Activation of neuronal nitric oxide synthase in cerebellum of chronic hepatic encephalopathy rats is associated with up-regulation of NADPH-producing pathway.
Cerebellum-associated functions get affected during mild hepatic encephalopathy (MHE) in patients with chronic liver failure (CLF). Involvement of nitrosative and antioxidant factors in the pathogenesis of chronic hepatic encephalopathy is an evolving concept and needs to be defined in a true CLF animal model. This article describes profiles of NADPH-dependent neuronal nitric oxide synthase (nNOS) and those of glutathione peroxidase and glutathione reductase (GR) vis-a-vis regulation of NADPH-producing pathway in the cerebellum of CLF rats induced by administration of thioacetamide (100 mg kg⁻¹ b.w., i.p.) up to 10 days and confirming MHE on Morris water maze tests. Significant increases in the expression of nNOS protein and nitric oxide (NOx) level coincided with a similar increment in NADPH-diaphorase activity in the cerebellum of CLF rats. Glutathione peroxidase and GR utilize NADPH to regenerate reduced glutathione (GSH) in the cells. Both these enzymes and GSH level were found to be static and thus suggested efficient turnover of GSH in the cerebellum of MHE rats. Relative levels of glucose-6-phosphate dehydrogenase (G6PD) vs. phosphofructokinase 2 (PFK2) determine the rate of pentose phosphate pathway (PPP) responsible to synthesize NADPH. The cerebellum of CLF rats showed overactivation of G6PD with a significant decline in the expression of PFK2 and thus suggested activation of PPP in the cerebellum during MHE. It is concluded that concordant activations of PPP and nNOS in cerebellum of MHE rats could be associated with the implication of NOx in the pathogenesis of MHE.
Singh
Santosh
S
Biochemistry and Molecular Biology Laboratory, Centre of Advanced Studies in Zoology, Banaras Hindu University, Varanasi 221005, India.
Trigun
Surendra K
SK
D000818:Animals; D015153:Blotting, Western; D002531:Cerebellum / Q000378:metabolism*; D002908:Chronic Disease; D004789:Enzyme Activation / Q000502:physiology; D006501:Hepatic Encephalopathy / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning; D009249:NADP / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation
D009249:NADP; D052248:Nitric Oxide Synthase Type I
J Neurosci Methods. 1984 May;11(1):47-60
6471907
J Histochem Cytochem. 1994 Oct;42(10):1309-15
7523486
Liver Int. 2009 Jul;29(6):783-8
19638106
Metab Brain Dis. 2004 Dec;19(3-4):313-29
15554424
Aliment Pharmacol Ther. 2007 Feb;25 Suppl 1:3-9
17295846
Arch Intern Med. 1980 Apr;140(4):519-21
7362383
Hepatology. 2004 Jul;40(1):73-9
15239088
Metab Brain Dis. 2007 Dec;22(3-4):199-218
17882538
Hepatology. 2002 Mar;35(3):716-21
11870389
Invest New Drugs. 2009 Dec;27(6):503-16
19043664
Metab Brain Dis. 2007 Dec;22(3-4):219-34
17823859
Hepatology. 1993 Nov;18(5):1061-8
8225210
Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):789-93
18455501
Neurochem Int. 2002 Aug-Sep;41(2-3):161-70
12020616
Electrophoresis. 2004 Sep;25(17):2926-31
15349931
Anal Biochem. 2002 Jul 1;306(1):79-82
12069417
Clin Sci (Lond). 1999 Sep;97(3):313-8
10464056
J Hepatol. 2003 May;38(5):583-90
12713868
Brain Res. 2005 Feb 9;1034(1-2):1-10
15713254
Exp Brain Res. 2006 Nov;175(2):292-304
16763833
Proc Natl Acad Sci U S A. 1990 May;87(9):3547-51
2333301
Free Radic Biol Med. 1999 Nov;27(9-10):951-65
10569628
Behav Brain Res. 2000 Apr;109(1):37-47
10699656
Neurochem Res. 2008 Jan;33(1):103-13
17676388
World J Gastroenterol. 2008 Jun 21;14(23):3609-15
18595126
J Neurochem. 2003 Aug;86(3):605-14
12859674
Prog Neurobiol. 2002 Jul;67(4):259-79
12207972
Am J Surg. 2001 Jul;182(1):58-63
11532417
Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7773-7
1715579
J Neurol Sci. 2007 Jan 15;252(1):67-75
17169376
Metab Brain Dis. 2005 Dec;20(4):399-408
16382350
J Neurochem. 1995 Aug;65(2):677-8
7542313
Exp Neurol. 2000 Feb;161(2):704-13
10686089
Neurochem Res. 2007 Mar;32(3):517-24
17268843
Histochem J. 1995 Oct;27(10):757-69
8575939
Nat Cell Biol. 2004 Jan;6(1):45-51
14688792
Clin Biochem. 2005 Aug;38(8):696-9
15963970
Trends Biochem Sci. 2001 Jan;26(1):30-5
11165514
J Gastroenterol Hepatol. 2006 Feb;21(2):358-66
16509859
Behav Brain Res. 2008 Mar 17;188(1):32-40
18063138
Curr Top Cell Regul. 1988;29:265-89
3293926
Brain Res. 2001 Aug 24;911(2):152-7
11511383
Eur J Neurosci. 1998 Oct;10(10):3201-9
9786213
Neurosci Res. 2005 Feb;51(2):185-97
15681036
Gut. 2007 Dec;56(12):1736-42
17660226
J Neurochem. 1994 Nov;63(5):1829-38
7931339
Arterioscler Thromb Vasc Biol. 2003 Mar 1;23(3):411-7
12615686
Exp Brain Res. 1999 Jul;127(1):1-11
10424409
J Neurosci Res. 2004 Feb 1;75(3):436-40
14743457
Neuroscience. 1992;46(4):755-84
1371855
Biochem J. 2001 Aug 1;357(Pt 3):593-615
11463332
J Neurol. 2006 Mar;253(3):349-56
16244813
Mutat Res. 1997 Dec 12;396(1-2):65-78
9434860
Neurochem Res. 2006 Jan;31(1):11-20
16474992
Brain Res. 2001 Sep 14;913(1):57-67
11532247
Neuroscience. 2004;126(4):879-87
15207323
J Mol Med (Berl). 2007 Mar;85(3):203-5
17273819
J Mol Med (Berl). 2007 Mar;85(3):237-45
17216205
J Biol Chem. 1992 Sep 5;267(25):17939-43
1325453
J Hepatol. 2006 Jan;44(1):104-10
16169117
Free Radic Biol Med. 1999 Jun;26(11-12):1369-74
10401599
J Neurochem. 2008 Aug;106(3):1440-9
18498443