Methods and compositions related to regulation of cytokine production by glycogen synthase kinase 3 (gsk-3)

Abstract

This invention relates generally to a method of treating inflammation and associated diseases and disorders by administering an agent that inhibits glycogen synthase kinase 3 activity.

1 . A method of treating endotoxic shock, comprising administering an effective amount of Gsk-3 inhibitor to a subject having endotoxic shock, wherein the inhibitor is lithium or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein the Gsk-3 inhibitor is administered systemically. 
     
     
         3 . The method of  claim 1 , wherein the administration is selected from the group consisting of topical, ophthalmic, vaginal, rectal, intranasal, oral, inhalation, parenteral, intravenous, intraperitoneal, intramuscular, subcutaneous, intracavity, and transdermal routes. 
     
     
         4 . The method of  claim 1 , wherein the pharmaceutically acceptable salt is lithium chloride. 
     
     
         5 . The method of  claim 1 , wherein the endotoxic shock is caused gram negative bacterial infection. 
     
     
         6 . The method of  claim 5 , wherein the bacterial infection is caused by bacteria selected from the group consisting of:  Clostridium tetani, Clostridium perfringens, Clostridium botulinum, Clostridium  species,  Pseudomonas aeruginosa, Pseudomonas  species,  Campylobacter  species,  Vibrio cholerae, Ehrlichia  species,  Actinobacillus pleuropneumoniae, Pasteurella haemolytica, Pasteurella multocida, Pasteurella  species,  Legionella pneumophila, Legionella  species,  Salmonella typhi, Salmonella  species,  Shigella  species,  Brucella abortus, Brucella  species,  Chlamydi trachomatis, Chlamydia psittaci, Coxiella burnetti, Escherichia coli, Neiserria meningitidis, Neiserria gonorrhea, Haemophilus influenzae, Haemophilus ducreyi, Hemophilus  species,  Yersinia pestis, Yersinia enterolitica, Yersinia  species,  Escherichia hirae, Escherichia  species,  Enterobacteriacae, Burkholderia cepacia, Burkholderia pseudomallei, Francisella tularensis, Bacteroides fragilis, Fusobascterium nucleatum, Provetella  species, and  Cowdria ruminantium.    
     
     
         7 . The method of  claim 2 , wherein the Gsk-3 inhibitor is administered to a subject at a time selected from the group consisting of at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, and at least 48 hours after infection. 
     
     
         8 . A method of treating microbial infection in a subject, comprising administering an effective amount of Gsk-3 inhibitor to the subject, wherein the inhibitor is lithium or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The method of  claim 8 , wherein the Gsk-3 inhibitor is administered systemically. 
     
     
         10 . The method of  claim 8 , wherein the administration is selected from the group consisting of topical, ophthalmic, vaginal, rectal, intranasal, oral, inhalation, parenteral, intravenous, intraperitoneal, intramuscular, subcutaneous, intracavity, and transdermal routes. 
     
     
         11 . The method of  claim 8 , wherein the pharmaceutically acceptable salt is lithium chloride. 
     
     
         12 . The method of  claim 8 , wherein microbial infection is caused by bacteria selected from the group consisting of:  Abiotrophia, Achromnzobacter, Acidaminiococcus, Acidovorax, Acinetobacter, Actinobacillus, Actinobaculum, Actinomadura, Actinoimyces, Aerococcus, Aeromonas, Afipia, Agrobacterium, Alcaligenes, Alloiococcus, Alteromonas, Amycolata, Amycolatopsis, Anaerobospirillum, Anaerorhabdus, Arachnia, Arcanobacterium, Arcobacter, Arthrobacter, Atopobium, Aureobacterium, Bacteroides, Balneatrix, Bartonella, Bergeyella, Bifidobacterium, Bilophila Branhamella, Borrelia, Bordetella, Brachyspira, Brevibacillus, Brevibacterium, Brevundimonas, Brucella, Burkholderia, Buttiauxella, Butyrivibrio, Calymmatobacterium, Campylobacter, Capnocytophaga, Cardiobacterium, Catonella, Cedecea, Cellulomonas, Centipeda, Chlamydia, Chlamydophila, Chromobacterium, Chyseobacterium, Chryseomonas, Citrobacter, Clostridium, Collinsella, Comamonas, Corynebacterium, Coxiella, Cryptobacterium, Delftia, Dermabacter, Dermatophilus, Desulfomonas, Desulfovibrio, Dialister, Dichelobacter, Dolosicoccus, Dolosigranulum, Edwardsiella, Eggerthella, Ehrlichia, Eikenella, Empedobacter; Enterobacter, Enterococcus, Erwinia, Erysipelothrix, Escherichia, Eubacterium, Ewingella, Exiguobacterium, Facklamia, Filifactor, Flavinmonas, Flavobacterium, Francisella, Fusobacterium, Gardnerella, Gemella, Globicatella, Gordona, Haemophilus, Hafnia, Helicobacter, Helococcus, Holdemania Ignavigranum, Johnsonella, Kingella, Klebsiella, Kocuria, Koserella, Kurthia, Kytococcus, Lactobacillus, Lactococcus, Lautropia, Leclercia, Legionella, Leminorella, Leptospira, Leptotrichia, Leuconostoc, Listeria, Listonella, Megasphaera, Methylobacterium, Microbacterium, Micrococcus, Mitsuokella, Mobiluncus, Moellerella, Moraxella, Morganella, Mycobacterium, Mycoplasmia, Myroidaes, Neisseria, Nocardia, Nocardiopsis, Ochrobactrum, Oeskovia, Oligella, Orientia, Paenibacillus, Pantoea, Parachlamiydia, Pasteurella, Pediococcus, Peptococcus, Peptostreptococcus, Photobacterium, Photorhabdus, Plesiomonas, Porphyrimonas, Prevotella, Propionibacterium, Proteus, Providencia, Pseudomonas, Pseudonocardia, Pseudoramibacter, Psychrobacter; Rahnella, Ralstonia, Rhodococcus, Rickettsia Rochalimaea Roseomonas, Rothia, Ruminococcus, Salmonella, Selenomonas, Serpulina, Serratia, Shewenella, Shigella, Simkania, Slackia, Sphingobacterium, Sphingomonas, Spirillum, Staphylococcus, Stenotrophomonas, Stomatococcus, Streptobacillus, Streptococcus, Streptomyces, Succinivibrio, Sutterella, Suttonella, Tatunella, Tissierella, Trabulsiella, Treponema, Tropheryma, Tsakainurella, Turicella, Ureaplasina, Vagococcus, Veillonella, Vibrio, Weeksella, Wolinella, Xanthomonas, Xenorhabdus, Yersinia , and  Yokenella  species. 
     
     
         13 . The method of  claim 8 , wherein the microbial infection is caused by a parasite selected from the group consisting of:  Toxoplasma gondii, Plasmodium  species,  Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Trypanosoma brucei, Trypanosoma cruzi, Leishmania, Leishmania major, Schistosoma  species,  Schistosoma mansoni , and  Entamoeba histolytica.    
     
     
         14 . The method of  claim 8 , wherein the microbial infection is caused by a fungus selected from the group consisting of:  Candida albicans, Cryptococcus neoformans, Histoplama capsulatum, Aspergillus fumigatus, Coccidiodes immitis, Paracoccidiodes brasiliensis, Blastoinyces dermitidis, Pneomocystis carnii, Penicillium marneffi , and  Alternaria alternata.    
     
     
         15 . The method of  claim 8 , wherein the Gsk-3 inhibitor is administered to a subject at a time selected from the group consisting of at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, and at least 48 hours after infection.