Basic fibroblast growth factor (FGF‐2) protects rat cochlear hair cells in organotypical culture from aminoglycoside injury

Abstract

Given the evidence that basic fibroblast growth factor (FGF-2) can protect neural and retinal cells from degeneration, we evaluated the potential of this growth factor to protect sensory cells in the inner ear. When sensory cells of the organ of Corti are exposed to aminoglycoside antibiotics such as neomycin either in vivo or in vitro, significant ototoxicity is observed. The in vitro cytotoxic effects of neomycin are dose and time dependent. In neonatal rat organ of Corti cultures, complete inner and outer hair cell destruction is observed at high (mM) concentrations of neomycin while inner hair cell survival and severely damaged outer hair cells are noted at moderate (microM) concentrations, with a maximal effect observed after 2 days of culture. Approximately 50% of cochlear outer hair cells are lost at a dose of 35 microM neomycin, and most surviving cells show disorganized stereocilia. Inner hair cells show primarily disorganization of their stereocilia. A significant protective effect is observed when the organ of Corti is pre-treated with FGF-2 (500 ng/ml) for 48 hours, and then FGF-2 is included with neomycin in the culture medium. A greater extent of outer hair cell survival and a significant decrease in stereociliary damage are noted with FGF-2. However, disorganization of inner hair cell stereocilia is unaffected by FGF-2. The protective effect of FGF-2 is specific, since interleukin-1B, nerve growth factor, tumor necrosis factor, and epidermal growth factor are ineffective, while retinoic acid and transforming growth factor alpha show only a moderate protective effect. These results confirm the potential of molecules like FGF-2 for preventing cell death due to a variety of causes.

Growth factor treatment enhances vestibular hair cell renewal and results in improved vestibular function

“…Several possibilities exist to explain the observed vestibular HC renewal in response to growth factor therapy. Several growth factors have been demonstrated both in vitro (24,(34)(35)(36) and in vivo (37,38) to protect auditory sensory cells from aminoglycoside toxicity. However, in all of these studies the protectant molecule had to be present before ototoxin exposure.…”

A PI3K Pathway Mediates Hair Cell Survival and Opposes Gentamicin Toxicity in Neonatal Rat Organ of Corti

“…PKC is a lipid activated serine/threonine kinase and has been known to have both antiapoptotic and proapoptotic functions depending on its isoforms (Webb et al 2000;Bright and Mochly-Rosen 2005). Certain PKC isoforms can promote cell survival by directly phosphorylating Raf-1 without Ras activation and leading to activate Raf/MEK/Erk pathways (Kolch et al 1993;Huang et al 1995;McCubrey et al 2000;Oliva et al 2005). PKC isoforms can be activated by either PLCg or PI3K.…”

“…Growth factors known to activate PI3K and H-Ras (GDNF, FGF) are one possibility. Such factors have been shown to protect hair cells from toxicity in vitro (Low et al 1996;Kawamoto et al 2003). Small molecule analogs of signaling molecules are another potential mechanism.…”

Protection of auditory receptors and neurons: Evidence for interactive damage

“…4-6). It has also been shown that hair cells can be protected from damage by the exposure to certain non-neurotrophic growth factors (7,8), indicating that hair cells can be influenced by the activation of the same cell survival programs that operate in other tissues.…”

“…Neuronal damage may in fact amplify the effects of stimuli that damage hair cells. Such transcellular damage cannot be the sole means of hair cell injury because hair cells can be damaged by ototoxins in culture without neurons present (7). However, the data of Duan et al (1) suggest that a process involving cochlear neurons may make a substantial contribution to hair cell damage in vivo.…”