The effects of isatin (2,3-dioxo-indole) and isatin analogues (5-methylisatin, 6-hydroxyisatin, 7-ethylisatin, N-acety- lisatin) were tested on prostaglandin E2 (PGE2)-induced fever in mice and rats. Two modes of administration were tested. Isatin or an analogue was injected simultaneously with PGE2 and the development of fever was tested, or the test compound was given 30 min following PGE2 administration and the effects on the already existing fever were measured, in mice and in rats. Isatin in a dose of 3.12 mg/kg ip was found to block the development of PGE2-induced fever in mice, while in a dose of 12.5 mg/kg ip it attenuated the existing fever. In rats isatin in a dose of 12.5 mg/kg ip blocked fever initiation, and at 25.0 mg/kg ip attenuated existing PGE2-induced fever. In mice, 5-methylisatin in a dose of 0.21 mg/kg ip blocked the initiation of fever, and at 6.72 mg/kg ip attenuated the existing fever. In rats in a dose of 3.36 mg/kg ip it blocked the development of fever, and at 13.44 mg/kg ip attenuated existing PGE2-induced fever. In mice 5,6-dimetylisatin in a dose of 0.02 mg/kg ip both blocked fever initiation and attenuated the existing fever in mice, in rats in a dose of 0.42 mg/kg ip it blocked the initiation of fever, and at 0.21 mg/kg ip attenuated the existing PGE2-induced fever. In mice 6-hydroxyisatin in a dose of 5.2 mg/kg blocked the development of fever, and at 10.4 mg/kg attenuated the existing fever. In rats in a dose of 10.40 mg/kg ip it blocked fever development and also attenuated the existing fever. In mice, 7-ethylisatin in a dose of 0.02 mg/kg ip both blocked fever initiation and also attenuated the existing fever. In rats, a dose of 0.11 mg/kg both blocked fever initiation and also attenuated the existing fever. In mice, N-acethylisatin in the dose of 0.005 mg/kg blocked fever initiation, while at 1.024 mg/kg it attenuated existing fever, in rats, in a dose of 0.096 mg/kg it blocked fever initiation, and at 0.384 mg/kg attenuated the existing fever. The results demonstrate that 7-ethyl- and N-acetylisatin are the most effective of these compounds both in blocking the development of PGE2-induced fever and also in attenuating existing the PGE 2-induced fever.
KeywordsIsatinsAntipyretic Action
A. E. Medvedev, A. Clow, M. Sandler and V. Glover, “Isatin-Link between Natriuretic Peptides and Monoa- mines?” Biochemical Pharmacology, Vol. 52, No. 3, 1996, pp. 385-391. doi:10.1016/0006-2952(96)00206-7
M. Sandler, A.E. Medvedev, N.G. Panova, S. Matta and V. Glover, “Isatin: From Monoamines Oxidase to Natriuretic Peptides, ”In: Magyar K. and Vizi E.S, Eds., Miles-Tone in Monoamines Oxidase Research: Discovery of (-) Deprenyl. Medicina Publishing House Co., Budapest. 2000, pp. 237- 251.
P. Watkins, A. Clow, V. Glover, J. Halket, A. Przy- Borowska and M. Sandler, “Isatin, Regional Distribution in Rat Brain and Tissue,” Neurochemistry International, Vol. 17, No. 2, 1990，pp. 321-323. doi:10.1016/0197-0186(90)90154-L
V. Glover, S. K. Bhattacharya, A. Charkrabarti and M. Sandler, “The Psychopharmacology of Isatin: Brief Review,” Stress Medicine, Vol. 14, No. 4, 1998, pp. 225- 229. doi:10.1002/(SICI)1099-1700(1998100)14:4 3.0.CO;2-P
S. K. Bhattacharya, M. Ramnathan and V. Glover, “Intra- ventricular Administration of Isatin in Rats: Antidiuretic Dipsogenic, Anorexiant and Emetic Effects,” Biogenic Amines Vol. 16, No. 1, 2000, pp. 63-71.
G. Telegdy, A. Adamik and V. Glover, “The Action of Isatin (2,3-Dioxoindole) an Endogenous Indole on Brain Natriuretic and C-Type Natriuretic Peptide-Induced Fac- Ilitation of Memory Consolidation in Passive-Avoidance Learning in Rats,” Brain Research Bulletin, Vol. 53, No. 3, 2000, pp. 367-370. doi:10.1016/S0361-9230(00)00359-2
V. Glover, A. E. Medvedev and M. Sandler, “Isatin a Potent Endogenous Antagonist of Guanylate Cyclase- Coupled Atrial Natriuretic Peptide Receptors,” Life Sciences, Vol. 57, No. 22, 1995. pp. 2073-2079. doi:10.1016/0024-3205(95)02189-P
A. E. Medvedev, O. Bussygyna, N. Pyatakova, V. Glover and I. Severina, “Effect of Isatin on Nitric Oxide -Stimulated Soluble Guanylate Cyclase from Human Platelets,” Biochemical Pharmacology, Vol. 63, No. 4, 2002. pp. 763-766. doi:10.1016/S0006-2952(01)00809-7
M. Crumeyrolle-Arias, A, Medvedev, A. Cardona, D. Barritault. and V. Glover, “In Situ Imaging of Specific Binding of H3-Isatin in Rats”, Journal of Neuro- chemistry, Vol. 84, No. 3, 2003, pp. 618-620. doi:10.1046/j.1471-4159.2003.01564.x
I. Pataki, á. Adamik and G. Telegdy, “Isatin (Indole-2,3- Dione) Inhibits Natriuretic Peptideinduced Hyperthermia in Rats,” Peptides Vol. 21, No. 3, 2000, pp. 373-377. doi:10.1016/S0196-9781(00)00149-2
I. Pataki, á. Adamik, V. Glover, G. Tóth and G. Telegdy, “The Effects of Isatin (Indole-2,3-Dione) on Pituitary Adenylate Cyclase-Activating Polypeptideinduced Hyperth- Ermia,” BMC Neuroscience, Vol. 3, 2002, pp. 1-4. doi:10.1186/1471-2202-3-2
N. J. Rothwell, “CNS Regulation of Thermogenesis,” Critical Reviewers in Neurobiology, Vol. 8, No. 1-2, 1994, pp. 1-10.
L. J. Pellegrino, A. S. Pellegrino and A. J. Cushman, “Stereo-taxic Atlas of the Rat Brain,” Plenum Press, New York, 1979, pp. 8-27.
C. S. Marvel and G. S. Hiers, “Isatin,” Organic Syntheses Collections, Vol. 1, 1941, pp. 321-324.
P. W. Sadler, “Separation of Isometric Isatins,” Journal of Organic Chemistry, Vol. 21, 1956, pp. 169-170. doi:10.1021/jo01108a004
J. Crippenberg, B. Honkanen and O. Patohaju, “Fungus Pigments V. Degradation of Anabaris,” Journal Acta Chemica Scandinavica, Vol. 11, l957, pp. 1485-1492.
D. J. Bauer and P. W. Sadler, “Structure-Activity Relations of the Antiviral Chemotherapeutic Activity of Beta-Thiosemicarbazone,” British Journal Pharma- cology, Vol. 10, 1960, pp. 1-10.
A. E. Medvedev, B. Goodwin, A. Clow, J, Halket, V. Glover and M. Sandler, “Inhibitory Protency of Some Isatin Analogues on Human Monoamine Oxidase A and B,” Biochemical Pharmacology, Vol. 33, l992, pp. 590 -592.
T. Oka, K. Oka and C. B. Saper, “Contrasting Effects of E type Prostaglandin (Ep) Receptor Agonist on Core Body Temperature in Rats,” Brain Research, Vol. 968, No. 2, 2003, pp. 256-262. doi:10.1016/S0006-8993(03)02268-6
K. Zacharowski, A. Olbrich, J Piper, G, Hafner, K. Kondo and K. Thiemermann, “Selective Activation of the Prostanoid Ep(3) Receptor Reduces Myocardial Infarct Size Receptor Reduces Myocardial Infarct Size in Rodents,” Arteriosclerosis Thrombosis Vascular Biol- ogy, Vol. 19, No. 9, 1999, pp. 2141-2147.
R. A. Coleman, W. L. Smith and S. Narumiya, “Interna- tional Union of Pharmacology Classification of Prostanoid Receptors: Properties, Distribution and Structure of the Receptors and Their Subtypes,” Pharmacology Reviews, Vol. 46, No. 2, 1994, pp. 205-229.
F. Ushikubi, E, Segi, Y. Sugimoto, T. Murata, T. Matsuoka, T, Kobayashi, H. Hizaki, K. Tuboi, M, Katsuyama, A. Ischikawa, T, Tanaka, N .Yoshida and S. Narumiya, “Impaired Febrile Response in Mice Lacking the Prostagalndin E Receptor Subtype EP3,” Nature, Vol. 395, No. 6699, 1998, pp. 281-284. doi:10.1038/26233
O. Buneeva, O. Gnedenko, V. Zgoda, A. Kopylov, V.Glover, A. Ivanov, A. Medvedev and V.Archakov, “Isatin-Binding Proteins of Rat and Mouse Brain: Proteomic Identification and Optical Biosensor Validation”. Proteomics, Vol. 10, No. 1, 2010 , pp. 23-37. doi:10.1002/pmic.200900492
A. Medvedev, O.Buneeva and V. Glover, “ Iological Targets for Isatin and Its Analogues: Implication for Therapy,” Biologics, Vol. 1, 2007, pp. 151-162.
W. M. Zawada, J. Clarke and W. D. Ruwe, “Naloxone differentially Alters Fevers Induced by Cytokines,” Neu- rochemistry International, Vol. 30, 1997, pp. 441- 448. doi:10.1016/S0197-0186(96)00080-0
S. M. Tsai, M. T. Lin, J .Wang and W. T. Huang, “Pyrogens Enhance Beta-Endorphin Release in Hypo- thalamus and Trigger Fever that Can be Attenuated by Buprenorphine,” Journal of Pharmacological Sciences, Vol. 93, No. 2, 2003, pp. 155-162.
X. Chen, R. Landgraf and Q. J. Pittman, “Differential Ventral Septal Vasopressin Release is Associate with Sexual Dimorphism in PGE2 Fever,” American Journal Physiology,’ Vol. 272, No. 5, 1997. pp. R1664-1669.
S. K. Bhattacharya, A .Charkrabarti and V. Glover, “Stress and Water Balance: The Roles of ANP, AVP and Isatin,” Indian Journal Experimental Biology, Vol. 36, 1998, pp. 1195-2000.
J. Roth, E. Zeisberger, S. Vybiral and L. Jansky, “Endo- genous Antipyretics:Neuropeptides and Glucocorticoids,” Frontiers in Bioscience, Vol. 9, No. 1-3, 2004, pp. 816- 826. doi:10.2741/1277
I. Pataki, á. Adamik, M. Jászberényi, M. Mácsai and G. Telegdy, “Involvement of Transmitters in Pituitary Adeny- Late Cyclase-Activating Polypeptide-Induced Hyper- thermia,” Regulatory Peptides, Vol. 115, No. 3, 2003, pp. 187-193. doi:10.1016/S0167-0115(03)00173-3
C. W. Simpson, W. D. Ruwe and R. D. Myers, “Pros- taglandins and Hypothalamic Neurotransmitter Receptors Involved in Hyperthermia: A Critical Evaluation. Neuro- science,” Biobehavioral Reviews, Vol. 18, No. 1, 1994, pp. 1-20. doi:10.1016/0149-7634(94)90033-7
S. F. Morrison, “Raphe Pallidus Neurons Mediate Prosta- Glandin E2-evoked Increases Brown Adipose Tissue Thermogenesis,” Neuroscience, Vol. 121, No. 1, 2003, pp. 17-24. doi:10.1016/S0306-4522(03)00363-4