Audiogenic Seizures in the Streptozotocin-Induced Rat Alzheimer’s Disease Model

Article type: Research Article

Authors: Alves, Suélen Santos^a | de Oliveira, José Antônio Cortes^b | Lazarini-Lopes, Willian^c | Servilha-Menezes, Gabriel^b | Grigório-de-Sant’Ana, Mariana^b | Del Vecchio, Flavio^b | Mazzei, Rodrigo Focosi^d | Sousa Almeida, Sebastião^d | da Silva Junior, Rui Milton Patrício^{e; *} | Garcia-Cairasco, Norberto^{a; b; *}

Affiliations: [a] Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School – University of São Paulo (FMRP-USP), São Paulo, Brazil | [b] Department of Physiology, Ribeirão Preto Medical School – University of São Paulo (FMRP-USP), São Paulo, Brazil | [c] Department of Pharmacology, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), São Paulo, Brazil | [d] Department of Psychology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto – University of São Paulo (FFCLRP-USP), São Paulo, Brazil | [e] University of Salamanca, Salamanca, Spain

Correspondence: [*] Correspondence to: Norberto Garcia-Cairasco, PhD, Department of Physiology, Ribeirão Preto Medical School – University of São Paulo, Av. Dos Bandeirantes 3900 – 14049-900 – Ribeirão Preto – SP, Brazil. E-mail: ngcairas@usp.br.; ORCID: 0000-0001-8857-3775 and Rui Milton Patrício da Silva Junior, University of Salamanca, Salamanca, Spain. E-mail: ruimiltonpsj@usal.es; ORCID: 0000-0002-7387-437X.

Abstract: Background:Alzheimer’s disease (AD) is a neurodegenerative and progressive disorder with no cure and constant failures in clinical trials. The main AD hallmarks are amyloid-β (Aβ) plaques, neurofibrillary tangles, and neurodegeneration. However, many other events have been implicated in AD pathogenesis. Epilepsy is a common comorbidity of AD and there is important evidence indicating a bidirectional link between these two disorders. Some studies suggest that disturbed insulin signaling might play an important role in this connection. Objective:To understand the effects of neuronal insulin resistance in the AD-epilepsy link. Methods:We submitted the streptozotocin (STZ) induced rat AD Model (icv-STZ AD) to an acute acoustic stimulus (AS), a known trigger of seizures. We also assessed animals’ performance in the memory test, the Morris water maze and the neuronal activity (c-Fos protein) induced by a single audiogenic seizure in regions that express high levels of insulin receptors. Results:We identified significant memory impairment and seizures in 71.43% of all icv-STZ/AS rats, in contrast to 22.22% of the vehicle group. After seizures, icv-STZ/AS rats presented higher number of c-Fos immunopositive cells in hippocampal, cortical, and hypothalamic regions. Conclusion:STZ may facilitate seizure generation and propagation by impairment of neuronal function, especially in regions that express high levels of insulin receptors. The data presented here indicate that the icv-STZ AD model might have implications not only for AD, but also for epilepsy. Finally, impaired insulin signaling might be one of the mechanisms by which AD presents a bidirectional connection to epilepsy.

Keywords: Acoustic stimulus, Alzheimer’s disease, epilepsy, insulin resistance, memory, seizures, streptozotocin

DOI: 10.3233/JAD-230153

Journal: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1179-1196, 2023