title: Phosphodiesterase type 4 inhibitor rolipram improves survival of spiral ganglion neurons in vitro.
abstract: Sensorineural deafness is caused by damage of hair cells followed by degeneration of the spiral ganglion neurons and can be moderated by cochlear implants. However, the benefit of the cochlear implant depends on the excitability of the spiral ganglion neurons. Therefore, current research focuses on the identification of agents that will preserve their degeneration. In this project we investigated the neuroprotective effect of Rolipram as a promising agent to improve the viability of the auditory neurons. It is a pharmaceutical agent that acts by selective inhibition of the phosphodiesterase 4 leading to an increase in cyclic AMP. Different studies reported a neuroprotective effect of Rolipram. However, its significance for the survival of SGN has not been reported so far. Thus, we isolated spiral ganglion cells of neonatal rats for cultivation with different Rolipram concentrations and determined the neuronal survival rate. Furthermore, we examined immunocytologically distinct proteins that might be involved in the neuroprotective signalling pathway of Rolipram and determined endogenous BDNF by ELISA. When applied at a concentration of 0.1 nM, Rolipram improved the survival of SGN in vitro. According to previous studies, our immunocytological data showed that Rolipram application induces the phosphorylation and thereby activation of the transcription factor CREB. This activation can be mediated by the cAMP-PKA-signalling pathway as well as via ERK as a part of the MAP-kinase pathway. However, only in cultures pre-treated with BDNF, an endogenous increase of BDNF was detected. We conclude that Rolipram has the potential to improve the vitality of neonatal auditory nerve cells in vitro. Further investigations are necessary to prove the effect of Rolipram in vivo in the adult organism after lesion of the hair cells and insertion of cochlear implants.
authors.affiliation: Department of Otolaryngology, Hannover Medical School, Hannover, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Kranz
authors.affiliation: Department of Otolaryngology, Hannover Medical School, Hannover, Germany.
authors.forename: Athanasia
authors.initials: A
authors.lastname: Warnecke
authors.affiliation: Department of Otolaryngology, Hannover Medical School, Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lenarz
authors.affiliation: Department of Otolaryngology, Hannover Medical School, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Durisin
authors.affiliation: Department of Otolaryngology, Hannover Medical School, Hannover, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Scheper
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D051381:Rats; D020889:Rolipram / Q000494:pharmacology*; D015398:Signal Transduction; D013136:Spiral Ganglion / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D058988:Phosphodiesterase 4 Inhibitors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram