Metformin Improves Spatial Memory and Reduces Seizure Severity in a Rat Model of Epilepsy and Alzheimer's Disease comorbidity via PI3K/Akt Signaling Pathway

Author(s)

Alves, Suelen Santos ; Rossi, Leticia ; de Oliveira, Jose Antonio Cortes ; Servilha-Menezes, Gabriel ; Grigorio-de-Sant'Ana, Mariana ; Mazzei, Rodrigo Focosi ; Almeida, Sebastiao Sousa ; Sebollela, Adriano ; da Silva Junior, Rui Milton Patricio ; Garcia-Cairasco, Norberto

• Document type: Journal article
• Source: Molecular Neurobiology; v. N/A, p. 28-pg., 2025-03-24.

Abstract

Emerging evidence suggests a bidirectional relationship between Alzheimer's disease (AD) and epilepsy. In our previous studies, we identified a partial AD-like phenotype associated with central insulin resistance in the Wistar audiogenic rat (WAR), a genetic model of epilepsy. We also found that intracerebroventricular administration of streptozotocin, a compound used to model diabetes and AD, exacerbates seizure susceptibility. Given the role of insulin signaling in both AD and epilepsy, we hypothesized that metformin (MET), an anti-diabetic drug known for enhancing insulin sensitivity, could be a potential therapeutic agent for both conditions. Our objective was to investigate MET's effects on brain insulin signaling, seizure activity, and AD-like pathology in WARs. Adult male WARs received oral MET (250 mg/kg) for 21 days. Audiogenic seizures were assessed using the Categorized Severity Index and Racine's scale. Spatial memory was tested with the Morris water maze (MWM), followed by Western blot analysis of hippocampal proteins. MET significantly reduced seizure severity and improved MWM performance. Although MET did not affect insulin receptor levels or activation, it increased phosphoinositide 3-kinase (PI3K), activated Akt, and increased glycogen synthase kinase-3 alpha/beta (GSK-3 alpha/beta) levels. MET also decreased amyloid beta precursor protein (A beta PP) levels but did not affect Tau phosphorylation. These results suggest that chronic MET treatment alleviates behaviors related to both AD and epilepsy in WARs and modulates insulin signaling independently of insulin receptor activation. Our findings highlight MET's potential as a therapeutic agent for managing comorbid AD and epilepsy, warranting further investigation into its mechanisms of action. (AU)

• FAPESP's process: 21/10925-8 - Neurotoxic beta-amyloid peptide oligomers: biochemical isolation, conformational studies and neutralization in Alzheimer's Disease models
• Grantee: Adriano Silva Sebollela
• Support Opportunities: Regular Research Grants
• FAPESP's process: 24/16992-7 - EXPLORING THE BIDIRECTIONAL RELATIONSHIP BETWEEN ALZHEIMER'S DISEASE AND EPILEPSY. AN ANALYSIS OF ALTERATIONS IN THE BRAIN INSULIN SIGNALING PATHWAY AS A POTENTIAL MECHANISM OF CONNECTION BETWEEN THE TWO CONDITIONS
• Grantee: Norberto Garcia Cairasco
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/02787-4 - Effects of cannabidiol vehiculated in nanoemulsion in rats submitted to the chemical model of temporal lobe epilepsy
• Grantee: Gabriel Servilha Menezes
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 17/21155-3 - Wistar audiogenic rat (WAR): a possible model for the study of Alzheimer's Disease related to insulin resistance
• Grantee: Suélen Santos Alves
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 14/50891-1 - INCT 2014: Translational Medicine
• Grantee: Jaime Eduardo Cecilio Hallak
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/05957-8 - Epilepsies and neuropsyquiatric comorbidities: characterization of the effects of the treatment with cannabidiol and HUF-101 in in vivo and in vitro experimental models
• Grantee: Norberto Garcia Cairasco
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/16574-2 - Unraveling the molecular and genetic mechanisms of epilepsy
• Grantee: Norberto Garcia Cairasco
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/00849-2 - Uncovering pathophysiological and molecular mechanisms involved in tumorigenesis by platforms for next-generation sequencing (NGS)
• Grantee: Rui Milton Patrício da Silva Junior
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 21/13622-6 - Assessing anxiety and painful hypersensitivity as comorbidities associated with Epilepsy: effects of cannabidiol treatment and the role of CB1, TRPV1 and 5-HT1A receptors
• Grantee: Willian Lazarini Lopes
• Support Opportunities: Scholarships in Brazil - Post-Doctoral