Neuroinflammation contributes to hypokinesia in rats with hepatic encephalopathy: ibuprofen restores its motor activity.
Patients with hepatic encephalopathy show altered motor function, psychomotor slowing, and hypokinesia, which are reproduced in rats with portacaval shunts (PCS). Increased extracellular glutamate in substantia nigra pars reticulata (SNr) is responsible for hypokinesia in PCS rats. The mechanisms by which liver failure leads to increased extracellular glutamate in SNr remain unclear. Inflammation seems to act synergistically with hyperammonemia to induce neurological alterations in hepatic encephalopathy. It is therefore possible that inflammation-associated alterations may contribute to motor alterations in hepatic encephalopathy. The aim of this work was to assess whether treatment with an antiinflammatory, ibuprofen, is able to normalize extracellular glutamate in SNr and/or to improve hypokinesia in PCS rats. The amounts of the glutamate transporters GLT-1 and EAAC-1 are reduced by 26% and 32%, respectively, in SNr of PCS rats. This reduction is associated with a tenfold increase in extracellular glutamate in SNr and a reduction in motor activity. Chronic treatment with 30 mg/kg ibuprofen completely normalizes the amount of GLT-1 and EAAC-1 and significantly reduces (by 53%) extracellular glutamate in SNr of PCS rats. Moreover, ibuprofen, at 15 or 30 (but not at 5) mg/kg/day, completely eliminates hypokinesia, restoring normal motor activity. This supports the idea that inflammation is a main contributor to the induction of hypokinesia in hepatic encephalopathy. Moreover, these data point to the possible therapeutic utility of decreasing inflammation, by safe procedures, in the treatment of the motor deficits in patients with hepatic encephalopathy.
Cauli
Omar
O
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Rodrigo
Regina
R
Piedrafita
Blanca
B
Llansola
Marta
M
Mansouri
Mohammad T
MT
Felipo
Vicente
V
D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000150:complications* / Q000503:physiopathology; D018476:Hypokinesia / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007052:Ibuprofen / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015151:Immunoblotting; D007249:Inflammation; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D018698:Glutamic Acid; D007052:Ibuprofen