title: Ibudilast (AV411), and its AV1013 analog, reduce HIV-1 replication and neuronal death induced by HIV-1 and morphine.
abstract: OBJECTIVE
  We explored the antiviral therapeutic potential of ibudilast (AV411, MN-166) and its amino analog, AV1013.
  
  
  METHODS
  We analyzed whether Ibudilast, a nonselective cyclic AMP phosphodiesterase inhibitor that has been used clinically in Asia for bronchial asthma, poststroke dizziness, and ocular allergies, and AV1013, attenuate HIV-1 replication and the synergistic interactions seen with opiate abuse-HIV-1 comorbidity in neuronal death and inflammation.
  
  
  RESULTS
  AV411 and AV1013 inhibited replication by HIV-1 in microglia and significantly suppressed Tat ± morphine-induced tumor necrosis factor-α and MIF production, the activation of the nuclear factor-kappa B subunit p65, and neuronal death. AV411 and AV1013 prevented HIV-1 replication, and attenuated tumor necrosis factor-α and MIF release at concentrations of 100  nmol/l and 1  μmol/l, which are likely achievable at clinical doses. More importantly, co-exposure with morphine did not negate the inhibitory actions of AV411.
  
  
  CONCLUSIONS
  Collectively, our data suggest that AV411 and its amino analog, AV1013, may be useful neuroprotective agents counteracting neurotoxicity caused by infected and activated glia, and implicate them as potential therapies for the management of HIV-associated neurocognitive disorders in an opioid-abusing population.
authors.affiliation: aDepartment of Pharmacology & Toxicology, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, Virginia, USA bDepartment of Microbiology & Immunology, Universidad Central del Caribe, Bayamón, Puerto Rico cDepartment of Anatomy & Neurobiology, Virginia Commonwealth University, Medical College of Virginia Campus dInstitute for Drug & Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Nazira
authors.initials: N
authors.lastname: El-Hage
authors.forename: Myosotys
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Podhaizer
authors.forename: Shiping
authors.initials: S
authors.lastname: Zou
authors.forename: Seth M
authors.initials: SM
authors.lastname: Dever
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Snider
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Beardsley
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015497:HIV-1 / Q000502:physiology*; D051379:Mice; D009020:Morphine / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D007212:Indolizines; D011720:Pyrazoles
chemical_list: D000998:Antiviral Agents; D009020:Morphine; D018696:Neuroprotective Agents; D011725:Pyridines; C573066:AV1013; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles
references.citation: Curr Pain Headache Rep. 2010 Apr;14(2):96-104
references.pmid: 20425198
references.citation: Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11466-71
references.pmid: 11027346
references.citation: J Neurosci. 2011 Dec 7;31(49):17835-47
references.pmid: 22159099
references.citation: Neurology. 2010 Mar 30;74(13):1018-9
references.pmid: 20200341
references.citation: Brain Behav Immun. 2009 May;23(4):492-7
references.pmid: 19486648
references.citation: J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Dec 15;10(5):511-21
references.pmid: 8548330
references.citation: Nat Rev Neurosci. 2007 Jan;8(1):33-44
references.pmid: 17180161
references.citation: Nat Rev Immunol. 2005 Jan;5(1):69-81
references.pmid: 15630430
references.citation: Brain Behav Immun. 2009 Feb;23(2):240-50
references.pmid: 18938237
references.citation: Pharmacol Res. 2002 Apr;45(4):305-11
references.pmid: 12030794
references.citation: Nature. 1995 Jun 8;375(6531):497-500
references.pmid: 7539892
references.citation: J Acquir Immune Defic Syndr. 2013 May 1;63(1):67-76
references.pmid: 23392462
references.citation: J Biol Chem. 2001 Dec 21;276(51):48093-9
references.pmid: 11677240
references.citation: Eur J Pharmacol. 2013 Feb 15;701(1-3):124-30
references.pmid: 23375937
references.citation: Curr Opin Neurol. 1996 Jun;9(3):221-5
references.pmid: 8839616
references.citation: Brain Res. 1989 Jul 10;491(2):394-7
references.pmid: 2765895
references.citation: Immunol Invest. 2011;40(5):498-522
references.pmid: 21425908
references.citation: Br J Clin Pharmacol. 2008 Dec;66(6):792-801
references.pmid: 19032723
references.citation: J Neuroimmune Pharmacol. 2012 Dec;7(4):877-91
references.pmid: 22101471
references.citation: Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13588-93
references.pmid: 23898208
references.citation: Brain Res. 1999 Aug 7;837(1-2):203-12
references.pmid: 10434004
references.citation: Neuropharmacology. 2004 Mar;46(3):404-11
references.pmid: 14975696
references.citation: Eur J Pharmacol. 2012 Mar 15;679(1-3):75-80
references.pmid: 22306241
references.citation: Glia. 2005 Apr 15;50(2):91-106
references.pmid: 15630704
references.citation: J Neuroimmune Pharmacol. 2008 Dec;3(4):275-85
references.pmid: 18815890
references.citation: Brain. 2011 Dec;134(Pt 12):3616-31
references.pmid: 22102648
references.citation: J Neurochem. 2007 Feb;100(3):567-86
references.pmid: 17173547
references.citation: Expert Opin Investig Drugs. 2012 Feb;21(2):169-78
references.pmid: 22233449
references.citation: Curr HIV Res. 2012 Jul;10(5):435-52
references.pmid: 22591368
references.citation: Brain Res. 2003 Nov 28;992(1):53-9
references.pmid: 14604772
references.citation: Mol Endocrinol. 2007 Jun;21(6):1267-80
references.pmid: 17389748
references.citation: PLoS One. 2011 Apr 08;6(4):e18633
references.pmid: 21494611
references.citation: Brain Res. 2012 Jan 11;1431:97-106
references.pmid: 22137656
references.citation: Mol Psychiatry. 2011 May;16(5):533-47
references.pmid: 20177408
references.citation: Eur J Clin Invest. 2006 Jul;36(7):447-58
references.pmid: 16796601
references.citation: Nat Rev Immunol. 2003 Oct;3(10):791-800
references.pmid: 14502271
references.citation: J Clin Invest. 2001 Jan;107(2):143-51
references.pmid: 11160127
references.citation: Expert Opin Pharmacother. 2009 Dec;10(17):2897-904
references.pmid: 19929708
references.citation: J Neurotrauma. 2012 Feb 10;29(3):600-10
references.pmid: 21806469
references.citation: Glia. 2002 Mar 15;37(4):291-306
references.pmid: 11870869
references.citation: Neurosci Lett. 2007 May 17;418(2):165-9
references.pmid: 17398001
references.citation: Cytokine. 2012 Nov;60(2):338-40
references.pmid: 22898393
references.citation: Nature. 2001 Apr 19;410(6831):988-94
references.pmid: 11309629
references.citation: J Neuroimmunol. 2004 Dec;157(1-2):3-10
references.pmid: 15579274
references.citation: Annu Rev Immunol. 1998;16:225-60
references.pmid: 9597130
references.citation: J Neurochem. 2000 Feb;74(2):633-40
references.pmid: 10646514
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11313-8
references.pmid: 20534506
references.citation: Life Sci. 2006 May 1;78(23):2663-8
references.pmid: 16313925
references.citation: J Immunol. 2007 Mar 1;178(5):3226-36
references.pmid: 17312171
references.citation: Brain Res. 2000 Dec 29;887(2):250-8
references.pmid: 11134613
references.citation: Nat Rev Neurosci. 2009 Jan;10(1):23-36
references.pmid: 19096368
references.citation: Eur J Pharmacol. 2010 Jul 10;637(1-3):102-8
references.pmid: 20399770
references.citation: J Biol Chem. 1996 Jun 28;271(26):15303-6
references.pmid: 8663435
references.citation: J Immunol. 2002 Oct 1;169(7):3589-99
references.pmid: 12244149
references.citation: PLoS One. 2008;3(12):e4093
references.pmid: 19116667
references.citation: Med Hypotheses. 2009 Dec;73(6):927-9
references.pmid: 19635651
references.citation: AIDS Res Treat. 2012;2012:953678
references.pmid: 22666564
references.citation: J Neurochem. 1998 Jun;70(6):2416-23
references.pmid: 9603206
references.citation: Int J Cell Biol. 2012;2012:139573
references.pmid: 22973314
references.citation: Neurology. 2010 Mar 30;74(13):1033-40
references.pmid: 20200338
references.citation: AIDS. 2013 Sep 10;27(14):2181-90
references.pmid: 23751259
references.citation: J Acquir Immune Defic Syndr. 2011 Oct 1;58(2):154-62
references.pmid: 21725250
references.citation: Virology. 2010 Mar 30;399(1):31-38
references.pmid: 20085845
references.citation: Glia. 2006 Jan 15;53(2):132-46
references.pmid: 16206161
references.citation: J Clin Invest. 2001 Jan;107(1):7-11
references.pmid: 11134171
references.citation: J Neurochem. 2009 Jan;108(1):202-15
references.pmid: 19054280
references.citation: Adv Pharmacol. 2014;69:1-69
references.pmid: 24484974
references.citation: Nature. 2001 Dec 20-27;414(6866):920-4
references.pmid: 11780066