Akt/Protein Kinase B Prevents Injury-Induced Motoneuron Death and Accelerates Axonal Regeneration

Abstract

Motoneurons require neurotrophic factors for their survival and axonal projection during development, as well as nerve regeneration. By using the axotomy-induced neuronal death paradigm and adenovirus-mediated gene transfer, we attempted to gain insight into the functional significances of major growth factor receptor downstream cascades, Ras-extracellular signalregulated kinase (Ras-ERK) pathway and phosphatidylinositol-3 kinase-Akt (PI3K-Akt) pathway. After neonatal hypoglossal nerve transection, the constitutively active Akt-overexpressing neurons could survive as well as those overexpressing Bcl-2, whereas the constitutively active ERK kinase (MEK)-overexpressing ones failed to survive. A dominant negative Akt experiment demonstrated that inhibition of Akt pathway hastened axotomy-induced neuronal death in the neonate. In addition, the dominant active Akt-overexpressing adult hypoglossal neurons showed accelerated axonal regeneration after axotomy. These results suggest that Akt plays dual roles in motoneuronal survival and nerve regeneration in vivo and that PI3K-Akt pathway is probably more vital in neuronal survival after injury than Ras-ERK pathway.

Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease

“…Akt also has been demonstrated to regulate axonal growth. In culture, Akt expression modifies axon branching of peripheral sensory neurons (13), and, in vivo, it regulates the rate of regeneration of peripheral motor nerves after axotomy (14). We demonstrate here in the central nervous system that Akt also regulates axon sprouting in both adult and aged animals, either in the presence or absence of injury.…”

“…Akt signaling mediates two principal cellular responses to neurotrophic factors. It maintains viability through antiapoptotic effects [reviewed in Brunet et al (12)], and it mediates effects on axonal caliber, branching (13), and regeneration (14). Almost all of these observations, however, have been made in vitro, and it has not been known whether they generalize to the in vivo context, particularly in the central nervous system.…”

Involvement of Acidic Fibroblast Growth Factor in Spinal Cord Injury Repair Processes Revealed by a Proteomics Approach

“…A previous study has shown that aFGF is able to protect PC12 cells from glutamate-induced apoptosis via activation of the PI3K/AKT/GSK-3␤ pathway. Furthermore the ERK, the Akt pathway, or both are crucial for neuron survival under cell death stress, and either ERK or Akt activation is enough to rescue PC12 cells from apoptosis induced by neuron growth factor withdraw (84,85).…”

Bcl-2 expression by retrograde transport of adenoviral vectors with Cre-loxP recombination system in motor neurons of mutant SOD1 transgenic mice

“…Namikawa et al 35 have reported that Akt/protein kinase B prevented injury-induced motor neuron death and accelerated axonal regeneration using the Cre-loxP system. In the present study, we did not show the effect of exogenous Bcl-2 in vivo motor neurons of mutant SOD1 transgenic mice; however, such studies have been ongoing.…”