A hypothermia mimetic molecule (zr17-2) reduces ganglion cell death, gliosis, and electroretinogram distortion in male rats subjected to perinatal asphyxia

Frontiers in Pharmacology

Pharmacology

Alfredo Martínez¹  Rafael Peláez²  Verónica B. Dorfman³  José M. Zapico⁴  Ana Ramos⁴  Beatriz de Pascual-Teresa⁴  Ignacio M. Larrayoz⁵  Manuel Soliño⁶  Daniela S. Contartese⁶  Nicolás S. Ciranna⁶  Juan Carlos Fernández⁶  Aníbal Sarotto⁶  Ronan Nakamura⁷  Manuel Rey-Funes⁷  César Fabián Loidl⁷  Juan José López-Costa⁷ 

[1]Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain

[2]Biomarkers and Molecular Signaling Group, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain

[3]Centro de Estudios Biomédicos Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, Buenos Aires, Argentina

[4]Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain

[5]Department of Nursing, Biomarkers, Artificial Intelligence, and Signaling (BIAS), University of La Rioja, Logroño, Spain

[6]Laboratorio de Neuropatología Experimental, Instituto de Biología Celular y Neurociencia “Prof. E. De Robertis” (IBCN), Facultad de Medicina, CONICET—Universidad de Buenos Aires, Buenos Aires, Argentina

[7]Laboratorio de Neuropatología Experimental, Instituto de Biología Celular y Neurociencia “Prof. E. De Robertis” (IBCN), Facultad de Medicina, CONICET—Universidad de Buenos Aires, Buenos Aires, Argentina

[8]Departamento de Biología Celular, Histología, Embriología y Genética, Instituto de Biología Celular y Neurociencia “Prof. E. De Robertis” (IBCN), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina

关键词: hypothermia;    perinatal asphyxia;    hypothermia mimetics;    apoptosis;    electroretinogram;    cold-shock proteins;    gliosis;   

DOI  :  10.3389/fphar.2023.1252184

 received in 2023-07-03, accepted in 2023-08-30,  发布年份 2023

来源: Frontiers

【 摘 要 】

Introduction: Perinatal asphyxia (PA) represents a major problem in perinatology and may cause visual losses, including blindness. We, and others, have shown that hypothermia prevents retinal symptoms associated to PA. In the present work, we evaluate whether a hypothermia mimetic small molecule, zr17-2, has similar effects in the context of PA.Methods: Four experimental groups were studied in male rats: Naturally born rats as controls (CTL), naturally born rats injected s.c. with 50 µL of 330 nmols/L zr17-2 (ZR), animals that were exposed to PA for 20 min at 37°C (PA), and rats that were exposed to PA and injected with zr17-2 (PA-ZR). Forty-five days after treatment, animals were subjected to electroretinography. In addition, morphological techniques (TUNEL, H&E, multiple immunofluorescence) were applied to the retinas.Results: A reduction in the amplitude of the a- and b-wave and oscillatory potentials (OP) of the electroretinogram (ERG) was detected in PA animals. Treatment with zr17-2 resulted in a significant amelioration of these parameters (p < 0.01). In PA animals, a large number of apoptotic cells was found in the GCL. This number was significantly reduced by treatment with the small molecule (p < 0.0001). In a similar way, the thickness of the inner retina and the intensity of GFAP immunoreactivity (gliosis) increased in PA retinas (p < 0.0001). These parameters were corrected by the administration of zr17-2 (p < 0.0001). Furthermore, injection of the small molecule in the absence of PA did not modify the ERG nor the morphological parameters studied, suggesting a lack of toxicity.Discussion: In conclusion, our results indicate that a single s.c. injection of zr17-2 in asphyctic neonates may provide a novel and efficacious method to prevent the visual sequelae of PA.

【 授权许可】

Unknown   
Copyright © 2023 Rey-Funes, Fernández, Peláez, Soliño, Contartese, Ciranna, Nakamura, Sarotto, Dorfman, Zapico, Ramos, de Pascual-Teresa, López-Costa, Larrayoz, Martínez and Loidl.