Effects of the Combination of High-intensity Interval Training and Ecdysterone on Learning and Memory Abilities, Antioxidant Enzymes Activities, and Neuronal Population in an Amyloid-beta-induced Rat Model of Alzheimer’s Disease

Aims: Oxidative stress and neuronal death are the primary reasons for the progression of amyloid-beta (Aβ) deposition and cognitive deficits in Alzheimer’s disease (AD). Ecdysterone (Ecdy), a common derivative of ecdysteroids, possesses free radical scavenging and cognitive-improving effects. High-intensity interval training (HIIT) may be a therapeutic strategy for improving cognitive decline and oxidative stress. The present study was aimed to evaluate the effect of HIIT alone and its combination with Ecdysterone on the changes in learning and memory functions, hippocampal antioxidant enzymes activities, and neuronal population after AD induced by Aβ in male rats.Materials and methods: Following ten days of Aβ-injection, HIIT exercise and Ecdysterone treatment (10 mg/kg/day; P.O.) were initiated and continued for eight consecutive weeks in rats. At the end of the treatment period, rat’s learning and memory functions were assessed using water-maze and passive-avoidance tests. Moreover, the activity of superoxide dismutase (SOD), catalase (CAT), Glutathione Peroxidase (GPx), Glutathione Reductase (GRx) and neuronal population were evaluated in rat’s brains.Results: The results indicated that Aβ injection disrupted spatial/passive avoidance learning and memory in both water-maze and passive-avoidance paradigms, accompanied by a decrease in the superoxide dismutase and catalase (as endogenous antioxidants) in rat hippocampus. Additionally, Aβ injection resulted in neuronal loss in the cerebral cortex and hippocampus. Although consumption of Ecdysterone separately improved spatial/passive avoidance learning and memory impairments, recovered hippocampal activity of SOD, CAT, GRx, GRx and prevented the hippocampal neuronal loss, its combination with HIIT resulted in a more powerful and effective amelioration in all the above-mentioned Aβ-neuropathological changes.Conclusion: The current work's data confirms that a combination of HIIT exercise and Ecdysterone treatment could be a promising potential therapeutic agent against AD-associated cognitive decline, owing to their free radical scavenging and neuroprotective properties.

The Effect of Kaempferol on Autophagy and Nrf-2 Signaling in a Rat Model of Aβ1-42-induced Alzheimer’s Disease

Background: Numerous pieces of evidence support that oxidative stress is a key factor in the pathogenesis of neurodegenerative diseases, like Alzheimer’s Disease (AD). Suppression of oxidative stress is an attractive strategy and flavonoids as potent natural antioxidants are extremely noticeable. Objectives: In this study, the effects of Kaempferol (KMP) were evaluated on passive avoidance memory, hippocampal Nrf-2, and beclin-1 expression in a rat model of Aβ1-42 –induced AD. Materials & Methods: Forty male Wistar rats weighing 200-250 g were divided into five groups (n=8); sham-operated, AD model, and KMP treatment (5, 7.5, 10 mg/kg, i.p. for three weeks). Animals received an intracerebroventricular injection of amyloid-beta (1-42) to establish an AD model. Passive avoidance memory of rats was evaluated using a shuttle box on day 21; Step-Through Latency (STL) and time spent in The Dark Compartment (TDC) were recorded. Then, hippocampus homogenates were used for biochemical and molecular analysis by real-time PCR, western blot, and ELISA. Results: It was found that KMP improved memory evidenced by increased STL (P≤0.05) and decreased TDC (p≤0.01). KMP also increased the levels of Total Antioxidant Capacity (TAC) in the hippocampus of rats (P≤0.05). In addition, KMP enhanced the expression of Nrf-2 mRNA (P≤0.001) and beclin-1 protein in the hippocampus tissues (P≤0.001). Conclusion: Overall, it is suggested that the memory-improving effect of KMP is mediated, at least in part, by enhancing Nrf-2 and TAC. KMP is also able to induce autophagy through the expression of beclin-1.

Dental Pulp Stem Cells Transplantation Improves Passive Avoidance Memory and Neuroinflammation in Trimethyltin-Induced Alzheimer’s Disease Rat Model

Background: According to the increasing incidence of Alzheimer’s disease (AD), this study aimed to investigate the effect of dental pulp stem cells (DPSCs) transplantation on passive avoidance memory and neuroinflammation in trimethyltin (TMT)-induced AD rat model. Materials and Methods: In this experimental study, 18 male Wistar rats were randomly divided into three groups: the control that rats received 8 mg/kg TMT plus 0.5 ml phosphate buffered saline (PBS) and TMT+DPSCs (TMT + 1×106 cells/ml DPSC in 0.5 ml PBS) groups. Then, after one month, passive avoidance test was performed. Also measured the Nuclear Factor Kappa-β (NF-Kβ) serum level and the percentage of damaged neurons in the hippocampus were determined. Results: DPSCs transplantation showed significantly increased step-through latency to the dark compartment in comparison with control and TMT+PBS groups in 24 hours after shock. Also, time spent in the dark compartment of TMT+DPSCs significantly decreased compared to control and TMT+PBS groups in 24 and 48 hours after shock (P<0.05). Furthermore, DPSCs transplantation significantly decreased the NF-Kβ serum level and percentage of damaged pyramidal neurons of CA1 compared with TMT+PBS (P<0.05). Conclusion: DPSCs transplantation improved memory and learning, regulated NF-Kβ serum level, and decreased damage neurons of CA1 hippocampus in TMT-induced AD rat model.

Behavioral response and erythrocyte chromophilia of rats in experimental traumatic brain injury

Введение. Патогенетические основы изменения микроциркуляции крови в головном мозге вследствие черепно-мозговой травмы (ЧМТ) изучены не в полной мере по причине высокой инвазивности нейроморфологических методов. Цель исследования - изучение поведенческого статуса и информативности цитохимических критериев хромофилии эритроцитов в качестве маркеров вазореактивности микрососудов головного мозга при черепно-мозговой травме у крыс. Методика. Объектом исследования являлись 3-месячные аутбредные крысы Wistar массой 250-270 г. Легкую и средней тяжести ЧМТ воспроизводили с применением модифицированной модели падающего груза для взрослых крыс. Через 2 ч, 1, 2, 8 и 14 сут после моделирования ЧМТ проводили неврологическое обследование животных по модифицированной шкале Neurological Severity Scores (mNSS), сенсомоторное - по степени тревожности в тесте «свет-темнота», поведение анализировали с использованием теста условной реакции пассивного избегания. С помощью хромаффинной реакции исследовали функциональное состояние эритроцитов. Срезы тканей головного мозга, окрашивали по Нисслю и гематоксилин-эозином, микроскопировали, проводили морфометрию цифровых изображений. Результаты. Неврологическое обследование при среднетяжелой ЧМТ показало очаговую симптоматику, соответствующую выраженным неврологическим расстройствам, тогда как после ЧМТ легкой степени у крыс отмечались незначительные нарушения координации. В тесте условной реакции пассивного избегания на 7-е сут у этих животных выявлено состояние повышенной тревожности. Морфометрический анализ препаратов головного мозга травмированных животных показал уменьшение диаметра просвета капилляров и выявил признаки гипоксии нейронов. Цитохимическая оценка эритроцитов, с привлечением количественного определения степени флуоресценции, выявила особенности окислительного метаболизма в клетках у травмированных крыс. Эти показатели коррелировали с морфологическими признаками гипоксии головного мозга. Заключение. В начальный посттравматический период отмечено уменьшение диаметра просвета капилляров нервной ткани, наличие морфологических признаков компенсации нейронов, что является локальной ответной реакцией клеток на ишемию головного мозга. В капиллярах определяется нарушение гемореологии, что является следствием изменения окислительно-восстановительных процессов вследствие гипоксии при внутричерепной травме. The pathogenetic basis of changes in blood microcirculation in the brain due to traumatic brain injury (TBI) has not been fully studied due to the highly invasive nature of neuromorphological methods. Aim: To study the behavioral status and informative value of cytochemical criteria for erythrocyte chromophilia as markers of cerebral microvessel vasoreactivity in rats with TBI. Methods. The study was conducted on 3-month-old Wistar albino, outbred rats weighing 250-270 g. Mild to moderate TBI was simulated using a modified falling weight model for adult rats. At 2 hrs, 1, 2, 8, and 14 days after TBI, a neurological examination was performed according to the modified Neurological Severity Score (mNSS) modified scale and a sensorimotor examination was performed according to the degree of anxiety in the light-dark test. Behavior was analyzed using the conditioned passive avoidance response test. The functional state of erythrocytes was studied using the chromaffin reaction. Brain tissue samples stained by Nissl and with hematoxylin-eosin were evaluated under a microscope, digital images were obtained, and morphometric processing was performed. Results. Neurological examination after moderate TBI showed focal symptoms corresponding to severe neurological disorders, while after mild TBI, rats had minor coordination disorders. In the conditioned passive avoidance response test on the 7th day, the rats showed a state of increased anxiety. Morphometric analysis of the brains showed a decrease in the diameter of capillary lumen and changes in neurons, indicating signs of hypoxia. The cytochemical assessment of erythrocytes, involving a quantitative determination of the degree of fluorescence, revealed features of cell oxidative metabolism in injured rats. Moreover, these indicators correlated with morphological signs of hypoxia in brain neural tissue. Conclusion. In the initial post-traumatic period, there was a decrease in the capillary lumen diameter of the brain neural tissue and the presence of morphological signs of neuronal compensation, which is a local response of cells to cerebral ischemia. Disorders of hemorheology were found. These changes were a consequence of altered redox processes due to hypoxia after intracranial injury.

Paternal Aggression in Early-Life Impairs the Spatial Memory and Passive Avoidance Learning in Adulthood of Male Rats: The Possible Role of DRD2

Negative early-life experiences (e.g., having an aggressive father) can leave long-lasting impacts on the behavior. However, it is not clear if they influence learning and memory. In this study, we investigated the influences that the presence of an aggressive father had on the level of passive avoidance learning and spatial memory. We also studied the changes in the dopamine receptor D2 (DRD2) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) gene expression in the hippocampus. Then, we evaluated if a DRD2 antagonist (Sulpiride, 0.125, 0.25, or 0.5 µg/rat) could modulate these changes. We found that the subjects exposed to early-life stress made by aggressive fathers had impaired passive avoidance learning and spatial memory than those with normal fathers. Treatment with Sulpiride improved passive avoidance learning and spatial memory in rats with aggressive fathers. The rats with aggressive fathers also had higher expression of the DRD2 gene in their hippocampus than those with normal fathers, while the PGC-1α gene expression was not different among groups. Treatment with Sulpiride (0.125, 0.25, or 0.5 µg/rat) reduced the DRD2 gene expression in those with aggressive fathers to the normal level in those with normal fathers. These data suggest that living in a shared place with an aggressive father, even without any physical contact, can detrimentally affect passive avoidance learning and spatial memory which is accompanied by the increased expression of the DRD2 gene. Also, Sulpiride as a dopaminergic antagonist could reverse this process.