Background and Aim: Hippocampal oxidative stress has a key role in the pathophysiology of Alzheimer’s disease (AD)-associated behavioral deficits. Ecdysterone (Ecdy), a natural product and major steroid hormone, exhibits anti-oxidative and neuroprotective effects. High-intensity interval training (HIIT) has emerged as an effective method for improving physiological brain functions. The present study was designed to investigate the comparative effects of separate and combined HIIT and Ecdy treatment on behavioral functions, hippocampal oxidative status, histological changes in an amyloid beta (Aβ)-induced rat model of AD. Methods: Rats were treated simultaneously with HIIT exercise and Ecdy (10 mg/kg/day, P.O.), starting 10 days after Aβ-injection, and they continued for eight consecutive weeks. At the end of the treatment course, behavioral functions of the rats were assessed by commonly-used behavioral paradigms. Subsequently, brain sample was collected for biochemical and histological analysis. Results: The results of behavioral tests illustrated that A? injection impaired learning and memory performances in both novel object recognition and Barnes maze testes, reduced exploratory/locomotor activities in open field test, enhanced anxiety-like behavior in elevated plus-maze. These behavioral deficits were accompanied by hippocampal oxidative stress (decreased total antioxidant capacity content and increased total oxidant status level), and neuronal loss in the cerebral cortex and hippocampus of the rats. HIIT and Ecdy improved anxiety-like behavior, attenuated total oxidant status, and prevented neuronal loss. However, their combination resulted in a more complete and powerful improvement in all the above-mentioned A?-related deficits. Conclusion: These data provide evidence that a combination of HIIT and Ecdy treatment improves Aβ-induced behavioral deficits, possibly through amelioration of hippocampal oxidative status and prevention of neuronal loss
