Impact of NMDA receptors block versus GABA-A receptors modulation on synaptic plasticity and brain electrical activity in metabolic syndrome

Purpose Metabolic syndrome (MetS) is a common disorder associated with disturbed neurotransmitter homeostasis. Memantine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, was first used in Alzheimer's disease. Allopregnanolone (Allo), a potent positive allosteric modulator of the Gamma-Amino-Butyric Acid (GABA)-A receptors, decreases in neurodegenerative diseases. The study investigated the impact of Memantine versus Allo administration on the animal model of MetS to clarify whether the mechanism of abnormalities is related more to excitatory or inhibitory neurotransmitter dysfunction. Materials and methods Fifty-six male rats were allocated into 7 groups: 4 control groups, 1 MetS group, and 2 treated MetS groups. They underwent assessment of cognition-related behavior by open field and forced swimming tests, electroencephalogram (EEG) recording, serum markers confirming the establishment of MetS model and hippocampal Glial Fibrillary Acidic Protein (GFAP) and Brain-Derived Neurotrophic Factor (BDNF). Results Allo improved anxiety-like behavior and decreased grooming frequency compared to Memantine. Both drugs increased GFAP and BDNF expression, improving synaptic plasticity and cognition-related behaviors. The therapeutic effect of Allo was more beneficial regarding lipid profile and anxiety. We reported progressive slowing of EEG waves in the MetS group with Memantine and Allo treatment with increased relative theta and decreased relative delta rhythms. Conclusions Both Allo and Memantine boosted the outcome parameters in the animal model of MetS. Allo markedly improved the anxiety-like behavior in the form of significantly decreased grooming frequency compared to the Memantine-treated groups. Both drugs were associated with increased hippocampal GFAP and BDNF expression, indicating an improvement in synaptic plasticity and so, cognition-related behaviors.