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Attenuation of Axonal Degeneration by Calcium Channel Inhibitors Improves Retinal Ganglion Cell Survival and Regeneration After Optic Nerve Crush

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Abstract

Axonal degeneration is one of the initial steps in many traumatic and neurodegenerative central nervous system (CNS) disorders and thus a promising therapeutic target. A focal axonal lesion is followed by acute axonal degeneration (AAD) of both adjacent axon parts, before proximal and distal parts follow different degenerative fates at later time points. Blocking calcium influx by calcium channel inhibitors was previously shown to attenuate AAD after optic nerve crush (ONC). However, it remains unclear whether the attenuation of AAD also promotes consecutive axonal regeneration. Here, we used a rat ONC model to study the effects of calcium channel inhibitors on axonal degeneration, retinal ganglion cell (RGC) survival, and axonal regeneration, as well as the molecular mechanisms involved. Application of calcium channel inhibitors attenuated AAD after ONC and preserved axonal integrity as visualized by live imaging of optic nerve axons. Consecutively, this resulted in improved survival of RGCs and improved axonal regeneration at 28 days after ONC. We show further that calcium channel inhibition attenuated lesion-induced calpain activation in the proximity of the crush and inhibited the activation of the c-Jun N-terminal kinase pathway. Pro-survival signaling via Akt in the retina was also increased. Our data thus show that attenuation of AAD improves consecutive neuronal survival and axonal regeneration and that calcium channel inhibitors could be valuable tools for therapeutic interventions in traumatic and degenerative CNS disorders.

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Acknowledgments

Paul Lingor was funded by the Else Kröner-Fresenius Foundation and the DFG-Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB). Vinicius Toledo Ribas is a fellow of the National Council for Scientific and Technological Development (CNPq), Brazil. We thank Elisabeth Barski and Vivian Dambeck for the excellent technical assistance. We thank Robert Siman from the University of Pennsylvania for the kind gift of the calpain-specific cleaved α-spectrin antibody.

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Authors and Affiliations

  1. Department of Neurology, University Medicine Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany

    Vinicius T. Ribas, Jan C. Koch, Uwe Michel, Mathias Bähr & Paul Lingor

  2. Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany

    Mathias Bähr & Paul Lingor

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  1. Vinicius T. Ribas
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  2. Jan C. Koch
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  3. Uwe Michel
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Correspondence to Paul Lingor.

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All animal experiments were performed with the approval of the governmental authorities and according to the legislation of the local animal research council of the State of Lower Saxony (Braunschweig), Germany.

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The authors declare that they have no competing interests.

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Ribas, V.T., Koch, J.C., Michel, U. et al. Attenuation of Axonal Degeneration by Calcium Channel Inhibitors Improves Retinal Ganglion Cell Survival and Regeneration After Optic Nerve Crush. Mol Neurobiol 54, 72–86 (2017). https://doi.org/10.1007/s12035-015-9676-2

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