Rescue and restoration of inner ear function: are growth factors useful?

Abstract

During recent years increased understanding of the molecular mechanisms of hair cell/neuronal death in the inner ear has started to offer new possibilities for preventing traumatic hair cell loss. In search for putative therapeutic agents, growth factors (GFs) have been proposed. GFs are a class of gene products (polypeptides) that are particularly important during development, regulating cell division and differentiation but also acting as survival factors during adulthood. Neurotrophins NT‐3 and BDNF, in particular, are putative therapeutic agents for cochlear and vestibular neurons as they and their receptors are present and active in the inner ear. For GF‐based pharmacological therapy, however, limits are set by the short half‐life of recombinant polypeptides and by the fact that these large molecules do not cross the blood labyrinthine barrier.

 New knowledge about the molecular mechanisms involved in stress‐induced hair‐cell death suggests that the intracellular signalling cascades involved in the commitment to and execution of cell death play key roles also in cochlear damage. Acoustic overstimulation and ototoxicity are stress stimuli that lead to oxidative stress followed by the death of hair cells. At least a subset of hair cells dies by apoptosis. The JNK (c‐Jun N‐terminal kinase) intracellular signalling pathway that couples exogenous stresses and cellular death is activated in cochlear hair cells after trauma. Inhibition of JNK activation by a small non‐protein compound, CEP‐1347, attenuates noise‐ and aminoglycoside‐induced hair‐cell death. Our results suggest that therapeutic intervention in the JNK signalling cascade may offer opportunities to treat inner ear‐specific injuries.

• noise
• ototoxicity
• hair cells
• apoptosis modulation
• neurotrophic factors
• JNK
• therapy