ABSTRACT
Early detection of optic neuropathy is crucial for initiating treatment that could delay or prevent visual field loss. Preclinical studies have advanced a number of potential neuroprotective strategies to prevent retinal ganglion cell (RGC) degeneration, but none have successfully completed clinical trials. One issue related to the lack of preclinical to clinical translation is the lack of preclinical morphometric assessments that could be used to track neuroprotection, as well as neurodegeneration, over time within the same animal. Thus, to assess whether clinically used morphometric assessments can identify neuroprotection of RGC, the current study compared optic nerve fractional anisotropy (FA) obtained with diffusion tensor imaging (DTI) and retinal nerve fiber layer (RNFL) thickness measured with spectral domain optical coherence tomography (SD-OCT) to observe not only the early progression of RGC axonal degeneration but to also discern which imaging modality identifies signs of neuroprotection during treatment with the alpha-adrenoceptor agonist brimonidine. Elevated and sustained intraocular pressure (IOP) was observed following laser photocoagulation of the trabecular meshwork in one eye of nonhuman primates (NHP). Either brimonidine (0.1%) or control treatment was instilled twice daily for two months. In control-treated eyes, increased IOP, increased vertical cup-to-disc (C/D), reduced rim-to-disc (R/D) ratio, decreased RNFL thickness and decreased FA were observed. While IOP remained elevated during the course of the study, brimonidine tended to delay the progression of RNFL thinning. However, in the same animal, optic nerve FA did not appear to decline. Brimonidine treatment did not affect other measures of RGC axonal degeneration. The current findings demonstrate that early progression of optic neuropathy can be tracked over time in a nonhuman primate model of ocular hypertension using either DTI or SD-OCT. Furthermore, the delayed changes to RNFL thickness and FA appear to be a neuroprotective effect of brimonidine independent of its effect on IOP.
ABSTRACT
A limitation of currently used preclinical models of colitis is that disease and treatment assessment methods differ from clinically used methods. Thus, a modified Mayo score and an endoscopic index (EI) were developed for use in cynomolgus macaques with 0.25% dextran sulfate sodium (DSS)-induced ulcerative colitis. Macaques were treated with water with DSS for two weeks followed by water without DSS for two weeks. Disease activity was classified according to a modified Mayo score: stool consistency, rectal bleeding, colonoscopy examination and global assessment. Findings on colonoscopy were further graded according the Rachmilewitz EI. To demonstrate the sensitivity of the modified Mayo score and EI to therapeutic intervention, macaques were treated with the anti-inflammatory steroid prednisolone followed eight weeks later by the integrin antibody vedolizumab. Before DSS treatment, normal stool consistency and no rectal bleeding were observed. Colonoscopy demonstrated no mucosal abnormalities. Following the first DSS treatment, Mayo score and EI indicated signs of mild colitis. Following subsequent DSS treatments, mild to moderate colitis emerged with each DSS treatment and reduced signs of colitis were observed 2 weeks after DSS treatment termination. Prednisolone treatment during DSS treatment suppressed the emergence of colitis. Vedolizumab reduced signs of colitis during DSS treatment and further reduced signs of colitis that persisted after termination of DSS treatment. The current study demonstrated the potential of utilizing clinical outcome measures to assess experimentally-induced colitis in the macaque. Furthermore, signs of colitis, as assessed with the current methods, were reduced following therapeutic treatment. The current findings suggest that clinically relevant outcome measures in the macaque model of ulcerative colitis could be used to test novel treatments.
