Glutamine metabolism and neuropathological disorders in experimental hepatic encephalopathy: effect of transplanted hepatocytes.
BACKGROUND
Physiopathology of hepatic encephalopathy remains unclear. Recent studies have suggested that ammonia would not act by itself but through an increase in glutamine in the brain. We have previously demonstrated that transplantation of syngeneic hepatocytes into the spleen was able to correct both behavioral deficits and plasma amino acid changes observed in portacaval shunted rats. The aim of the present work was to show a correlation between the correction of chronic hepatic encephalopathy by means of intrasplenic hepatocyte transplantation and two parameters, brain glutamine concentration and ultrastructural aspects of astrocytes.


METHODS
Inbred male Wistar Furth rats were divided into three groups: sham-operated rats (n = 10), rats subjected to portacaval shunt (n = 10), and rats subjected to portacaval shunt and intrasplenic hepatocellular transplantation of 10(7) hepatocytes isolated from livers of syngeneic rats (n = 10). Chronic hepatic encephalopathy was quantified 30 and 60 days after operation by means of nose-poke exploration and spontaneous activity. Pathologic examination and measurement of glutamine concentrations in the corpus striatus and in the cerebral cortex were performed 60 days after operation.


RESULTS
Portacaval shunt rats showed reduced spontaneous activity and nose-poke exploration scores. After portacaval shunt a significant glutamine increase occurred in the corpus striatus and in the cerebral cortex when compared with sham rats (p < 0.05). Ultrastructural examination showed modification of astrocytes named Alzheimer type II after portacaval shunt. Correction of behavioral abnormalities by means of intrasplenic hepatocyte transplantation was associated with partial correction of striatal glutamine increase and with decrease in astrocyte alterations. Cortex glutamine concentration in portacaval shunt-intrasplenic hepatocyte transplantation group and in portacaval shunt rats did not differ significantly.


CONCLUSIONS
These data show that intrasplenic hepatocyte transplantation not only prevents neurologic disorders of hepatic encephalopathy but can also decrease glutamine and ultrastructural alterations in the corpus striatus in an experimental model of chronic liver failure. These data are in favor of the involvement of glutamine in chronic hepatic encephalopathy. These results suggest that intrasplenic hepatocyte transplantation might be of therapeutic interest in chronic liver failure.
Mariani
P
P
Institut National de la Santé et de la Recherche Médicale U.402, Hôpital Saint-Antoine, Paris, France.
Coudray-Lucas
C
C
Baudrimont
M
M
Ribeiro
J
J
Legendre
C
C
Delelo
R
R
Cynober
L
L
Balladur
P
P
Nordlinger
B
B
D000818:Animals; D001253:Astrocytes / Q000648:ultrastructure; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005973:Glutamine / Q000378:metabolism*; D006501:Hepatic Encephalopathy / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D016031:Liver Transplantation; D008297:Male; D051381:Rats; D011920:Rats, Inbred WF; D013154:Spleen / Q000473:pathology
D005973:Glutamine