Neuroprotective effects of low-dose G-CSF plus meloxicam in a rat model of anterior ischemic optic neuropathy

Abstract

Non-arteritic anterior ischemic optic neuropathy (NAION) causes a sudden loss of vision and lacks effective treatment. Granulocyte colony-stimulating factor (G-CSF) provides neuroprotection against the experimental optic nerve injuries but also induce leukocytosis upon typical administration. We found synergetic neuroprotective effects of meloxicam and low dose G-CSF without leukocytosis in a rat model of anterior ischemic optic neuropathy (rAION). The WBC counts in the low-dose G-CSF-plus meloxicam-treated group were similar to the sham-operated group. Combination treatment of lowdose G-CSF plus meloxicam preserved RGCs survival and visual function, reduced RGC apoptosis and the macrophages infiltration, and promote more M2 phenotype of macrophage/microglial transition than the low-dose GCSF treatment or the meloxicam treatment. Moreover, the combination treatment induced higher serine/threonine kinase 1 (Akt1) expression. The combination treatment of low-dose G-CSF plus meloxicam lessened the leukocytotic side effect and provided neuroprotective effects via Akt1 activation in the rAION model. This approach provides crucial preclinical information for the development of alternative therapy in AION. Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy in people older than 50 years. The estimated mean annual incidence rates of NAION are 2.3-10.3 per 100,000 in the United States and 3.72 per 100,000 in Taiwan 1-3. The debilitating consequences for patients with NAION include severe vision impairment and visual field defect. The primarily proposed pathogenesis of NAION is the transient nonperfusion or hypoperfusion of the optic nerve head and loss of retinal ganglion cells (RGCs) following ischemic insults. The histologic evidence in an early clinical case of human NAION demonstrated the presence of apoptotic cells in the RGC layer by 30 days after the event. This reaction eventually results in RGC death and vision loss 4. Currently, no definite treatment for NAION is available. Halting the injury and loss of RGCs may, therefore, rescue the visual deterioration and be a potential treatment strategy. Granulocyte colony-stimulating factor (G-CSF), a member of the cytokine family of growth factors, is a 19.6-kDa glycoprotein. It is commonly applied clinically to treat neutropenia 5. G-CSF can induce the mobilization of CD34 + hematopoietic stem cells from the bone marrow into the peripheral blood. G-CSF is commonly used in clinics for stem cell mobilization and bone marrow reconstitution 6-8. Our previous studies have demonstrated that G-CSF exerts neuroprotective effects on a rat model of anterior ischemic optic neuropathy (rAION). The protective effects of G-CSF on the rAION model are achieved through dual mechanisms of anti-inflammation and antiapoptosis 9,10. The antiapoptotic effect of G-CSF occurs through the activation of a variety of intracellular

The Benefits and Hazards of Intravitreal Mesenchymal Stem Cell (MSC) Based-Therapies in the Experimental Ischemic Optic Neuropathy

“…FVEPs were recorded in both eyes to examine the pattern of FVEPs. This procedure was approved by the Institutional Animal Care and Use Committee (IACUC) and was described in detail in our previous studies [ 36 , 37 ]. In brief, after administering the general anesthesia, the skin covering the skull was incised, and the brain surface was exposed using a dental drill.…”

“…Rats were euthanized by a gradual increase of CO 2 concentration (5 L/min) inside the sealed cage. The enucleated eyeballs along with ON were removed from the surrounding connective tissues, muscles, and cornea by microscissors to improve the fixation process [ 36 , 37 ]. Six eyeballs per group were then transferred to 4% paraformaldehyde for 1 h at room temperature.…”

Granulocyte Colony-Stimulating Factor-Induced TAF9 Modulates P53-TRIAP1-CASP3 Axis to Prevent Retinal Ganglion Cell Death after Optic Nerve Ischemia

“…The procedure of rAION induction was described in our previous study [31]. Before general anesthesia, all rats were administered Mydrin-P (Santan, Shiga, Japan) and Alcaine (Alcon, Texas, USA) eye drops for pupil dilation and topical anesthesia, respectively.…”

“…FVEP measurements were performed as described in our previous study [31]. After general anesthesia, the sagittal region of the skull was opened in the rats.…”

“…RGCs were labeled as described in our previous study [31]. Brie y, retrograde tracer dye uorogold was injected into the superior colliculus one week before the rats were euthanized.…”