Evidence of disturbed insulin signaling in animal models of Alzheimer's disease.

Since glucose reuptake by neurons is mostly independent of insulin, it has been an intriguing question whether insulin has or not any roles in the brain. Consequently, the identification of insulin receptors in the central nervous system has fueled investigations of insulin functions in the brain. It is also already known that insulin can influence glucose reuptake by neurons, mostly during activities that have the highest energy demand. The identification of high density of insulin receptors in the hippocampus also suggests that insulin may present important roles related to memory. In this context, studies have reported worse performance in cognitive tests among diabetic patients. In addition, alterations in the regulation of central insulin pathways have been observed in the brains of Alzheimer's disease (AD) patients. In fact, some authors have proposed AD as a third type of diabetes and recently, our group proposed insulin resistance as a common link between different AD hypotheses. Therefore, in the present narrative review, we intend to revise and gather the evidence of disturbed insulin signaling in experimental animal models of AD.

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

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-ß (Aß) 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.

Effect of Vagus Nerve Stimulation on the GASH/Sal Audiogenic-Seizure-Prone Hamster.

Vagus nerve stimulation (VNS) is an adjuvant neuromodulation therapy for the treatment of refractory epilepsy. However, the mechanisms behind its effectiveness are not fully understood. Our aim was to develop a VNS protocol for the Genetic Audiogenic Seizure Hamster from Salamanca (GASH/Sal) in order to evaluate the mechanisms of action of the therapy. The rodents were subject to VNS for 14 days using clinical stimulation parameters by implanting a clinically available neurostimulation device or our own prototype for laboratory animals. The neuroethological assessment of seizures and general behavior were performed before surgery, and after 7, 10, and 14 days of VNS. Moreover, potential side effects were examined. Finally, the expression of 23 inflammatory markers in plasma and the left-brain hemisphere was evaluated. VNS significantly reduced seizure severity in GASH/Sal without side effects. No differences were observed between the neurostimulation devices. GASH/Sal treated with VNS showed statistically significant reduced levels of interleukin IL-1ß, monocyte chemoattractant protein MCP-1, matrix metalloproteinases (MMP-2, MMP-3), and tumor necrosis factor TNF-α in the brain. The described experimental design allows for the study of VNS effects and mechanisms of action using an implantable device. This was achieved in a model of convulsive seizures in which VNS is effective and shows an anti-inflammatory effect.

A complex systems view on the current hypotheses of epilepsy pharmacoresistance.

Drug-resistant epilepsy remains to this day as a highly prevalent condition affecting around one-third of patients with epilepsy, despite all the research and the development of several new antiseizure medications (ASMs) over the last decades. Epilepsies are multifactorial complex diseases, commonly associated with psychiatric, neurological, and somatic comorbidities. Thus, to solve the puzzling problem of pharmacoresistance, the diagnosis and modeling of epilepsy and comorbidities need to change toward a complex system approach. In this review, we have summarized the sequence of events for the definition of epilepsies and comorbidities, the search for mechanisms, and the major hypotheses of pharmacoresistance, drawing attention to some of the many converging aspects between the proposed mechanisms, their supporting evidence, and comorbidities-related alterations. The use of systems biology applied to epileptology may lead to the discovery of new targets and the development of new ASMs, as may advance our understanding of the epilepsies and their comorbidities, providing much deeper insight on multidrug pharmacoresistance.

Insulin Resistance as a Common Link Between Current Alzheimer's Disease Hypotheses.

Almost 115 years ago, Alois Alzheimer described Alzheimer's disease (AD) for the first time. Since then, many hypotheses have been proposed. However, AD remains a severe health public problem. The current medical approaches for AD are limited to symptomatic interventions and the complexity of this disease has led to a failure rate of approximately 99.6%in AD clinical trials. In fact, no new drug has been approved for AD treatment since 2003. These failures indicate that we are failing in mimicking this disease in experimental models. Although most studies have focused on the amyloid cascade hypothesis of AD, the literature has made clear that AD is rather a multifactorial disorder. Therefore, the persistence in a single theory has resulted in lost opportunities. In this review, we aim to present the striking points of the long scientific path followed since the description of the first AD case and the main AD hypotheses discussed over the last decades. We also propose insulin resistance as a common link between many other hypotheses.

Cannabinoid Receptor Type 1 (CB1R) Expression in Limbic Brain Structures After Acute and Chronic Seizures in a Genetic Model of Epilepsy.

The endocannabinoid system (ECS) is related to several physiological processes, associated to the modulation of brain excitability, with impact in the expression of susceptibility and control of epileptic seizures. The cannabinoid receptor type 1 (CB1R) is widely expressed in the brain, especially in forebrain limbic structures. Changes in CB1R expression are associated with epileptic seizures in animal models and humans. The Wistar Audiogenic Rat (WAR) strain is a genetic model of epilepsy capable of mimicking tonic-clonic and limbic seizures in response to intense sound stimulation. The WAR strain presents several behavioral and physiological alterations associated with seizure susceptibility, but the ECS has never been explored in this strain. Therefore, the aim of the present study was to characterize CB1R expression in forebrain limbic structures important to limbic seizure expression in WARs. We used a detailed anatomical analysis to assess the effects of acute and chronic audiogenic seizures on CB1R expression in several layers and regions of hippocampus and amygdala. WARs showed increased CB1R immunostaining in the inner molecular layer of the hippocampus, when compared to control Wistar rats. Acute and chronic audiogenic seizures increased CB1R immunostaining in several regions of the dorsal hippocampus and amygdala of WARs. Also, changes in CB1R expression in the amygdala, but not in the hippocampus, were associated with limbic recruitment and limbic seizure severity in WARs. Our results suggest that endogenous alterations in CB1R immunostaining in WARs could be associated with genetic susceptibility to audiogenic seizures. We also demonstrated CB1R neuroplastic changes associated with acute and chronic seizures in the amygdala and hippocampus. Moreover, the present study brings important information regarding CB1R and seizure susceptibility in a genetic model of seizures and supports the relationship between ECS and epilepsy.