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

Shaimaa Nasr Amin; Sherif Ahmed Shaltout; Walaa Bayoumie El Gazzar; Noha Samir Abdel Latif; Ghadah Nazar Al-Jussani; Yasmeen Jamal Alabdallat; Khaled Anwer Albakri; Dalia Azmy Elberry

doi:10.1016/j.advms.2024.03.008

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

Adv Med Sci. 2024 Mar;69(1):176-189. doi: 10.1016/j.advms.2024.03.008. Epub 2024 Mar 30.

Authors

Shaimaa Nasr Amin¹, Sherif Ahmed Shaltout², Walaa Bayoumie El Gazzar³, Noha Samir Abdel Latif⁴, Ghadah Nazar Al-Jussani⁵, Yasmeen Jamal Alabdallat⁶, Khaled Anwer Albakri⁶, Dalia Azmy Elberry⁷

Affiliations

¹ Department of Anatomy, Physiology and Biochemistry, Faculty of Medicine, The Hashemite University, Zarqa, Jordan; Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt. Electronic address: shaimaa@hu.edu.jo.
² Department of Pharmacology, Public Health, and Clinical Skills, Faculty of Medicine, The Hashemite University, Zarqa, Jordan; Department of Pharmacology, Faculty of Medicine, Benha University, Benha, Egypt.
³ Department of Anatomy, Physiology and Biochemistry, Faculty of Medicine, The Hashemite University, Zarqa, Jordan; Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Benha, Egypt.
⁴ Department of Medical Pharmacology, Faculty of Medicine, Cairo University Cairo, Egypt; Department of Medical Pharmacology, Armed Forces College of Medicine, Cairo, Egypt.
⁵ Department of Microbiology, Pathology and Forensic Medicine, Faculty of Medicine, The Hashemite University, Zarqa, Jordan.
⁶ Faculty of Medicine, The Hashemite University, Zarqa, Jordan.
⁷ Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt.

PMID: 38561071
DOI: 10.1016/j.advms.2024.03.008

Abstract

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.

Keywords: Cognition; EEG; GABA-A; Metabolic syndrome; NMDAR.

MeSH terms

Animals
Brain / drug effects
Brain / metabolism
Brain-Derived Neurotrophic Factor / metabolism
Disease Models, Animal
Male
Memantine* / pharmacology
Metabolic Syndrome* / drug therapy
Metabolic Syndrome* / metabolism
Neuronal Plasticity* / drug effects
Pregnanolone / metabolism
Pregnanolone / pharmacology
Rats
Rats, Wistar
Receptors, GABA-A* / metabolism
Receptors, N-Methyl-D-Aspartate* / metabolism

Substances

Receptors, N-Methyl-D-Aspartate
Memantine
Receptors, GABA-A
Brain-Derived Neurotrophic Factor
Pregnanolone