Carnosine and l-arginine attenuate the downregulation of brain monoamines and gamma aminobutyric acid; reverse apoptosis and upregulate the expression of angiogenic factors in a model of hemic hypoxia in rats

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2020-03, Vol.393 (3), p.381-394
• Main Authors: Attia, Hala, Fadda, Laila, Al-Rasheed, Nouf, Al-Rasheed, Nawal, Maysarah, Nadia
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inducing Agents - metabolism; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Arginine; Arginine - administration & dosage; Bcl-2 protein; Biogenic Monoamines - antagonists & inhibitors; Biogenic Monoamines - metabolism; Biomedical and Life Sciences; Biomedicine; Brain - drug effects; Brain - metabolism; Carnosine; Carnosine - administration & dosage; Caspase-3; Dopamine; Down-Regulation - drug effects; Down-Regulation - physiology; Drug Therapy, Combination; gamma-Aminobutyric Acid - metabolism; Gene Expression; Hematologic Diseases - drug therapy; Hematologic Diseases - metabolism; Hypoxia; Hypoxia - drug therapy; Hypoxia - metabolism; Inflammation; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; Interleukin 6; Male; Monoamines; Neurosciences; Neurotoxicity; NF-κB protein; Norepinephrine; Original Article; Pharmacology/Toxicology; Random Allocation; Rats; Rats, Wistar; Serotonin; Sodium nitrite; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Up-Regulation; Vascular endothelial growth factor; γ-Aminobutyric acid
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-019-01738-8

Purpose : The purpose of the present study was to investigate the preventive effect of l -arginine (ARG) and carnosine (CAR) on hypoxia-induced neurotoxicity in rats. The impact on neuro-inflammation, apoptosis, angiogenesis, and the brain levels of monoamines and GABA were investigated. Methods : Rats were divided into the following: normal control, hypoxia model induced by sodium nitrite (75 mg/kg s.c), and hypoxic rats pre-treated with CAR (250 mg/kg), ARG (200 mg/kg), and their combination. Results : Data revealed that hypoxia induced significant elevation of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and its receptor reflecting the stimulation of angiogenesis. Hypoxia also resulted in increased inflammatory mediators-including nuclear factor kappa B (NF-κB ) , tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). In addition, hypoxia initiates cerebral apoptosis as revealed by increased caspase-3 and BAX with reduced Bcl-2. These changes were associated with reduced brain levels of GABA and monoamines including noradrenaline (NADR), dopamine (DOP), and serotonin (SER). Pre-treatment with ARG and/or CAR significantly mitigated the neural changes induced by hypoxia and attenuated the elevated levels of NF-κB, TNF-α, IL-6, caspase-3, and BAX, while ameliorated the reduced levels of Bcl-2, NADR, DOP, SER, and GABA, with the best improvement observed with the combination. Further elevation of the angiogenic markers was observed indicating their role in boosting oxygen delivery to brain. Conclusion : CAR, ARG, and, importantly, their combination could effectively protect against hypoxia-induced neurotoxicity, via their angiogenic, anti-inflammatory, and anti-apoptotic properties in addition to reversing the effect on GABA and monoamines.