Anticonvulsive evaluation of THIP in the murine pentylenetetrazole kindling model: lack of anticonvulsive effect of THIP despite functional δ-subunit-containing GABAA receptors in dentate gyrus granule cells
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Anticonvulsive evaluation of THIP in the murine pentylenetetrazole kindling model : lack of anticonvulsive effect of THIP despite functional δ-subunit-containing GABAA receptors in dentate gyrus granule cells. / Simonsen, Charlotte; Boddum, Kim; von Schoubye, Nadia L; Kloppenburg, Alissa; Sønderskov, Kasper; Hansen, Suzanne L; Kristiansen, Uffe.
In: Pharmacology Research & Perspectives, Vol. 5, No. 4, e00322, 08.2017.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Anticonvulsive evaluation of THIP in the murine pentylenetetrazole kindling model
T2 - lack of anticonvulsive effect of THIP despite functional δ-subunit-containing GABAA receptors in dentate gyrus granule cells
AU - Simonsen, Charlotte
AU - Boddum, Kim
AU - von Schoubye, Nadia L
AU - Kloppenburg, Alissa
AU - Sønderskov, Kasper
AU - Hansen, Suzanne L
AU - Kristiansen, Uffe
N1 - © 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.
PY - 2017/8
Y1 - 2017/8
N2 - THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a GABAA receptor agonist with varying potencies and efficacies at γ-subunit-containing receptors. More importantly, THIP acts as a selective superagonist at δ-subunit-containing receptors (δ-GABAA Rs) at clinically relevant concentrations. Evaluation of THIP as a potential anticonvulsant has given contradictory results in different animal models and for this reason, we reevaluated the anticonvulsive properties of THIP in the murine pentylenetetrazole (PTZ) kindling model. As loss of δ-GABAA R in the dentate gyrus has been associated with several animal models of epilepsy, we first investigated the presence of functional δ-GABAA receptors. Both immunohistochemistry and Western blot data demonstrated that δ-GABAA R expression is not only present in the dentate gyrus, but also the expression level was enhanced in the early phase after PTZ kindling. Whole-cell patch-clamp studies in acute hippocampal brain slices revealed that THIP was indeed able to induce a tonic inhibition in dentate gyrus granule cells. However, THIP induced a tonic current of similar magnitude in the PTZ-kindled mice compared to saline-treated animals despite the observed upregulation of δ-GABAA Rs. Even in the demonstrated presence of functional δ-GABAA Rs, THIP (0.5-4 mg/kg) showed no anticonvulsive effect in the PTZ kindling model using a comprehensive in vivo evaluation of the anticonvulsive properties.
AB - THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a GABAA receptor agonist with varying potencies and efficacies at γ-subunit-containing receptors. More importantly, THIP acts as a selective superagonist at δ-subunit-containing receptors (δ-GABAA Rs) at clinically relevant concentrations. Evaluation of THIP as a potential anticonvulsant has given contradictory results in different animal models and for this reason, we reevaluated the anticonvulsive properties of THIP in the murine pentylenetetrazole (PTZ) kindling model. As loss of δ-GABAA R in the dentate gyrus has been associated with several animal models of epilepsy, we first investigated the presence of functional δ-GABAA receptors. Both immunohistochemistry and Western blot data demonstrated that δ-GABAA R expression is not only present in the dentate gyrus, but also the expression level was enhanced in the early phase after PTZ kindling. Whole-cell patch-clamp studies in acute hippocampal brain slices revealed that THIP was indeed able to induce a tonic inhibition in dentate gyrus granule cells. However, THIP induced a tonic current of similar magnitude in the PTZ-kindled mice compared to saline-treated animals despite the observed upregulation of δ-GABAA Rs. Even in the demonstrated presence of functional δ-GABAA Rs, THIP (0.5-4 mg/kg) showed no anticonvulsive effect in the PTZ kindling model using a comprehensive in vivo evaluation of the anticonvulsive properties.
KW - Journal Article
U2 - 10.1002/prp2.322
DO - 10.1002/prp2.322
M3 - Journal article
C2 - 28805971
VL - 5
JO - Pharmacology Research & Perspectives
JF - Pharmacology Research & Perspectives
SN - 2052-1707
IS - 4
M1 - e00322
ER -
ID: 182510665