Activation of protein kinase CbetaI constitutes a new neurotrophic pathway for deafferented spiral ganglion neurons.
In mammals, degeneration of peripheral auditory neurons constitutes one of the main causes of sensorineural hearing loss. Unfortunately, to date, pharmacological interventions aimed at counteracting this condition have not presented complete effectiveness in protecting the integrity of cochlear neural elements. In this context, the protein kinase C (PKC) family of enzymes are important signalling molecules that play a role in preventing neurodegeneration after nervous system injury. The present study demonstrates, for the first time, that the PKC signalling pathway is directly neurotrophic to axotomised spiral ganglion neurons (SGNs). We found that PKCbetaI was strictly expressed by postnatal and adult SGNs both in situ and in vitro. In cultures of SGNs, we observed that activators of PKC, such as phorbol esters and bryostatin 1, induced neuronal survival and neurite regrowth in a manner dependent on the activation of PKCbetaI. The neuroprotective effects of PKC activators were suppressed by pre-treatment with LY294002 (a PI3K inhibitor) and with U0126 (a MEK inhibitor), indicating that PKC activators promote the survival and neurite outgrowth of SGNs by both PI3K/Akt and MEK/ERK-dependent mechanisms. In addition, whereas combining the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) was shown to provide only an additive effect on SGN survival, the interaction between PKC and neurotrophin signalling gave rise to a synergistic increase in SGN survival. Taken together, the data indicate that PKCbetaI activation represents a key factor for the protection of the integrity of neural elements in the cochlea.
Lallemend
François
F
Research Centre for Cellular and Molecular Neurobiology, Developmental Neurobiology Unit, University of Liège, Av. de l'Hopital 1 B36, 4000 Liège, Belgium. flallemend@student.ulg.ac.be
Hadjab
Saïda
S
Hans
Grégory
G
Moonen
Gustave
G
Lefebvre
Philippe P
PP
Malgrange
Brigitte
B
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019771:Axotomy; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D054713:Bryostatins; D002070:Butadienes / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D009025:Morpholines / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D009416:Nerve Regeneration / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism; D020933:Neurotrophin 3 / Q000378:metabolism; D009570:Nitriles / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D051381:Rats; D017208:Rats, Wistar; D013136:Spiral Ganglion / Q000166:cytology*; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism
D000970:Antineoplastic Agents; D019208:Brain-Derived Neurotrophic Factor; D054713:Bryostatins; D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D018942:Macrolides; D009025:Morpholines; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D009570:Nitriles; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C046785:bryostatin 1; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D013755:Tetradecanoylphorbol Acetate