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.

A Genetic Model of Epilepsy with a Partial Alzheimer's Disease-Like Phenotype and Central Insulin Resistance.

Studies have suggested an important connection between epilepsy and Alzheimer's disease (AD), mostly due to the high number of patients diagnosed with AD who develop epileptic seizures later on. However, this link is not well understood. Previous studies from our group have identified memory impairment and metabolic abnormalities in the Wistar audiogenic rat (WAR) strain, a genetic model of epilepsy. Our goal was to investigate AD behavioral and molecular alterations, including brain insulin resistance, in naïve (seizure-free) animals of the WAR strain. We used the Morris water maze (MWM) test to evaluate spatial learning and memory performance and hippocampal tissue to verify possible molecular and immunohistochemical alterations. WARs presented worse performance in the MWM test (p < 0.0001), higher levels of hyperphosphorylated tau (S396) (p < 0.0001) and phosphorylated glycogen synthase kinase 3 (S21/9) (p < 0.05), and lower insulin receptor levels (p < 0.05). Conversely, WARs and Wistar controls present progressive increase in amyloid fibrils (p < 0.0001) and low levels of soluble amyloid-ß. Interestingly, the detected alterations were age-dependent, reaching larger differences in aged than in young adult animals. In summary, the present study provides evidence of a partial AD-like phenotype, including altered regulation of insulin signaling, in a genetic model of epilepsy. Together, these data contribute to the understanding of the connection between epilepsy and AD as comorbidities. Moreover, since both tau hyperphosphorylation and altered insulin signaling have already been reported in epilepsy and AD, these two events should be considered as important components in the interconnection between epilepsy and AD pathogenesis and, therefore, potential therapeutic targets in this field.

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.

The influence of the cannabinoid receptor CB1 on the periaqueductal gray in mice treated with photobiomodulation after chronic constriction injury of the sciatic nerve: a placebo-controlled trial / Influência do receptor canabinóide CB1 na substância cinzenta periaquedutal em camundongos tratados por fotobiomodulação após constrição crônica do nervo ciático: ensaio controlado por placebo

ABSTRACT BACKGROUND AND OBJECTIVES: Studies have demonstrated that the cannabinoid CB1 receptor is involved in the modulation of pain, mainly by activating the descending pain control pathway. However, the role of photobiomodulation in this process is not well elucidated. Thus, the present study aimed to investigate the involvement of the CB1 receptor in the supraspinal photobiomodulation-induced antinociception. METHODS: Male albino swiss mice were submitted to chronic constriction injury and treated with photobiomodulation. To evaluate the supraspinal involvement of the CB1 receptor in the photobiomodulation-induced antinociception, the cannabinoid CB1 receptor antagonist AM251 (0.1µg/vol 0.2µL) was injected 5 minutes before the photobiomodulation treatment. The photobiomodulation treatment was performed on the fifth day after the stereotactic surgery and chronic constriction injury at a dose of 50J/cm2 in acute condition. The hot plate and von Frey monofilaments tests were performed to evaluate the thermal and mechanical pain sensitivity, respectively. RESULTS: The thermal and mechanical nociceptive threshold was higher in mice with chronic constriction injury, injected with saline and treated with photobiomodulation at the dose of 50J/cm2 in both the hot plate (p<0.001) and von Frey (p>0.001) tests. These antinociceptive effects were not detected in mice with chronic constriction injury pre-treated with AM251. CONCLUSION: The present study suggests that CB1 receptors located in Supraspinal structures, participate in the control of neuropathic pain following photobiomodulation treatment in animals undergoing chronic constriction injury.

RESUMO JUSTIFICATIVA E OBJETIVOS: Estudos demonstraram que o receptor canabinóide CB1 está envolvido na modulação da dor, principalmente pela ativação da via descendente de controle da dor, porém o papel da fotobiomodulação nesse processo não é bem elucidado. Assim, o presente estudo teve como objetivo investigar o envolvimento do receptor CB1 na antinocicepção induzida pela fotobiomodulação a nível supraespinhal. MÉTODOS: Camundongos machos suíço albinos foram submetidos à lesão por constrição crônica e tratados com fotobiomodulação. Para avaliar o envolvimento supraespinhal do receptor CB1 na antinocicepção induzida por fotobiomodulação foi injetado o antagonista do receptor canabinóide CB1, AM251 (0,1µg/vol 0,2µL) 5 minutos antes do tratamento com fotobiomodulação. O tratamento de fotobiomodulação foi realizado no quinto dia após cirurgia estereotática e lesão por constrição crônica, na dose de 50J/cm2 em estado agudo. Os testes de placa quente e monofilamentos de von Frey foram realizados para avaliar a sensibilidade térmica e mecânica à dor, respectivamente. RESULTADOS: O limiar térmico e mecânico nociceptivo foi maior nos camundongos com lesão por constrição crônica, injetados com solução salina e tratados com fotobiomodulação na dose de 50J/cm2 nos testes de placa quente (p<0,001) e von Frey (p>0,001). Esses efeitos antinociceptivos não foram detectados em camundongos com lesão por constrição crônica tratados com AM251. CONCLUSÃO: O presente estudo sugere que os receptores CB1 localizados nas estruturas supraespinhais participam do controle da dor neuropática, após tratamento com fotobiomodulação em animais submetidos à lesão por constrição crônica.