title: Neurological sequelae induced by alphavirus infection of the CNS are attenuated by treatment with the glutamine antagonist 6-diazo-5-oxo-l-norleucine.
abstract: Recovery from encephalomyelitis induced by infection with mosquito-borne alphaviruses is associated with a high risk of lifelong debilitating neurological deficits. Infection of mice with the prototypic alphavirus, Sindbis virus, provides an animal model with which to study disease mechanisms and examine potential therapeutics. Infectious virus is cleared from the brain within a week after infection, but viral RNA is cleared slowly and persists for the life of the animal. However, no studies have examined the effect of infection on neurocognitive function over time. In the present study, we examined neurocognitive function at different phases of infection in 5-week-old C57BL/6 mice intranasally inoculated with Sindbis virus. At the peak of active virus infection, mice demonstrated hyperactivity, decreased anxiety, and marked hippocampal-dependent memory deficits, the latter of which persisted beyond clearance of infectious virus and resolution of clinical signs of disease. Previous studies indicate that neuronal damage during alphavirus encephalomyelitis is primarily due to inflammatory cell infiltration and glutamate excitotoxicity rather than directly by virus infection. Therefore, mice were treated with 6-diazo-5-oxo-l-norleucine (DON), a glutamine antagonist that can suppress both the immune response and excitotoxicity. Treatment with DON decreased inflammatory cell infiltration and cell death in the hippocampus and partially prevented development of clinical signs and neurocognitive impairment despite the presence of infectious virus and high viral RNA levels. This study presents the first report of neurocognitive sequelae in mice with alphavirus encephalomyelitis and provides a model system for further elucidation of the pathogenesis of virus infection and assessment of potential therapies.
authors: Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors: Michelle C
authors: MC
authors: Potter
authors: Victoria K
authors: VK
authors: Baxter
authors: Robert W
authors: RW
authors: Mathey
authors: Jesse
authors: J
authors: Alt
authors: Camilo
authors: C
authors: Rojas
authors: Diane E
authors: DE
authors: Griffin
authors: Barbara S
authors: BS
authors: Slusher
mesh_terms: D018354:Alphavirus Infections / Q000150:complications*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D003980:Diazooxonorleucine / Q000494:pharmacology*; D004195:Disease Models, Animal; D018792:Encephalitis, Viral / Q000150:complications*; D004797:Enzyme-Linked Immunosorbent Assay; D005973:Glutamine / Q000037:antagonists & inhibitors; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D012845:Sindbis Virus
chemical_list: D000964:Antimetabolites, Antineoplastic; D003980:Diazooxonorleucine; D005973:Glutamine
references: Immunity. 2011 Dec 23;35(6):871-82
references: 22195744
references: Behav Pharmacol. 2002 Jul;13(4):287-94
references: 12218509
references: Behav Neurosci. 1997 Feb;111(1):104-13
references: 9109628
references: Virology. 2003 Jun 20;311(1):28-39
references: 12832200
references: J Virol. 2011 Nov;85(21):11490-501
references: 21865385
references: Int J Cancer. 2010 Nov 15;127(10):2478-85
references: 20473919
references: Behav Neurosci. 1992 Apr;106(2):274-85
references: 1590953
references: Am J Trop Med Hyg. 1995 Jan;52(1):8-13
references: 7856830
references: Nature. 1978 Feb 16;271(5646):676-7
references: 625338
references: Neuroscience. 2006 Sep 1;141(3):1149-62
references: 16753269
references: Ann Neurol. 2004 Apr;55(4):541-9
references: 15048893
references: Q J Exp Physiol. 1985 Oct;70(4):473-89
references: 3909197
references: Front Behav Neurosci. 2014 Apr 01;8:112
references: 24744710
references: J Neurosci. 1999 Oct 15;19(20):9054-62
references: 10516322
references: Antiviral Res. 2010 Feb;85(2):328-45
references: 19857523
references: Science. 2001 Jul 13;293(5528):303-6
references: 11452126
references: Ann Neurol. 2010 Jun;67(6):699-714
references: 20517932
references: Learn Mem. 1994 May-Jun;1(1):34-44
references: 10467584
references: Cancer Treat Rep. 1980;64(12):1247-51
references: 7471114
references: Eur J Pharmacol. 2003 Feb 28;463(1-3):217-23
references: 12600712
references: J Immunol. 1999 Feb 1;162(3):1624-32
references: 9973422
references: Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18868-73
references: 20921411
references: Biol Psychiatry. 2013 Mar 1;73(5):443-53
references: 23218253
references: J Neuroimmune Pharmacol. 2013 Jun;8(3):594-607
references: 23553365
references: Arch Med Res. 2002 Jul-Aug;33(4):330-42
references: 12234522
references: J Virol. 2000 Jun;74(11):5352-6
references: 10799613
references: PLoS Negl Trop Dis. 2010;4(5):e646
references: 20520794
references: J Virol. 1988 Jul;62(7):2329-36
references: 2836615
references: J Neuroinflammation. 2011;8:23
references: 21388530
references: Emerg Infect Dis. 2013 Feb;19(2):194-201; quiz 352
references: 23343480
references: Invest New Drugs. 1990 Feb;8(1):113-9
references: 2188926
references: Neurology. 1955 Apr;5(4):223-35
references: 14370373
references: Neurosci Biobehav Rev. 2006;30(2):188-202
references: 16120461
references: Tohoku J Exp Med. 2009 Feb;217(2):87-92
references: 19212100
references: PLoS Curr. 2010 Dec 07;2:RRN1201
references: 21152076
references: Pediatrics. 2008 Feb;121(2):e358-65
references: 18245408
references: Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15625-30
references: 20713712
references: J Virol. 1992 Nov;66(11):6429-35
references: 1383564
references: Cancer Treat Rep. 1981 Nov-Dec;65(11-12):1031-6
references: 7296548
references: Neurology. 1971 Sep;21(9):969-74
references: 5106260
references: Calif Med. 1953 Nov;79(5):362-6
references: 13106712
references: Nat Rev Neurosci. 2013 Jun;14(6):417-28
references: 23635870
references: Brain Res. 1979 Oct 26;176(1):91-100
references: 487185
references: Lab Invest. 1987 Apr;56(4):418-23
references: 3031369
references: Ann Surg. 1993 Dec;218(6):715-28
references: 8257221
references: J Neurosci. 2006 May 17;26(20):5484-91
references: 16707800
references: Neurobiol Dis. 2014 Apr;64:98-106
references: 24412221
references: Prog Neurobiol. 2010 Jun;91(2):95-101
references: 20004230
references: J Neurosci. 2012 Mar 21;32(12):3958-68
references: 22442063
references: Cancer Treat Rep. 1982 May;66(5):1215-7
references: 7083223
references: Dev Neurobiol. 2012 Jun;72(6):943-52
references: 22252978
references: Science. 1991 Nov 8;254(5033):856-60
references: 1658936
references: Behav Neurosci. 1993 Oct;107(5):887-91
references: 8280399
references: Neurobiol Learn Mem. 2009 May;91(4):393-401
references: 19100850
references: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3575-80
references: 18296635
references: Lancet. 1996 Aug 17;348(9025):436-40
references: 8709783
references: Annu Rev Entomol. 2009;54:17-35
references: 19067628
references: Pediatrics. 2006 Mar;117(3):763-70
references: 16510656