Alves Suélen Santos, Rossi Letícia, de Oliveira Jose Antonio Cortes, Servilha-Menezes Gabriel, Grigorio-de-Sant'Ana Mariana, Mazzei Rodrigo Focosi, Almeida Sebastião Sousa, Sebollela Adriano, da Silva Junior Rui Milton Patrício, Garcia-Cairasco Norberto
Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School University of São Paulo (FMRP-USP), Ribeirão Preto, Brazil.
Department of Physiology, Neurophysiology and Experimental Neuroethology Laboratory, Ribeirão Preto Medical School University of São Paulo (FMRP-USP), Ribeirão Preto, Brazil.
Mol Neurobiol. 2025 Mar 24. doi: 10.1007/s12035-025-04844-2.
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-3α/β (GSK-3α/β) levels. MET also decreased amyloid β precursor protein (AβPP) 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.
新出现的证据表明，阿尔茨海默病（AD）与癫痫之间存在双向关系。在我们之前的研究中，我们在Wistar听源性大鼠（WAR）中发现了一种与中枢胰岛素抵抗相关的部分AD样表型，WAR是一种癫痫的遗传模型。我们还发现，脑室内注射链脲佐菌素（一种用于模拟糖尿病和AD的化合物）会加剧癫痫易感性。鉴于胰岛素信号在AD和癫痫中的作用，我们假设二甲双胍（MET），一种以增强胰岛素敏感性而闻名的抗糖尿病药物，可能是这两种疾病的潜在治疗剂。我们的目的是研究MET对WARs脑胰岛素信号、癫痫活动和AD样病理的影响。成年雄性WARs口服MET（250mg/kg），持续21天。使用分类严重指数和拉辛量表评估听源性癫痫发作。用莫里斯水迷宫（MWM）测试空间记忆，随后对海马蛋白进行蛋白质免疫印迹分析。MET显著降低了癫痫发作严重程度并改善了MWM表现。尽管MET不影响胰岛素受体水平或激活，但它增加了磷酸肌醇3激酶（PI3K），激活了Akt，并增加了糖原合酶激酶-3α/β（GSK-3α/β）水平。MET还降低了淀粉样β前体蛋白（AβPP）水平，但不影响Tau磷酸化。这些结果表明，慢性MET治疗可减轻WARs中与AD和癫痫相关的行为，并独立于胰岛素受体激活调节胰岛素信号。我们的研究结果突出了MET作为治疗AD和癫痫合并症的治疗剂的潜力，值得进一步研究其作用机制。
