum based chemotherapeutic agents  Both - damage hair cells in basal turn of organ of corti  - spiral gan neurons  - lateral wall tissues (func deficits)

1. AMINOGLYOSIDE OTO

   Nota:

   • - used in treatment of tuberculosis (streptomycin, gentamicin) - serious gram -ve back infections (back endocarditis, UTIs, pneumonia) 
2. APOPTOTIC CELL DEATH

   Nota:

   • ROS two forms of apoptosis - extrinsic (death R mediated apop) - intrinsic (mitochon mediated cascade) DIS DA ONE (next page)
   • Intrinsic mitochon mediated apoptosis - induced by aminoglycosides in cochlea  --> activation of stress activated JNK (protein kinases) --> with increase intracellular Ca and release of cytochrome C from mito --> cyt C --> activation of camasses 8, 9, 3--> cell death pathway 
3. CISPLATIN AND CARBOPLATIN

   Nota:

   • - Platnium containing anti cancer drugs (testicular, ovarian, bladder, head and neck, lung) --> nephrotoxicity, neurotoxicity, ototoxicity.  go on next page
   • Cisplatin toxicity - high incidence of hearing loss (80%) - ototox: tinnitus and bilateral high freq sensorineural hearing loss - prod of ROS --> capase dep app pathways  - ototox can be ameliorated by protective agents targeting oxidative stress and and apoptosis

1. The 5 things

   Nota:

   • - reduce glutamate excitotoxicity (NMDA inhib) - ensure good coach BF - suppression of inflammation  - antioxidants to restore normal balance with the free radicals - inhibit apop pathways to preserve hair cells
2. FREE RADS and ANTIOX BALANCE

   Nota:

   • we can preserve hair cells by increasing antiox supplies.  - application of exogenous anti-ox molecules or systematically in the body  - endogenously by sound conditioning 
3. ANTIOXS

   Nota:

   • molecules that scavenge molecules and convert them to less dangerous molecules.  - glutathione - vitamins A C E - Mg - catalase - superoxide dismutase - various peroxides 
4. HAIR CELL REGENE

   Nota:

   • gene transfer tech stem cells replacement Atoh1/GFP+ cells show morphological and molecular correlates of interaction and synaptogenesis