Cognitive enhancing effects of an AMPA receptor positive modulator on place learning in mice

TY - JOUR

T1 - Cognitive enhancing effects of an AMPA receptor positive modulator on place learning in mice

AU - Rytter, Hana Malá

AU - Chen, Yuxia

AU - Worm, Vivi Hu

AU - Kure, Julie

AU - Kaae, Birgitte H.

AU - Madsen, Ulf

AU - Badolo, Lassina

AU - Pickering, Darryl S

AU - Mogensen, Jesper

PY - 2012/1/1

Y1 - 2012/1/1

N2 - This study presents an in vivo investigation of the arylpropylsulfonamide α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor positive modulator (R,R)-N,N-(2,20-[biphenyl-4-40-diyl]bis[propane-2,1-diyl])dimethanesulfonamide (PIMSD). The pharmacokinetics of the drug were examined in male C57BL/6J mice and the drug concentration in blood plasma determined after subcutaneous injection of 1mg/kg b.w. This analysis revealed a rapid increase of the plasma concentration, peaking within 30min after administration with a T 1/2 of approximately 30min and a peak plasma concentration of about 2μM. Analysis of brain tissue homogenates also indicated blood-brain barrier permeability of the compound. Cognitive enhancing effects of the drug were then studied on place learning in male C57BL/6J mice in a water maze. In order to elucidate the potential positive effects of PIMSD on spatial learning the muscarinergic antagonist scopolamine was utilized, which is known to impair spatial learning ability. The mice were divided into four groups and subjected to two sequential subcutaneous injections administered 25min prior to behavioural testing: (1) vehicle/vehicle; (2) PIMSD/vehicle; (3) scopolamine/vehicle; (4) PIMSD/scopolamine. PIMSD at a dose of 3mg/kg b.w. was able to partially reverse the impairment given by 0.5mg/kg b.w. scopolamine. These results suggest that arylpropylsulfonamides such as PIMSD may have a therapeutic use in the enhancement of cognitive function and support the hypothesis that AMPA receptor potentiation is one mechanism that can be targeted for diseases of cognitive impairment.

AB - This study presents an in vivo investigation of the arylpropylsulfonamide α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor positive modulator (R,R)-N,N-(2,20-[biphenyl-4-40-diyl]bis[propane-2,1-diyl])dimethanesulfonamide (PIMSD). The pharmacokinetics of the drug were examined in male C57BL/6J mice and the drug concentration in blood plasma determined after subcutaneous injection of 1mg/kg b.w. This analysis revealed a rapid increase of the plasma concentration, peaking within 30min after administration with a T 1/2 of approximately 30min and a peak plasma concentration of about 2μM. Analysis of brain tissue homogenates also indicated blood-brain barrier permeability of the compound. Cognitive enhancing effects of the drug were then studied on place learning in male C57BL/6J mice in a water maze. In order to elucidate the potential positive effects of PIMSD on spatial learning the muscarinergic antagonist scopolamine was utilized, which is known to impair spatial learning ability. The mice were divided into four groups and subjected to two sequential subcutaneous injections administered 25min prior to behavioural testing: (1) vehicle/vehicle; (2) PIMSD/vehicle; (3) scopolamine/vehicle; (4) PIMSD/scopolamine. PIMSD at a dose of 3mg/kg b.w. was able to partially reverse the impairment given by 0.5mg/kg b.w. scopolamine. These results suggest that arylpropylsulfonamides such as PIMSD may have a therapeutic use in the enhancement of cognitive function and support the hypothesis that AMPA receptor potentiation is one mechanism that can be targeted for diseases of cognitive impairment.

KW - Faculty of Social Sciences

KW - AMPA

KW - modulator

KW - glutamat

KW - kognitiv fremmer

KW - mus

KW - dyremodel

KW - place learning

KW - spatiel indlæring

KW - spatiel hukommelse

KW - farmakologi

KW - skopolamin

KW - hukommelse

KW - indlæring

KW - vandlabyrint

KW - AMPA receptor potentiator

KW - Alzheimers demens

KW - biarylpropylsulfonamide

M3 - Journal article

SN - 0166-4328

VL - 226

SP - 18

EP - 25

JO - Behavioural Brain Research

JF - Behavioural Brain Research

IS - 1

ER -