RESUMO
There are no known drugs or drug combinations that promote substantial central nervous system axonal regeneration after injury. We used systems pharmacology approaches to model pathways underlying axonal growth and identify a four-drug combination that regulates multiple subcellular processes in the cell body and axons using the optic nerve crush model in rats. We intravitreally injected agonists HU-210 (cannabinoid receptor-1) and IL-6 (interleukin 6 receptor) to stimulate retinal ganglion cells for axonal growth. We applied, in gel foam at the site of nerve injury, Taxol to stabilize growing microtubules, and activated protein C to clear the debris field since computational models predicted that this drug combination regulating two subcellular processes at the growth cone produces synergistic growth. Physiologically, drug treatment restored or preserved pattern electroretinograms and some of the animals had detectable visual evoked potentials in the brain and behavioral optokinetic responses. Morphology experiments show that the four-drug combination protects axons or promotes axonal regrowth to the optic chiasm and beyond. We conclude that spatially targeted drug treatment is therapeutically relevant and can restore limited functional recovery.
RESUMO
Rats are a popular animal model for vision research and for investigating disorders of the visual system. The study aimed to quantify the spatiotemporal contrast sensitivity function (CSF) of healthy adult Brown-Norway rats under scotopic and photopic illumination. Animals were trained to jump onto the one of two adjacent platforms behind which was displayed a sinewave grating pattern. Contrast thresholds of light- and dark-adapted rats were determined using a staircase method of adjustment for gratings that varied in spatial frequency (sf) and temporal frequency (tf) and ranged several log-units in mean luminance. Photopic CSFs showed strong bandpass spatial tuning, consistent with prior measurements, and weak bandpass temporal tuning. CSFs were parameterized by a truncated log-parabola model, yielding a peak contrast sensitivity of 52⯱â¯9, peak sf of 0.17⯱â¯0.05 cycles/degree, sf limit of 1.6⯱â¯0.3 cycles/degree, low sf attenuation of 85⯱â¯9%, peak tf of 1.7⯱â¯1.1â¯Hz, extrapolated tf limit of 166⯱â¯44â¯Hz, and low tf attenuation of 55⯱â¯12%. CSFs became more lowpass and decreased systematically in contrast sensitivity and spatiotemporal acuity as mean luminance was reduced. CSFs were also measured via the visual head-tracking reflex. Photopic contrast sensitivity, spatial acuity, and temporal acuity were all markedly below that of the grating detection task and optomotor findings for other rat strains. The CSF data provide a comprehensive and quantitative description of rat spatial and temporal vision and a benchmark for evaluating effects of ocular diseases on their ability to see.
