Abstract
Ethyl 3, 4, 5-trihydroxybenzoate (GAE) is a major bioactive constituent of Hippophae Rhamnoides L. leaves and extract prepared from H. rhamnoides leaves exhibited radioprotective and pharmacological activity. Radiomodifying properties of polyphenol compounds through free radical neutralizing have been reported earlier. However, to date pharmacokinetic (PK) and biodistribution of polyphenol compounds post 60Co-γ-irradiation (5 Gy) exposure have not been studied yet. The study aims to investigate the radio modifying and inflammatory action, PK and biodistribution of GAE at a radioprotective dose and changes, if any, induced after irradiation. Male C 57 BL/6 mice (28–30 g) were administered GAE (200 mg/kg b.wt) orally 15 minutes post to irradiation. Mice were sacrificed at 15, 30 min, 1,2,4,8 and 24 h. PK and biodistribution of GAE in plasma and tissues were studied. The radiomodifying potential was assessed in terms of mitigating NF-kB activity and SGOT, SGPT, urea and creatinine levels in liver and kidney post irradiation. Our study suggested the potential use of GAE as radiomodifying agent inhibits NF-kB expression and maintains the SGOT 24.10 ± 2.4, SGPT 36.01 ± 6.1 U/l, urea18.16 ± 0.003, and creatinine 1.05 ± 0.04 mg/dL upto 8 h in comparison to irradiated mice. Moreover, in biodistribution studies, showed that GAE crosses the blood-brain barrier and is found in brain tissue. Plasma level of GAE peaked at about 15 min, with Cmax 4390.85 ± 285.20 in GAE and in 3391.78 ± 78.13 ng/mL in radiation + GAE-treated animals, Biodistribution resulted in the highest concentration to be found in liver and kidney. These radiomodifying and pharmacokinetic result may be useful for study of the bioactive mechanism associated with radiation injury and to develop a potent formulation of GAE for clinical application.
Highlights
Administered in accordance to their classification, in radioprotector agent should be administered prior to exposure, in radiomitigator agent should be administered shortly after the exposure but before the onset of symptoms and in therapeutic agent should be administered after the injury and onset of physical symptoms[3,4]
The alteration in the level of GAE post irradiation is identified by observing changes in pharmacokinetic parameters and biodistribution patterns and by investigating liver and kidney function as well measurement of Nuclear factor kB (NF-kB) activity in order to assess the inflammation associated with radiation exposure
NMR spectrum of GAE isolated from Hippophae Rhamnoides leaves exhibited and displayed a triplet three protons 3 H,t, (J = 6.8,7.2hz) and 4.19,1 H,d, (J = 6.8hz, CH2 a), 4.22, 1 H,d,(J = 7.2hz, CH2 b), were displayed. 13C NMR spectrum of GAE displayed a peak 14.7 due to methyl group (CH3), 60.4 due to CH2 group other peaks at 108.9 (C-1), 120.03 (C-2 and C-6), 138.7 (C-3 and C-5), 146.01 (C-4), were structurally indicative of the phenyl ring a sharp peak at 166.28 confirmed the presence of carbonyl group of the ethyl carboxylate group
Summary
Administered in accordance to their classification, in radioprotector agent should be administered prior to exposure, in radiomitigator agent should be administered shortly after the exposure but before the onset of symptoms and in therapeutic agent should be administered after the injury and onset of physical symptoms[3,4]. After extensive screening of molecules and failure of most of these synthetic compounds, researchers turned their attention toward phytochemical and plant extracts to investigate radioprotective efficacy[7,8]. GAE, C9H10O5 has molecular weight 198.17 g/mol (Fig. 1) It is a colorless or slightly yellow crystalline compound possessing anti-inflammatory[12], antibacterial[13], and anticancer properties[14]. Changes in pharmacokinetic properties of polyphenols compounds induced by the exposure of the organism to ionizing radiation have been rarely studied. The alteration in the level of GAE post irradiation is identified by observing changes in pharmacokinetic parameters and biodistribution patterns and by investigating liver and kidney function as well measurement of NF-kB activity in order to assess the inflammation associated with radiation exposure. The pharmacokinetic, biodistribution and radiomodifying study of GAE in animal model will help in understanding the GAE distribution mechanism as well further assist in achieving better application for the development of GAE as radiomodifying agents
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