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GR3027 antagonizes GABAA receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy.

Johansson M, Agusti A, Llansola M, Montoliu C, Strömberg J, Malinina E, Ragagnin G, Doverskog M, Bäckström T, Felipo V - Am. J. Physiol. Gastrointest. Liver Physiol. (2015)

Bottom Line: Current treatments for HE, mainly directed to reduction of ammonia levels, are not effective enough because they cannot completely eliminate hyperammonemia and inflammation, which induce the neurological alterations.Studies in animal models show that overactivation of GABAA receptors is involved in cognitive and motor impairment in HE and that reducing this activation restores these functions.GR3027 is a novel approach to treatment of HE that would normalize neurological functions altered because of enhanced GABAergic tone, affording more complete normalization of cognitive and motor function than current treatments for HE.

View Article: PubMed Central - PubMed

Affiliation: Umecrine Cognition AB, Solna, Sweden; Umeå Neurosteroid Research Center, Department of Clinical Sciences, Umeå University, Umeå, Sweden;

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GR3027 restores motor coordination in beam walking in hyperammonemic and PCS rats. A: control (C V) or hyperammonemic (HA V) rats treated with vehicle and hyperammonemic rats treated with 3 (HA 3), 10 (HA 10), or 20 (HA 20) mg/kg GR3027. B: sham-operated control rats (SM V) or PCS rats treated with vehicle (PCS V) and PCS rats treated with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg GR3027. Values are means ± SE for number of rats indicated under each bar. *Different from control or sham-operated rats: *P < 0.05. Different from hyperammonemic or PCS rats: aP < 0.05, aaP < 0.01, aaaP < 0.001.
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Figure 3: GR3027 restores motor coordination in beam walking in hyperammonemic and PCS rats. A: control (C V) or hyperammonemic (HA V) rats treated with vehicle and hyperammonemic rats treated with 3 (HA 3), 10 (HA 10), or 20 (HA 20) mg/kg GR3027. B: sham-operated control rats (SM V) or PCS rats treated with vehicle (PCS V) and PCS rats treated with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg GR3027. Values are means ± SE for number of rats indicated under each bar. *Different from control or sham-operated rats: *P < 0.05. Different from hyperammonemic or PCS rats: aP < 0.05, aaP < 0.01, aaaP < 0.001.

Mentions: Hyperammonemic rats show motor incoordination in beam walking, with more (P < 0.05) slips (1.4 ± 0.1) than control rats (1.0 ± 0.1). GR3027 restores motor coordination (Fig. 3A) at 3 mg/kg (0.8 ± 0.1 slips, P < 0.05) and 20 mg/kg (0.8 ± 0.1 slips, P < 0.05). At 10 mg/kg GR3027 also normalized motor coordination (1.0 ± 0.2 slips), but not significantly (Fig. 3A).


GR3027 antagonizes GABAA receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy.

Johansson M, Agusti A, Llansola M, Montoliu C, Strömberg J, Malinina E, Ragagnin G, Doverskog M, Bäckström T, Felipo V - Am. J. Physiol. Gastrointest. Liver Physiol. (2015)

GR3027 restores motor coordination in beam walking in hyperammonemic and PCS rats. A: control (C V) or hyperammonemic (HA V) rats treated with vehicle and hyperammonemic rats treated with 3 (HA 3), 10 (HA 10), or 20 (HA 20) mg/kg GR3027. B: sham-operated control rats (SM V) or PCS rats treated with vehicle (PCS V) and PCS rats treated with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg GR3027. Values are means ± SE for number of rats indicated under each bar. *Different from control or sham-operated rats: *P < 0.05. Different from hyperammonemic or PCS rats: aP < 0.05, aaP < 0.01, aaaP < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556948&req=5

Figure 3: GR3027 restores motor coordination in beam walking in hyperammonemic and PCS rats. A: control (C V) or hyperammonemic (HA V) rats treated with vehicle and hyperammonemic rats treated with 3 (HA 3), 10 (HA 10), or 20 (HA 20) mg/kg GR3027. B: sham-operated control rats (SM V) or PCS rats treated with vehicle (PCS V) and PCS rats treated with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg GR3027. Values are means ± SE for number of rats indicated under each bar. *Different from control or sham-operated rats: *P < 0.05. Different from hyperammonemic or PCS rats: aP < 0.05, aaP < 0.01, aaaP < 0.001.
Mentions: Hyperammonemic rats show motor incoordination in beam walking, with more (P < 0.05) slips (1.4 ± 0.1) than control rats (1.0 ± 0.1). GR3027 restores motor coordination (Fig. 3A) at 3 mg/kg (0.8 ± 0.1 slips, P < 0.05) and 20 mg/kg (0.8 ± 0.1 slips, P < 0.05). At 10 mg/kg GR3027 also normalized motor coordination (1.0 ± 0.2 slips), but not significantly (Fig. 3A).

Bottom Line: Current treatments for HE, mainly directed to reduction of ammonia levels, are not effective enough because they cannot completely eliminate hyperammonemia and inflammation, which induce the neurological alterations.Studies in animal models show that overactivation of GABAA receptors is involved in cognitive and motor impairment in HE and that reducing this activation restores these functions.GR3027 is a novel approach to treatment of HE that would normalize neurological functions altered because of enhanced GABAergic tone, affording more complete normalization of cognitive and motor function than current treatments for HE.

View Article: PubMed Central - PubMed

Affiliation: Umecrine Cognition AB, Solna, Sweden; Umeå Neurosteroid Research Center, Department of Clinical Sciences, Umeå University, Umeå, Sweden;

Show MeSH
Related in: MedlinePlus