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W. S. Cheung, L. Guo, N. Wood, M. F. Cordeiro; Assessment of a P38 Mitogen-Activated Protein Kinase (MAPK) Inhibitor in Experimental Glaucoma. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5496. doi: https://doi.org/.
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Inhibition of the mitogen-activated protein kinase (MAPK) p38 has been advocated as a neuroprotective strategy in stroke and focal ischaemia, where its activation is associated with inflammatory cytokine production and cell death following cellular stress. In this study, we have investigated the effects of a novel p38 MAPK inhibitor in experimental glaucoma.
Preliminary studies were performed to identify the most effective dose of a p38 MAPK inhibitor (0, 100, 200 and 500nM p38; Scios Inc. USA) using 12 Dark Agouti (DA) rats treated with intravitreal staurosporine, and assessed using DARC, with methods we have previously described. 40 DA rats with surgically-induced chronic ocular hypertension (OHT) were then randomly treated with intravitreal 200 nM p38 or vehicle control at the time of IOP elevation. DARC imaging was performed at 1.5, 3 and 8 weeks to assess RGC apoptosis in vivo. Histological analysis was also performed randomly at 1.5, 3 (n = 5 each treatment group) and 8 weeks (n=10).
The p38 MAPK inhibitor (200 nM) significantly reduced RGC apoptosis in the OHT model compared to vehicle control at 1.5 (p= 0.028) & 3 (p=0.017) weeks after IOP elevation. This was not significant however at 8 weeks. Levels of RGC apoptosis compared to control were quantified as 63.4%, 43.1%, and 18.3% at 1.5, 3 and 8 weeks respectively, with efficacy demonstrated both in vivo and histologically.
These results show that intravitreal p38 has a neuroprotective effect on RGC apoptosis in vivo in experimental glaucoma, and after a single application was able to affect the peak level of RGC apoptosis in this model 3 weeks after IOP elevation. Its effects by 8 weeks had decreased, suggesting that repeated applications may be an appropriate future dosing regimens. Our studies, however, suggest that inhibition of the mitogen-activated protein kinase (MAPK) pathway is a new and potential strategy for treatment of glaucoma, and needs further investigation.
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