Memantine/Aripiprazole Combination Alleviates Cognitive Dysfunction in Valproic Acid Rat Model of Autism: Hippocampal CREB/BDNF Signaling and Glutamate Homeostasis

• Published in: Neurotherapeutics Vol. 20; no. 2; pp. 464 - 483
• Main Authors: Zohny, Sohir M., Habib, Mohamed Z., Mohamad, Magda I., Elayat, Wael M., Elhossiny, Reham M., El-Salam, Mohamed F. Abd, Hassan, Ghada A. M., Aboul-Fotouh, Sawsan
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-03-2023; Springer Nature B.V
• Subjects: Animal models; Animals; Apoptosis; Aripiprazole; Aripiprazole - adverse effects; Autism; Autism Spectrum Disorder - chemically induced; Autism Spectrum Disorder - drug therapy; Autistic Disorder - chemically induced; Autistic Disorder - drug therapy; Biomedical and Life Sciences; Biomedicine; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Cognitive ability; Cognitive Dysfunction - chemically induced; Cognitive Dysfunction - complications; Cognitive Dysfunction - drug therapy; Cyclic AMP response element-binding protein; Disease Models, Animal; Female; gamma-Aminobutyric Acid - pharmacology; Gene expression; Glutamatergic transmission; Glutamates - adverse effects; Glutamic acid transporter; Hippocampus; Homeostasis; Male; Maze learning; Memantine; Memantine - adverse effects; Neurobiology; Neurofibrillary tangles; Neurology; Neurosciences; Neurosurgery; Original; Original Article; Pregnancy; Protein structure; Proteins; Rats; Rats, Wistar; Sodium valproate; Spatial discrimination learning; Stereotyped behavior; Therapeutic targets; Valproic Acid; γ-Aminobutyric acid; Memantine; Astrocyte; Aripiprazole; Glutamate; Autism spectrum disorder; Cognitive dysfunction
• ISSN: 1933-7213; 1878-7479; 1878-7479
• DOI: 10.1007/s13311-023-01360-w

Summary
Significant efforts are increasingly directed towards identifying novel therapeutic targets for autism spectrum disorder (ASD) with a rising role of aberrant glutamatergic transmission in the pathogenesis of ASD-associated cellular and behavioral deficits. This study aimed at investigating the role of chronic memantine (20 mg/kg/day) and aripiprazole (3 mg/kg/day) combination therapy in the management of prenatal sodium valproate (VPA)-induced autistic-like/cognitive deficits in male Wistar rats. Pregnant female rats received a single intraperitoneal injection of VPA (600 mg/kg) to induce autistic-like behaviors in their offspring. Prenatal VPA induced autistic-like symptoms (decreased social interaction and the appearance of stereotyped behavior) with deficits in spatial learning (in Morris water maze) and cognitive flexibility (in the attentional set-shifting task) in addition to decreased hippocampal protein levels of phosphorylated cAMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and gene expression of glutamate transporter-1 (
Glt-1
) with a decline in GABA/glutamate ratio (both measured by HPLC). These were accompanied by the appearance of numerous neurofibrillary tangles (NFTs) with enhanced apoptosis in hippocampal sections. Memantine/aripiprazole combination increased the protein levels of p-CREB, BDNF, and
Glt-1
gene expression with restoration of GABA/glutamate balance, attenuation of VPA-induced neurodegenerative changes and autistic-like symptoms, and improvement of cognitive performance. This study draws attention to the favorable cognitive effects of memantine/aripiprazole combination in autistic subjects which could be mediated via enhancing CREB/BDNF signaling with increased expression of astrocytic
Glt-1
and restoration of GABA/glutamate balance, leading to inhibition of hippocampal NFTs formation and neuronal apoptosis.