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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 partially restores the circadian rhythm of spontaneous motor activity. Ambulatory counts (A–D) and vertical activity (E–H) were assessed in control (C) and hyperammonemic (HA) rats (A, C, E, G) treated with vehicle (V) or with 20 mg/kg GR3027 and in sham-operated control rats (SMV) or PCS rats (B, D, F, H) treated with vehicle (PCSV) or with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg GR3027. Motor activity during night and day is shown in A, B, E and F and the ratios of activity night to day in C, D, G, and H. Values are means ± SE of 8 rats per group. Different from hyperammonemic or PCS rats: aP < 0.05, aaP < 0.01. Different from control/sham: *P < 0.05, **P < 0.01, ***P < 0.001.
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Figure 6: GR3027 partially restores the circadian rhythm of spontaneous motor activity. Ambulatory counts (A–D) and vertical activity (E–H) were assessed in control (C) and hyperammonemic (HA) rats (A, C, E, G) treated with vehicle (V) or with 20 mg/kg GR3027 and in sham-operated control rats (SMV) or PCS rats (B, D, F, H) treated with vehicle (PCSV) or with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg GR3027. Motor activity during night and day is shown in A, B, E and F and the ratios of activity night to day in C, D, G, and H. Values are means ± SE of 8 rats per group. Different from hyperammonemic or PCS rats: aP < 0.05, aaP < 0.01. Different from control/sham: *P < 0.05, **P < 0.01, ***P < 0.001.

Mentions: PCS rats show reduced motor activity (ambulatory counts) during the night (active phase for rats), showing 1,849 ± 176 counts, which is lower (P < 0.05) than in control rats (4,546 ± 584 counts). GR3027 at 0.7 mg/kg increased (P < 0.05) the activity in PCS rats to 2,652 ± 275 counts. At 2.5 mg/kg GR3027 did not affect ambulatory counts (2,235 ± 170 counts) (Fig. 6B).


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 partially restores the circadian rhythm of spontaneous motor activity. Ambulatory counts (A–D) and vertical activity (E–H) were assessed in control (C) and hyperammonemic (HA) rats (A, C, E, G) treated with vehicle (V) or with 20 mg/kg GR3027 and in sham-operated control rats (SMV) or PCS rats (B, D, F, H) treated with vehicle (PCSV) or with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg GR3027. Motor activity during night and day is shown in A, B, E and F and the ratios of activity night to day in C, D, G, and H. Values are means ± SE of 8 rats per group. Different from hyperammonemic or PCS rats: aP < 0.05, aaP < 0.01. Different from control/sham: *P < 0.05, **P < 0.01, ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4556948&req=5

Figure 6: GR3027 partially restores the circadian rhythm of spontaneous motor activity. Ambulatory counts (A–D) and vertical activity (E–H) were assessed in control (C) and hyperammonemic (HA) rats (A, C, E, G) treated with vehicle (V) or with 20 mg/kg GR3027 and in sham-operated control rats (SMV) or PCS rats (B, D, F, H) treated with vehicle (PCSV) or with 0.7 (PCS0.7) or 2.5 (PCS2.5) mg/kg GR3027. Motor activity during night and day is shown in A, B, E and F and the ratios of activity night to day in C, D, G, and H. Values are means ± SE of 8 rats per group. Different from hyperammonemic or PCS rats: aP < 0.05, aaP < 0.01. Different from control/sham: *P < 0.05, **P < 0.01, ***P < 0.001.
Mentions: PCS rats show reduced motor activity (ambulatory counts) during the night (active phase for rats), showing 1,849 ± 176 counts, which is lower (P < 0.05) than in control rats (4,546 ± 584 counts). GR3027 at 0.7 mg/kg increased (P < 0.05) the activity in PCS rats to 2,652 ± 275 counts. At 2.5 mg/kg GR3027 did not affect ambulatory counts (2,235 ± 170 counts) (Fig. 6B).

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