The hippocampus of Ames dwarf mice exhibits enhanced antioxidative defenses following kainic acid-induced oxidative stress.
BACKGROUND
The vulnerability of the hippocampus to the effects of aging has been found to be associated with a decline in growth hormone/insulin like growth factor-1 (GH/IGF-1), and an increase in oxidative stress. We have evidence that long-living GH-deficient Ames dwarf mice have enhanced antioxidant protection in the periphery but the protection in the central nervous system is less clear.


METHODS
In the present study, we evaluated the antioxidative defense enzyme status in the hippocampus of Ames dwarf and wild type mice at 3, 12 and 24 months of age and examined the ability of each genotype to resist kainic acid-induced (KA) oxidative stress. An equiseizure concentration of KA was administered such that both genotypes responded with similar seizure scores and lipid peroxidation.


RESULTS
We found that GH-sufficient wild type mice showed an increase in oxidative stress as indicated by the reduced ratio of glutathione: glutathione disulfide following KA injection while this ratio was maintained in GH-deficient Ames dwarf mice. In addition, glutathione peroxidase activity (GPx) as well as GPx1 mRNA expression was enhanced in KA-injected Ames dwarf mice but decreased in wild type mice. There was no induction of Nrf-2 (an oxidative stress-induced transcription factor) gene expression in Ames dwarf mice following KA further suggesting maintenance of antioxidant defense in GH-deficiency under oxidative stress conditions.


CONCLUSIONS
Therefore, based on equiseizure administration of KA, Ames dwarf mice have an enhanced antioxidant defense capacity in the hippocampus similar to that observed in the periphery. This improved defense capability in the brain is likely due to increased GPx availability in Ames mice and may contribute to their enhanced longevity.
Sharma
Sunita
S
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58203, USA.
Rakoczy
Sharlene
S
Dahlheimer
Kristine
K
Brown-Borg
Holly
H
D000375:Aging / Q000378:metabolism; D000818:Animals; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism*; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007608:Kainic Acid / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D023421:Models, Animal; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology
D018690:Excitatory Amino Acid Agonists; D051267:NF-E2-Related Factor 2; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005982:Glutathione Transferase; D005978:Glutathione; D007608:Kainic Acid; D019803:Glutathione Disulfide
J Neurosci Res. 2009 Feb 15;87(3):710-22
18816793
Brain Res. 1997 Jun 20;760(1-2):277-80
9237547
Gen Pharmacol. 1994 Jan;25(1):97-102
8026720
Free Radic Biol Med. 2001 Jun 1;30(11):1191-212
11368918
Free Radic Biol Med. 2008 Aug 15;45(4):443-52
18501200
Mech Ageing Dev. 2010 Jun;131(6):422-35
20561541
Endocrinology. 2010 Jul;151(7):3267-76
20410204
Neuropharmacology. 2004 Mar;46(4):580-9
14975682
Annu Rev Pharmacol Toxicol. 2007;47:89-116
16968214
Am J Physiol Endocrinol Metab. 2005 Jul;289(1):E23-9
15701676
J Neurosci Res. 2007 Feb 15;85(3):497-503
17171703
Exp Neurol. 1983 Feb;79(2):422-33
6822273
Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7915-22
8367443
Exp Brain Res. 2000 Jun;132(4):510-6
10912831
J Am Aging Assoc. 2001 Jul;24(3):85-96
23604879
J Neurochem. 1992 Nov;59(5):1609-23
1402908
J Neurotrauma. 2005 Jul;22(7):719-32
16004576
J Neurosci Methods. 2009 Apr 30;179(1):1-8
19167427
Exp Gerontol. 1996 May-Jun;31(3):365-72
9415119
Methods Enzymol. 1984;105:114-21
6727659
Carcinogenesis. 1987 Dec;8(12):1929-32
3119248
Neurobiol Aging. 1995 Jul-Aug;16(4):661-74
8544918
Neuroscience. 1980;5(6):991-1014
7402461
Anal Biochem. 1976 May 7;72:248-54
942051
Behav Brain Res. 2002 Apr 1;131(1-2):211-20
11844588
Exp Gerontol. 2000 Mar;35(2):199-212
10767579
Arch Biochem Biophys. 1996 Sep 1;333(1):189-97
8806770
Free Radic Biol Med. 2000 Apr 15;28(8):1214-21
10889451
Neuroreport. 1991 Jun;2(6):345-7
1832987
Brain Res. 1997 Mar 14;751(1):37-46
9098566
Exp Gerontol. 2005 Jan-Feb;40(1-2):115-20
15664737
Free Radic Biol Med. 2000 Mar 1;28(5):779-85
10754274
Neurosci Lett. 2000 Mar 3;281(1):65-8
10686417
Brain Res Brain Res Rev. 2001 Dec;38(1-2):61-78
11750927
Free Radic Biol Med. 1996;20(6):821-30
8728030
Ann Neurol. 1992;32 Suppl:S10-5
1510365
Exp Neurol. 2006 Feb;197(2):309-17
16364299
Proc Natl Acad Sci U S A. 1996 May 14;93(10):4765-9
8643477
Mech Ageing Dev. 1994 Oct 20;76(2-3):215-24
7885066
Hippocampus. 2008;18(3):239-44
18000817
J Neurosci Methods. 1998 Jan 31;79(1):115-21
9531467
Glia. 2005 Aug 15;51(3):173-86
15800930
Exp Neurol. 2000 Nov;166(1):173-9
11031093
Neurochem Int. 2008 May;52(6):1134-47
18226427
Brain Res. 1996 Jul 15;727(1-2):133-44
8842391
Ageing Res Rev. 2007 May;6(1):28-45
17360245
Mech Ageing Dev. 2003 Dec;124(10-12):1013-24
14659590
Brain Res Brain Res Rev. 2001 Aug;36(1):60-90
11516773
J Neural Transm (Vienna). 2001;108(8-9):955-67
11716148
Endocrine. 1999 Aug;11(1):41-8
10668640
Neurobiol Aging. 2008 Nov;29(11):1680-9
17524525
Brain Res Mol Brain Res. 1997 Aug;48(1):145-8
9379835
J Gerontol A Biol Sci Med Sci. 2009 Aug;64(8):819-27
19414510
Cell Mol Neurobiol. 2005 Dec;25(8):1255-64
16388336
Brain Res Brain Res Rev. 1997 Dec;25(3):335-58
9495562
Brain Res. 2004 Oct 22;1024(1-2):59-76
15451367
Adv Enzymol Relat Areas Mol Biol. 1993;66:149-201
8430514
Mol Chem Neuropathol. 1992 Aug;17(1):51-63
1326973
Chem Res Toxicol. 1997 May;10(5):485-94
9168245
Exp Biol Med (Maywood). 2002 Feb;227(2):94-104
11815672
Cancer Res. 1982 May;42(5):1955-61
7066906
Free Radic Res. 1996 Aug;25(2):149-59
8885333
Biol Chem. 1997 Aug;378(8):793-802
9377474
Genome Res. 1996 Oct;6(10):986-94
8908518
Endocrine. 2003 Feb-Mar;20(1-2):149-54
12668880
Cell Signal. 2008 Apr;20(4):645-58
18248956
Respir Physiol. 2001 Nov 15;128(3):379-91
11718765
Electroencephalogr Clin Neurophysiol. 1972 Mar;32(3):281-94
4110397
Ann Neurol. 2009 May;65(5):540-9
19475669
Neurology. 1998 Dec;51(6):1562-6
9855502
Exp Gerontol. 2001 Feb;36(2):209-20
11226737
Mol Cell Probes. 2002 Feb;16(1):25-30
12005444
Anal Biochem. 1980 Jul 15;106(1):207-12
7416462
J Neurosci Res. 2004 Nov 15;78(4):520-32
15468179
Brain Res. 2005 Feb 21;1035(1):24-31
15713273
Brain Res. 2008 May 13;1209:85-91
18406401
Free Radic Biol Med. 2009 Feb 15;46(4):443-53
19028565
Life Sci. 1993;53(10):857-64
8394966
Methods Enzymol. 1985;113:484-90
3003504
Mech Ageing Dev. 2006 Jan;127(1):57-63
16243379
Peptides. 1986 Jan-Feb;7(1):155-9
3520509
Neuroscience. 1995 Aug;67(3):551-9
7675186
Free Radic Biol Med. 1991;11(1):81-128
1937131
Neuroscience. 2007 Jul 29;147(4):1114-8
17590518
Mol Cell Neurosci. 2008 Sep;39(1):125-32
18619545
Exp Gerontol. 2009 Jan-Feb;44(1-2):10-9
18675334
J Biol Chem. 1974 Nov 25;249(22):7130-9
4436300
FASEB J. 2002 Jun;16(8):781-90
12039859
Neurochem Res. 2000 Oct;25(9-10):1439-51
11059815
Brain Res. 2000 Apr 17;862(1-2):83-9
10799672
Neurochem Res. 2004 Nov;29(11):2105-12
15662844
Cell Death Differ. 2002 Sep;9(9):1007-16
12181751
J Pineal Res. 2003 Mar;34(2):95-102
12562500
Free Radic Biol Med. 1995 Jun;18(6):993-1002
7628735
Exp Mol Pathol. 2008 Oct;85(2):135-40
18586238
J Neurochem. 2006 Sep;98(6):1852-65
16945104