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Review
. 2022 Jun 27;23(13):7143.
doi: 10.3390/ijms23137143.

Erythropoietin in Optic Neuropathies: Current Future Strategies for Optic Nerve Protection and Repair

Yi-Fen Lai  1 , Ting-Yi Lin  1 , Pin-Kuan Ho  2 , Yi-Hao Chen  1 , Yu-Chuan Huang  3   4 , Da-Wen Lu  1
Affiliations
Review

Erythropoietin in Optic Neuropathies: Current Future Strategies for Optic Nerve Protection and Repair

Yi-Fen Lai et al. Int J Mol Sci. .

Abstract

Erythropoietin (EPO) is known as a hormone for erythropoiesis in response to anemia and hypoxia. However, the effect of EPO is not only limited to hematopoietic tissue. Several studies have highlighted the neuroprotective function of EPO in extra-hematopoietic tissues, especially the retina. EPO could interact with its heterodimer receptor (EPOR/βcR) to exert its anti-apoptosis, anti-inflammation and anti-oxidation effects in preventing retinal ganglion cells death through different intracellular signaling pathways. In this review, we summarized the available pre-clinical studies of EPO in treating glaucomatous optic neuropathy, optic neuritis, non-arteritic anterior ischemic optic neuropathy and traumatic optic neuropathy. In addition, we explore the future strategies of EPO for optic nerve protection and repair, including advances in EPO derivates, and EPO deliveries. These strategies will lead to a new chapter in the treatment of optic neuropathy.

Keywords: erythropoietin; neuroprotection; optic nerve protection; optic neuropathy; retinal ganglion cell.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Binding of EPO to EPOR induces JAK-2 phosphorylation, dimerization, and subsequently activate STAT5/3, Ras/Raf/MEK/ERK, PI3-K/Akt, and NF-κB pathways. JAK-2 phosphorylates STAT5 or STAT3, leading to the dimerization of STAT5 (STAT3). STAT5 (STAT3) and the last signaling molecule in the MAPK pathway translocate into the nucleus and upregulate the expression of antiapoptotic Bcl-2 and Bcl-xL. Activation of PI3-k/Akt pathway increases endothelial nitric oxide synthase (eNOS) protein expression and NO production, which could increase blood flow and attenuate regional injury. PI3-k/Akt pathway also phosphorylates transcription factor GATA-1 and Foxo3 A, which enhance the expression of antiapoptosis proteins. Activation of the IKK complex by Akt phosphorylates IκB, resulting in its ubiquitination, and degradation, and in the releases of bound NF-κB. Free NF-κB translocates into the nucleus and exerts its antiapoptosis activity through the expression of inhibitors of apoptotic proteins (IAPs). Furthermore, binding of EPO to EPOR/βcR activates Wnt signaling, which inhibits GSK-3β phosphorylation and allow β-catenin to stabilize and accumulate in the cytoplasm in a non-phosphorylated form. Free β-catenin translocates into the nucleus and trigger transcription of Wnt-target gene responsible for cell antiapoptosis and the development of nervous system. Activation of NMDA receptors allows the influx of Ca2+, which induces excitotoxicity via initiation of the μ-calpain/Bax/cytochrome c/caspase-9 pathway. The caspases result in DNA fragmentation and lead to cell apoptosis. Activation of PI3-K/Akt pathway could also inhibit caspase activity by preventing cytochrome c leakage from mitochondria, thus inhibiting DNA degradation.
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