Indomethacin improves locomotor deficit and reduces brain concentrations of neuroinhibitory steroids in rats following portacaval anastomosis

Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric complication of both acute and chronic liver failure characterized by progressive neuronal inhibition. Some neurosteroids are potent positive allosteric modulators of the gamma-aminobutyric acid (GABA)-A receptor complex, and 'increased GABAergic tone' has been proposed to explain the neuroinhibition characteristics of HE. Brain levels of the neurosteroids pregnenolone, allopregnanolone and tetrahydrodesoxycorticosterone (THDOC) and the functional status of the GABA-A receptor complex were assessed in rats following portacaval anastomosis (PCA). Effects of indomethacin, an inhibitor of the 3alpha-hydroxysteroid dehydrogenase enzyme involved in neurosteroid synthesis, on PCA rat locomotor activity and brain neurosteroid levels were also assessed. Significant increases of the neurosteroid pregnenolone (2.6-fold), allopregnanolone (1.7-fold) and THDOC (4.7-fold) were observed in brains of PCA rats. Brain levels of these neurosteroids were in the nanomolar range, sufficient to exert positive allosteric modulatory effects at the GABA-A receptor. Indomethacin (0.1-5 mg kg(-1)) ameliorated dose-dependently the locomotor deficit of PCA rats and concomitantly normalized brain levels of allopregnanolone and THDOC. Increased brain levels of neurosteroids with positive allosteric modulatory actions at the neuronal GABA-A receptor offer a cogent explanation for the notion of 'increased GABAergic tone' in HE. Pharmacological approaches using agents that either reduce neurosteroid synthesis or modulate the neurosteroid site on GABA-A receptor could offer new therapeutic tools for the management and treatment of HE.

Behavioral alterations and Fos protein immunoreactivity in brain regions of bile duct-ligated cirrhotic rats

“…Thus, the results of this particular study do not allow the conclusion that no anxiety-related effects were found in BDL animals. Furthermore, in another study (Ahboucha et al 2008) performed with rats with portacaval anastomosis tested in the EPM, no anxiety-related effects were found, but deficits in the animals' motor behavior were observed, thus compromising any conclusion regarding anxiety parameters. On the other hand, the anxiogenic effects observed were consistent with clinical descriptions of HE patients (Butterworth 2003, Sakamoto et al 2012.…”

“…According to the HESA, psychomotor impairment would describe a more severe grade of encephalopathy (stage 2 HE). Although in some of the studies conducted with different animal models of HE, decreases in locomotor activity were observed (Ahboucha et al 2008, Leke et al 2012, in others, no motor alterations were found (Sergeeva et al 2005). In fact, some studies have suggested that depending on the test used to measure motor activity, deficits may or may not be obtained.…”

Contributions of Microdialysis to New Alternative Therapeutics for Hepatic Encephalopathy

“…The spherical adsorptive carbon AST-120, was able to reduce ammonia levels in experimental animal models [28]. HPN-100 is a pro-drug which, although not yet tested on patients with liver disease, is thought to ameliorate the clinical condition of HE.…”

Hepatic encephalopathy: An updated approach from pathogenesis to treatment

“…According to current evidence, inflammatory mediators play an important role in inducing the neurophysiological brain alterations observed in patients with HE [103]. Based on this observation, experimental studies have been conducted on animal models, proving the ability of indomethacin [104] and ibuprofen [105] to ameliorate the cerebral symptoms observed in HE patients. L-methinine S-sulfoximine (MSO), an irreversible inhibitor of GS, can prove of therapeutic value for patients with HE, given the fact that it can lower brain glutamine levels and therefore prevent astrocyte swelling and cerebral edema [106].…”