Meningitis-associated hearing loss: protection against cochlear neuronal damage by adjunctive therapy with neurotrophins.
Dr Matthias Klein, Professor Hans-Walter Pfister
- Start Date:
01 January 2006
Klinikum Grosshadern Ludwig Maximilians University, Munich, Germany
One of the most common long term residues in survivors of bacterial meningitis is the development of hearing loss, which affects up to 30%. The reason for hearing loss in bacterial meningitis is the development of suppurative labyrinthitis which quickly destroys the blood-labyrinth barrier and leads to damage of the Organ of Corti. After recovery, massive loss of neuronal cells in the cochlear spiral ganglion is noted that increases over time. As a result, therapy with cochlear implants is often limited since it is dependent on the survival of the cochlear nerve. One explanation for the degeneration of the neurons is a missing neurotrophic input from
to the previously damaged Organ of Corti. A recent experimental study has shown that neuronal loss can be prevented by the administration of neurotrophic agents. However, this studiy has used clinically impractical intrathecal micropumps to administer neurotrophins. Here, the potential of a systemic administration of new and altered neurotrophic agents that have the potential to cross the blood-brain and blood-labyrinth barrier will be evaluated in an animal model of pneumococcal meningitis. Briefly, C57BL/6 mice will be infected by an intracisternal injection of Streptococcus pneumoniae. The infected animals will receive antibiotic therapy with ceftriaxone starting 24h after infection. In addition, adjunctive therapy with lecithinized- or pegylated- brain derived neurotrophic factor (BDNF), the immune modulator glatiramer acetate, neurotrophin-3 (NT-3) or placebo will be administered systemically for 2 weeks. Hearing will be assessed by auditory brainstem responses (ABR) and the cochlea will be evaluated histologically for neuronal cell counts in the spiral ganglion, damage to the Organ of Corti, labyrinthitis ossificans, and damage to the blood-labyrinth barrier. Using immunohistochemistry, the density of the neurotrophin receptors TrkB, and TrkC will be assessed and the endogenous production of neurotrophins will be evaluated immunhistochemically and by in situ hybridization.