G-CSF administration attenuates brain injury in rats following carbon monoxide poisoning via different mechanisms.
Acute severe carbon monoxide (CO) poisoning induces hypoxia that leads to cardiovascular and nervous systems disturbances. Different complex mechanisms lead to CO neurotoxicity including lipid peroxidation, inflammatory and immune-mediated reactions, myelin degeneration and finally neuronal apoptosis and necrosis. Granulocyte colony-stimulating factor (G-CSF) is considered to be a novel neuroprotective agent. In this study, we evaluated the efficacy of G-CSF therapy on CO neurotoxicity in rats with acute CO poisoning. Rats were exposed to 3000 ppm CO in air (0.3%) for 1 h, and then different doses (50,100, and 150 µg/kg) of G-CSF or normal saline were administrated intraperitoneally. Water content of brain as an indicator for total edema and blood brain barrier integrity (Evans blue extravasation) were evaluated. Malondialydehyde was determined in order to evaluate the effect of G-CSF on CO-induced lipid peroxidation in brain tissues. Also, the effect of G-CSF on myeloperoxidase activity in the brain tissue was evaluated. The effect of G-CSF administration on induced apoptosis in the brain was measured using TUNEL method. To evaluate the level of MBP, STAT3 and pSTAT3 and HO-1 proteins and the effect of G-CSF on these proteins Western blotting was carried out. G-CSF reduced water content of the edematous poisoned brains (100 µg/kg) and BBB permeability (100 and 150 µg/kg) (P < 0.05). G-CSF (150 µg/kg) reduced the MDA level in the brain tissues (P < 0.05 as compared to CO poisoned animals). G-CSF did not decrease the MPO activity after CO poisoning in any doses. G-CSF significantly reduced the number of apoptotic neurons and Caspase 3 protein levels in the brain. Western blotting results showed that G-CSF treatment enhanced expression of HO-1 and MBP, STAT3 and pSTAT3 proteins in the brain tissues. Based on our results, a single dose of G-CSF immediately after CO poisoning significantly attenuates CO neurotoxicity via different mechanisms. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 37-47, 2017.
Department of Pharmacology and Toxicology, School of Pharmacy, Baqiyatallah University of Medical Sciences, Tehran, Iran.
Maryam
M
Ghorbani
Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.|Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Amir Hooshang
AH
Mohammadpour
Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.|Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Khalil
K
Abnous
Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran.
Ahmad Reza
AR
Movassaghi
Department of Anatomy, School of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran.
Javad Raouf
JR
Sarshoori
Department of Physiology and Pharmacology, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran.
Shabnam
S
Shahsavand
Department of Pharmacodynamics and Toxicology, School of Pharmacy, Zabol University of Medical Sciences, Zabol, Iran.
Mahmoud
M
Hashemzaei
Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.|Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.|Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Seyed Adel
SA
Moallem
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D001927:Brain Diseases / Q000139:chemically induced* / Q000401:mortality / Q000517:prevention & control*; D001929:Brain Edema / Q000139:chemically induced / Q000473:pathology; D002249:Carbon Monoxide Poisoning / Q000401:mortality / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects / Q000627:therapeutic use*; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007274:Injections, Intraperitoneal; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009186:Myelin Sheath / Q000187:drug effects; D009336:Necrosis; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
D000975:Antioxidants; D018696:Neuroprotective Agents; D016179:Granulocyte Colony-Stimulating Factor
apoptosis; carbon monoxide poisoning; granulocyte colony stimulating factor; malondialydehyde; myelin basic protein; myeloperoxidase; neurotoxicity; rat