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DUAL TARGETING OF G9A AND HISTAMINE H3 RECEPTORS IMPROVES COGNITIVE FUNCTION AND REDUCES OXIDATIVE STRESS IN BTBR MICE
Malak Hajarand 3 co-authors
United Arab Emirates University, College of Medicine and Health Sciences
FENS Forum 2026 (2026)
Barcelona, Spain
Presenter and authors
Presenter
Malak Hajar
United Arab Emirates University, College of Medicine and Health Sciences
Co-authors
Petrilla Jayaprakash; Holger Stark; Bassem Sadek
Abstract
Cognitive impairment remains a major therapeutic challenge in neurodevelopmental and neuropsychiatric disorders. Targeting both epigenetic regulation and histaminergic signalling has emerged as a promising strategy for cognitive enhancement. A-366, a potent G9a inhibitor with histamine H3 receptor (H3R) antagonistic activity, represents a novel dual-acting compound with therapeutic potential. In this study, we investigated the effects of chronic A-366 administration on cognitive function and oxidative stress in the BTBR T+tf/J mouse model, an idiopathic model of autism.
Male BTBR T+tf/J mice were administered A-366 (0.5–2 mg/kg, i.p.) daily for 21 days. Cognitive behaviour was evaluated using the Fear Conditioning Test, Novel Object Recognition Test, and Open Field Test. Following behavioural assessments, hippocampal tissues were collected to measure oxidative stress markers, including superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels.
Chronic administration of A-366 significantly improved cognitive performance in BTBR mice, evidenced by enhanced contextual and cued memory in the Fear Conditioning Test, increased discrimination indices in the Novel Object Recognition Test, and maintained exploratory behaviour in the Open Field Test. Biochemical analysis revealed elevated superoxide dismutase (SOD) activity and reduced malondialdehyde (MDA) levels in hippocampal tissue, indicating a reduction in oxidative stress.
Dual targeting of G9a and H3R demonstrates significant memory-enhancing effects in BTBR mice, mediated through combined modulation of epigenetic mechanisms and histaminergic signalling, with improved oxidative balance. These findings support the potential therapeutic value of dual-targeting G9a inhibitors/H3R antagonists as a promising class for the development of novel therapies for cognitive impairments associated with neurodevelopmental and neuropsychiatric disorders.
Male BTBR T+tf/J mice were administered A-366 (0.5–2 mg/kg, i.p.) daily for 21 days. Cognitive behaviour was evaluated using the Fear Conditioning Test, Novel Object Recognition Test, and Open Field Test. Following behavioural assessments, hippocampal tissues were collected to measure oxidative stress markers, including superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels.
Chronic administration of A-366 significantly improved cognitive performance in BTBR mice, evidenced by enhanced contextual and cued memory in the Fear Conditioning Test, increased discrimination indices in the Novel Object Recognition Test, and maintained exploratory behaviour in the Open Field Test. Biochemical analysis revealed elevated superoxide dismutase (SOD) activity and reduced malondialdehyde (MDA) levels in hippocampal tissue, indicating a reduction in oxidative stress.
Dual targeting of G9a and H3R demonstrates significant memory-enhancing effects in BTBR mice, mediated through combined modulation of epigenetic mechanisms and histaminergic signalling, with improved oxidative balance. These findings support the potential therapeutic value of dual-targeting G9a inhibitors/H3R antagonists as a promising class for the development of novel therapies for cognitive impairments associated with neurodevelopmental and neuropsychiatric disorders.