Contartese Daniela S, Rey-Funes Manuel, Peláez Rafael, Soliño Manuel, Fernández Juan C, Nakamura Ronan, Ciranna Nicolás S, Sarotto Aníbal, Dorfman Verónica B, López-Costa Juan J, Zapico José M, Ramos Ana, de Pascual-Teresa Beatriz, Larrayoz Ignacio M, Loidl César F, Martínez Alfredo
Departamento de Biología Celular, Histología, Embriología y Genética, Instituto de Biología Celular y Neurociencia "Prof. E. De Robertis" (IBCN), UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
Biomarkers and Molecular Signaling, Neurodegenerative Diseases Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain.
Front Pharmacol. 2023 Jan 23;14:1112318. doi: 10.3389/fphar.2023.1112318. eCollection 2023.
Ocular and periocular traumatisms may result in loss of vision. Our previous work showed that therapeutic hypothermia prevents retinal damage caused by traumatic neuropathy. We also generated and characterized small molecules that elicit the beneficial effects of hypothermia at normal body temperature. Here we investigate whether one of these mimetic molecules, zr17-2, is able to preserve the function of eyes exposed to trauma. Intraorbital optic nerve crush (IONC) or sham manipulation was applied to Sprague-Dawley rats. One hour after surgery, 5.0 µl of 330 nmol/L zr17-2 or PBS, as vehicle, were injected in the vitreum of treated animals. Electroretinograms were performed 21 days after surgery and a- and b-wave amplitude, as well as oscillatory potentials (OP), were calculated. Some animals were sacrificed 6 days after surgery for TUNEL analysis. All animal experiments were approved by the local ethics board. Our previous studies showed that zr17-2 does not cross the blood-ocular barrier, thus preventing systemic treatment. Here we show that intravitreal injection of zr17-2 results in a very significant prevention of retinal damage, providing preclinical support for its pharmacological use in ocular conditions. As previously reported, IONC resulted in a drastic reduction in the amplitude of the b-wave ( < 0.0001) and OPs ( < 0.05), a large decrease in the number of RGCs ( < 0.0001), and a large increase in the number of apoptotic cells in the GCL and the INL ( < 0.0001). Interestingly, injection of zr17-2 largely prevented all these parameters, in a very similar pattern to that elicited by therapeutic hypothermia. The small molecule was also able to reduce oxidative stress-induced retinal cell death . In summary, we have shown that intravitreal injection of the hypothermia mimetic, zr17-2, significantly reduces the morphological and electrophysiological consequences of ocular traumatism and may represent a new treatment option for this cause of visual loss.
眼及眼周创伤可能导致视力丧失。我们之前的研究表明，治疗性低温可预防创伤性神经病变引起的视网膜损伤。我们还生成并鉴定了能在正常体温下发挥低温有益作用的小分子。在此，我们研究这些模拟分子之一zr17 - 2是否能够保护受创伤的眼睛功能。对斯普拉格 - 道利大鼠进行眶内视神经挤压（IONC）或假手术操作。术后1小时，将5.0微升330纳摩尔/升的zr17 - 2或作为对照的PBS注射到受试动物的玻璃体中。术后21天进行视网膜电图检查，并计算a波和b波振幅以及振荡电位（OP）。部分动物在术后6天处死进行TUNEL分析。所有动物实验均经当地伦理委员会批准。我们之前的研究表明，zr17 - 2不能穿过血眼屏障，因此无法进行全身治疗。在此我们表明，玻璃体腔内注射zr17 - 2可非常显著地预防视网膜损伤，为其在眼部疾病中的药理学应用提供了临床前支持。如先前报道，IONC导致b波振幅急剧降低（<0.0001）和OP降低（<0.05），视网膜神经节细胞数量大幅减少（<0.0001），以及神经节细胞层（GCL）和内核层（INL）中凋亡细胞数量大幅增加（<0.0001）。有趣的是，注射zr17 - 2在很大程度上预防了所有这些参数变化，其模式与治疗性低温所引发的模式非常相似。该小分子还能够减少氧化应激诱导的视网膜细胞死亡。总之，我们已经表明，玻璃体腔内注射低温模拟物zr17 - 2可显著减轻眼外伤的形态学和电生理学后果，可能代表了这种视力丧失病因的一种新治疗选择。
