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Study of the Influence of Gamma Radiation on Certain Pharmacological and Biochemical Actions of Leiurus Quinquestriatus Scorpion Venom

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Study of the Influence of Gamma Radiation on Certain Pharmacological and Biochemical Actions of Leiurus Quinquestriatus Scorpion Venom Study of the Influence of Gamma Radiation on Certain Pharmacological and Biochemical Actions of Leiurus quinquestriatus Scorpion Venom Thesis submitted for the partial fulfillment of the Master Degree in Pharmaceutical Sciences (Pharmacology and Toxicology) By Heba Abd El-Monem Mohamed Abd Rabo B. Pharm. Sci. (Faculty of Pharmacy, Cairo University) 2006 Pharmacist in National Center for Radiation Research and Technology Atomic Energy Authority Under the Supervision of Dr. Sanaa A. Kenawy Dr. Esmat A. Shaaban Professor of Pharmacology Professor of Pharmacology and Toxicology and Toxicology Department of Pharmacology Department of Pharmacology Faculty of Pharmacy National Center for Radiation Cairo University Research and Technology Atomic Energy Authority Faculty of Pharmacy Cairo University 2012 سورة البقرة , اﻷية ۲٥٥ Acknowledgements First of all, thanks to ALLAH for giving me everything to accomplish this work and support to achieve my goal. I would like to express my deepest appreciation and deepest gratitude to Dr. Sanaa A. Kenawy, Professor of Pharmacology & Toxicology,Faculty of Pharmacy, Cairo University, for her keen supervision and continuous encouragement. She offered deep experience, unlimited support, valuable suggestions and sincere advice. It was a great honor to work under her supervision. To her, I owe a great deal of gratitude and thanks. I am sincerely grateful and I have no adequate word to Dr. Esmat A. Shaaban, Professor of Pharmacology & Toxicology, National Center for Radiation Research & Technology, for her suggestion for the research point, generous helps, supervision, encouragement, practical support throughout this study and valuable guidance which assisted me greatly in completing this work. I greatly appreciate the help and co-operation of Dr. Aber M. Amin, Assist. Prof. of Biochemistry & Labeled Compound, Hot Lab Center, Atomic Energy Authority, for her kindness, valuable technical advice, effort and deep experiences to stimulate me and push me forward. Special thanks are also to Dr. Magd El-Din Raieh, Professor of Radiochemistry, Hot Lab Center, Atomic Energy Authority, for effective advice, valuable discussion, fruitful comments, continuous encouragment and fatherhood sensation. This work was possible through the moral support and facilities given by Dr. Mona A. El-Ghazaly, Professor of Pharmacology & Toxicology, head of National Center for Radiation Research & Technology, so my sincere gratitude for her aid. A special word of thankfulness is directed to my professors and colleagues in the National Center for Radiation Research & Technology, for their friendly support and concern. Endless thanks to all who helped me even just a kind word thought this work. No words can express my gratitude to my family, great thanks and appreciation will not be enough to express my feeling to my mother, my father, my brother, my sister, for their patience and encouragement throughout the progress of this work. Heba Abd El-Monem Mohamed Abd Rabo Contents Subject Page List of Tables……………………………………………................... i List of Figures…………………………………………………..…… ii List of Abbreviations…………..………………………….………… iv Introduction Scorpions……………….. …………………………………………. 1 Composition of Leiurus quinquestriatus venom…………………… 5 The pharmacological actions of irradiated L.q scorpion 8 venom……………………………………………………………… Potential use of the scorpion venom ……………….……………… 12 Antivenin ………………………………………………………….. 14 Mechanism of antivenin ………………………………………….. 14 Treatment of scorpion poisoning ………….................................. 16 Radiation………………………………………………………….. 19 Types of ionizing radiations………............................................. 20 Radiation dose units………………………………………………. 21 Use of radiation in medicine………………………………..…….. 22 Effect of radiation on proteins……………………………….. 23 Labeling of scorpion venom……………………………………… 25 Radiochemistry of iodine……………………………………..….. 25 Iodine isotopes………………………………............................... 25 Radioiodination methods………….…...…..…............................. 28 Electrophilic aromatic substitution ……………………………….. 28 Purification of radioiodinated compounds.................................... 31 Aim of the Work……………………………………………….……. 32 Materials and Methods…………………………………………….. Materials.…………………………………………………….…… 33 Experimental design…………………………………………....... 36 Methods………………………………………………………….. 39 Median lethal dose (LD50)…………………………………….. ... 39 Immunological properties (double immunodiffusion technique).. 40 Labeling of scorpion venom…………………………………… 42 Iodination of scorpion venom…………………………………. 43 Determination of radiochemical yield ………………………… 43 Study of the factors affecting the labeling yield………………. 44 In-vitro stability of the125I- labeled scorpion venom………….. 45 In-vivo biodistribution of the125I- labeled scorpion venom in mice 45 Determination of plasma lipid peroxides (MDA) …..................... 46 Determination of blood glutathione (GSH) …………………..… 48 Contents (cont.) Subject Page Determination of serum alanine aminotransferase (ALT) activity 51 Determination of serum aspartate aminotransferase (AST) activity 53 Determination of serum cholesterol concentration …………........ 55 Determination of serum triglycerides concentration …………….. 56 Determination of serum HDL–cholesterol concentration ……….. 58 Determination of serum LDL–cholesterol concentration …….….. 59 Determination of serum creatine kinase (CK) …………………… 59 Determination of serum creatine kinase isoenzyme (CK-MB)….. 61 Determination of serum lactate dehydrogenase activity (LDH)….. 62 Statistical Analysis………………………………………………… 64 Results………………………………………………………………... 65 Discussion…………………………………………………………….. 106 Summary and Conclusions………………………………….………. 118 References……………………………………………………………. 122 ١ ..……………………………………………………Arabic Summary List of Tables Table No Title Page (i): Nuclear properties and uses of some radioiodine 26 (1): Determination of LD50 for native Leiurus quinquestriatus (L.q) scorpion venom (1mg/ml) in male mice…………..…………………………………………. 66 (2): Determination of LD50 for 1.5 KGy γ-irradiated Leiurus quinquestriatus (L.q) scorpion venom (1mg/ml) in male mice…………………………………………………….. 67 (3): Determination of LD50 for 3 KGy γ-irradiated Leiurus quinquestriatus (L.q) scorpion venom (1mg/ml) in male mice……..……………………………………………… 68 (4): LD50 for native, 1.5 and 3 KGy γ-irradiated Leiurus quinquestriatus (L.q) scorpion venom…………………. 69 125 (5): The In-vitro stability of I-L.q scorpion venom……… 80 125 (6): Biodistribution pattern of I- L.q scorpion venom in different organs or body fluids in normal mice at different time intervals……..………………………….. 82 (7): Brain/ Blood ratio of 125I- L.q scorpion venom in normal mice at different time intervals………………………… 83 (8): Effect of native and 1.5 KGy gamma irradiated Leiurus quinquestriatus (L.q) scorpion venom on lipid peroxides (MDA) and blood glutathione (GSH) level in rats…………………………………………………….. 86 (9): Effect of native and 1.5 KGy gamma irradiated Leiurus quinquestriatus (L.q) scorpion venom on serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in rats…..…………………………… 90 (10): Effect of native and 1.5 KGy gamma irradiated Leiurus quinquestriatus (L.q) scorpion venom on total cholesterol, triglycerides, HDL-cholesterol and LDL- cholesterol levels in rats …...…………………………. 96 (11): Effect of native and 1.5 KGy gamma irradiated Leiurus quinquestriatus (L.q) scorpion venom on creatine kinase, creatine kinase-MB and lactate dehydrogenase activities in rats ……………………………………..… 102 i List of Figures Figures Title Page No. (i): Leiurus quinquestriatus scorpion ….. ……………… 2 (ii): Different types of electromagnetic radiation...……… 19 (iii): Abilities of three different types of ionizing radiatian to penetrate solid matter.….………………………… 20 (iv): Electrophilic radioiodination of tyrosine residue of a protein or peptide chain…………………………………….. 29 (v): N-chloro compounds commonly employed as oxidants for electrophilic radioiodination to terminate electrophilic radioiodination reactions………………… 30 (vi): Standard curve for malondialdehyde (MDA)…………. 47 (vii): Standard curve for blood glutathione (GSH)…………. 50 (viii): Standard curve for alanine aminotransferase (ALT) activity………………………………………………….. 52 (ix): Standard curve for aspartate aminotransferase (AST) activity………………………………………………….. 54 (1): Effect of 1.5 KGy & 3 KGy γ-irradiation on median lethal dose (LD50) of native Leiurus quinquestriatus scorpion venom (L.q)……………………………………………. 70 (2): Immunodiffusion reaction of horse serum polyvalent antivenin with native (non-irradiated), 1.5 KGy & 3 KGy γ- irradiated Leiurus quinquestriatus (L.q) scorpion venom……………………………………………………. 72 (3): Radiochemical yield of 125I-L.q scorpion venom as a function of scorpion venom amount……………………. 75 (4): Radiochemical yield of 125I-L.q scorpion venom as a function of chloramine-T concentration………………... 76 (5): Radiochemical yield of 125I- L.q scorpion venom as a function of reaction temperature………………………. 77 (6): Radiochemical yield of 125I- L.q scorpion venom as a function of reaction time……………………………….. 78 (7): Radiochemical yield of 125I- L.q scorpion venom as a function of pH of reaction mixture……………………... 79 (8): Effect of native and 1.5 KGy gamma irradiated Leiurus quinquestriatus (L.q) scorpion venom on plasma lipid peroxides (MDA) in rats………………………………. 87 ii (9): Effect of native and 1.5 KGy gamma irradiated Leiurus quinquestriatus (L.q) scorpion venom on blood glutathione (GSH) in rats…………………………………………… 88 (10): Effect of native and 1.5 KGy gamma irradiated Leiurus
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