A longitudinal comparison in cynomolgus macaques of the effect of brimonidine on optic nerve neuropathy using diffusion tensor imaging magnetic resonance imaging and spectral domain optical coherence tomography.

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.

Exploratory clinical characterization of experimentally-induced ulcerative colitis nonhuman primates.

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.

Pharmacologic Modulation of Noxious Stimulus-evoked Brain Activation in Cynomolgus Macaques Observed with Functional Neuroimaging.

Maintaining effective analgesia during invasive procedures performed under general anesthesia is important for minimizing postoperative complications and ensuring satisfactory patient wellbeing and recovery. While patients under deep sedation may demonstrate an apparent lack of response to noxious stimulation, areas of the brain related to pain perception may still be activated. Thus, these patients may still experience pain during invasive procedures. The current study used anesthetized or sedated cynomolgus macaques and functional magnetic resonance imaging (fMRI) to assess the activation of the parts of the brain involved in pain perception during the application of peripheral noxious stimuli. Noxious pressure applied to the foot resulted in the bilateral activation of secondary somatosensory cortex (SII) and insular cortex (Ins), which are both involved in pain perception, in macaques under either propofol or pentobarbital sedation. No activation of SII/Ins was observed in macaques treated with either isoflurane or a combination of medetomidine, midazolam, and butorphanol. No movement or other reflexes were observed in response to noxious pressure during stimulation under anesthesia or sedation. The current findings show that despite the lack of visible behavioral symptoms of pain during anesthesia or sedation, brain activation suggests the presence of pain depending on the anesthetic agent used. These data suggest that fMRI could be used to noninvasively assess pain and to confirm the analgesic efficacy of currently used anesthetics. By assessing analgesic efficacy, researchers may refine their experiments, and design protocols that improve analgesia under anesthesia.