Different protection mechanisms after pretreatment with glycine or alpha-lipoic acid in a rat model of warm hepatic ischemia.
OBJECTIVE
Alpha-lipoic (LA) acid pretreatment has previously been described to reduce ischemia/reperfusion injury (IRI) after warm liver ischemia, whereas glycine pretreatment has been shown to be protective mostly in models of cold hepatic ischemia. The aim of this study was to determine whether glycine decreases IRI after warm hepatic ischemia. Furthermore we investigated whether doses of LA other than those used previously are also protective against IRI after warm hepatic ischemia.


METHODS
Selective liver ischemia was maintained over a period of 90 min. In long-term as well as short-term experiments we studied IRI in several groups comparing animal survival as the pivotal endpoint.


RESULTS
Animal survival was improved by glycine and 5,000 micromol LA, whereas all animals died within 3 days after pretreatment with 50 micromol LA. In the glycine group we observed a tendency towards decreased apoptosis-related cell death measured by the activity of caspase-3 in liver tissue and the percentage of TUNEL-positive hepatocytes in comparison to the untreated group. Serum alpha-glutathione S-transferase, lipid peroxidation, and caspase-3 activity as well as the percentage of TUNEL-positive hepatocytes and the percentage of liver necrosis were only significantly decreased by 5,000 micromol LA pretreatment. Liver tissue levels of tumor necrosis factor (TNF)alpha were reduced only in the glycine group whereas TNFalpha was increased in the untreated as well as the LA group. Levels of TNFalpha mRNA were upregulated in both the glycine- and LA-pretreated groups.


CONCLUSIONS
Our data show that increased animal survival by glycine was accompanied by a reduced TNFalpha content in liver tissue. Protection by glycine is likely to result from a reduction in adverse TNFalpha effects. Administration of high-dose LA on the other hand led to a significant reduction in necrosis- and apoptosis-related cell death in IRI of the liver without a reduction in liver TNFalpha.
Duenschede
Friedrich
F
Department of General and Abdominal Surgery, University Hospital Mainz, Mainz, Germany. duenschede@ach.klinik.uni-mainz.de
Westermann
Stefanie
S
Riegler
Nina
N
Miesner
Imke
I
Erbes
Kirsten
K
Ewald
Patrick
P
Kircher
Achim
A
Schaefer
Hella
H
Schneider
Julius
J
Schad
Arno
A
Dutkowski
P
P
Kiemer
A K
AK
Junginger
Theodor
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019610:Cytoprotection; D005982:Glutathione Transferase / Q000378:metabolism; D005998:Glycine / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008084:Lipoxygenase / Q000032:analysis; D008099:Liver / Q000098:blood supply* / Q000201:enzymology; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D015427:Reperfusion Injury / Q000517:prevention & control*; D008063:Thioctic Acid / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics; D052096:Warm Ischemia
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D008063:Thioctic Acid; D007770:L-Lactate Dehydrogenase; D008084:Lipoxygenase; D005982:Glutathione Transferase; D005998:Glycine