Carvedilol Promotes Retinal Ganglion Cell Survival Following Optic Nerve Injury via ASK1-p38 MAPK Pathway

Author(s): Bei Liu*, Yu-Jia Liu.

Journal Name: CNS & Neurological Disorders - Drug Targets
(Formerly Current Drug Targets - CNS & Neurological Disorders)

Volume 18 , Issue 9 , 2019

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Graphical Abstract:


Abstract:

Background: Carvedilol, which is considered as a nonselective β-adrenoreceptor blocker, has many pleiotropic activities. It also causes great impact on neuroprotection because of its antioxidant ability, which suggested that carvedilol may be effective in protecting RGCs from increased oxidative stress.

Objective: To examine the effects of carvedilol on preventing Retinal Ganglion Cell (RGC) death in a mouse model of Optic Nerve Injury (ONI).

Methods: C57BL/6J mice were subjected to Optic Nerve Injury (ONI) model and treated with carvedilol or placebo. Histological and morphometric studies were performed; the RGC number, the amount of neurons in the ganglion cell layer and the thickness of the Inner Retinal Layer (IRL) was quantified. The average thickness of Ganglion Cell Complex (GCC) was determined by the Spectral- Domain OCT (SD-OCT) assay. Immunohistochemistry, western blot and quantitative real-time PCR analysis were also applied.

Results: Daily treatment of carvedilol reduced RGC death following ONI, and in vivo retinal imaging revealed that carvedilol can effectively prevent retinal degeneration. The expression of chemokines important for micorglia recruitment was deceased with carvedilol ingestion and the accumulation of retinal microglia is reduced consequently. In addition, the ONI-induced expression of inducible nitric oxide synthase in the retina was inhibited with carvedilol treatment in the retina. We also discovered that carvedilol suppressed ONI-induced activation of Apoptosis Signal-regulating Kinase-1 (ASK1) and p38 Mitogen-Activated Protein Kinase (MAPK) pathway.

Conclusion: The results of this study indicate that carvedilol can stimulate neuroprotection and neuroregeneration, and may be useful for treatment of various neurodegenerative diseases.

Keywords: Carvedilol, retinal ganglion cell, optic nerve injury, microglia, p38 MPAK, optic neuropathy.

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VOLUME: 18
ISSUE: 9
Year: 2019
Page: [695 - 704]
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DOI: 10.2174/1871527318666191002095456
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