A hypothermia mimetic molecule (zr17-2) reduces ganglion cell death and electroretinogram distortion in a rat model of intraorbital optic nerve crush (IONC)

DANIELA S. CONTARTESE, MANUEL REY-FUNES, RAFAEL PELÁEZ, MANUEL SOLIÑO, JUAN C. FERNÁNDEZ, RONAN NAKAMURA, VERÓNICA B. DORFMAN, JUAN J. LÓPEZ-COSTA, JOSÉ M. ZAPICO4, BEATRIZ DE PASCUAL-TERESA, IGNACIO M. LARRAYOZ; CÉSAR F. LOIDL; ALFREDO MARTÍNEZ

FRONTIERS IN PHARMACOLOGY

Frontiers Media SA

Año: 2023

1663-9812

Ocular and periocular traumatisms may result in loss of vision. Our previous workshowed that therapeutic hypothermia prevents retinal damage caused by traumaticneuropathy. We also generated and characterized small molecules that elicit thebeneficial effects of hypothermia at normal body temperature. Here we investigatewhether one of these mimetic molecules, zr17-2, is able to preserve the function ofeyes exposed to trauma. Intraorbital optic nerve crush (IONC) or sham manipulationwas applied to Sprague-Dawley rats. One hour after surgery, 5.0 μl of 330 nmol/Lzr17-2 or PBS, as vehicle, were injected in the vitreum of treated animals.Electroretinograms were performed 21 days after surgery and a- and b-waveamplitude, as well as oscillatory potentials (OP), were calculated. Some animalswere sacrificed 6 days after surgery for TUNEL analysis. All animal experiments wereapproved by the local ethics board. Our previous studies showed that zr17-2 doesnot cross the blood-ocular barrier, thus preventing systemic treatment. Here weshow that intravitreal injection of zr17-2 results in a very significant prevention ofretinal damage, providing preclinical support for its pharmacological use in ocularconditions. As previously reported, IONC resulted in a drastic reduction in theamplitude of the b-wave (p < 0.0001) and OPs (p < 0.05); a large decrease in thenumber of RGCs (p < 0.0001), and a large increase in the number of apoptotic cells inthe GCL and the INL (p < 0.0001). Interestingly, injection of zr17-2 largely preventedall these parameters, in a very similar pattern to that elicited by therapeutichypothermia. The small molecule was also able to reduce oxidative stressinducedretinal cell death in vitro. In summary, we have shown that intravitrealinjection of the hypothermia mimetic, zr17-2, significantly reduces themorphological and electrophysiological consequences of ocular traumatism andmay represent a new treatment option for this cause of visual loss.