Exercise and Urtica dioica extract ameliorate hippocampal insulin signaling, oxidative stress, neuroinflammation, and cognitive function in STZ-induced diabetic rats.

INTRODUCTION: Diabetes mellitus is related to cognitive impairments and molecular abnormalities of the hippocampus. A growing body of evidence suggests that Urtica dioica (Ud) and exercise training (ET) have potential therapeutic effects on diabetes and its related complications. Therefore, we hypothesized that the combined effect of exercise training (ET) and Ud might play an important role in insulin signaling pathway, oxidative stress, neuroinflammation, and cognitive impairment in diabetic rats. METHODS: Forty animals were divided into five groups (N = 8): healthy-sedentary (H-sed), diabetes-sedentary (D-sed), diabetes-exercise training (D-ET), diabetes-Urtica dioica (D-Ud), diabetes-exercise training-Urtica dioica (D-ET-Ud). Streptozotocin (STZ) (Single dosage; 45 mg/kg, i.p.) was used to induce diabetes. Then, ET (moderate intensity/5day/week) and Ud extract (50 mg/kg, oral/daily) were administered for six weeks. We also investigated the effects of ET and Ud on cognitive performance (assessed through Morris Water Maze tests), antioxidant capacity, and lipid peroxidation markers in hippocampus. Furthermore, we measured levels of insulin sensitivity and signaling factors (insulin-Ins, insulin receptor-IR and insulin-like growth factor-1 receptor-IGF-1R), and neuroinflammatory markers (IL-1 ß, TNF-α). This was followed by TUNEL assessment of the apoptosis rate in all regions of the hippocampus. RESULTS: D-sed rats compared to H-sed animals showed significant impairments (P < 0.001) in hippocampal insulin sensitivity and signaling, oxidative stress, neuroinflammation, and apoptosis, which resulted in cognitive dysfunction. Ud extract and ET treatment effectively improved these impairments in D-ET (P < 0.001), D-Ud (P < 0.05), and D-ET-Ud (P < 0.001) groups compared to D-sed rats. Moreover, diabetes mediated hippocampal oxidative stress, neuroinflammation, insulin signaling deficits, apoptosis, and cognitive dysfunction was further reversed by chronic Ud+ET administration in D-ET-Ud rats (P < 0.001) compared to D-sed animals. CONCLUSIONS: Ud extract and ET ameliorate cognitive dysfunction via improvement in hippocampal oxidative stress, neuroinflammation, insulin signaling pathway, and apoptosis in STZ-induced diabetic rats. The results of this study provide new experimental evidence for using Ud+ET in the treatment of hippocampal complications and cognitive dysfunction caused by diabetes.

Effects of endurance exercise and Urtica dioica on the functional, histological and molecular aspects of the hippocampus in STZ-Induced diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Many body systems and organs, including the hippocampus, are affected by diabetes, and undergo changes that may increase the risk of cognitive decline. Urtica dioica (UD) has long been recognized as a medicinal plant with beneficial effects on blood glucose control in diabetes. AIM OF THE STUDY: The present study aimed to investigate the effect of endurance exercise (Ex), along with Urtica dioica (UD) hydro-alcoholic extract on some functional, histological, and molecular aspects of the hippocampus in streptozotocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: 60 male Wistar rats were divided into five groups (N = 12): healthy control (H-C), diabetes control (D-C), diabetes exercise (D-Ex), diabetes Urtica dioica (D-UD), and diabetes exercise Urtica dioica (D-Ex-UD). Diabetes was induced intraperitoneally by STZ (45 mg/kg) injection. Two weeks after the injection by STZ, Ex (moderate intensity/5day/week) and gavage of UD extract (50mg/kg/day) was performed for six weeks. Cognitive functions were evaluated by the Morris Water Maze test, routine histological examination, and molecular studies were done via Hematoxylin & Eosin stain, and Western blot. RESULTS: Diabetic rats showed spatial learning and memory deficits, as well as negatively affects to the tissue and structure of the hippocampus in the dentate gyrus (DG) and cornu ammonis (CA) areas. Ex + UD treatment caused a decrease of neural disorganization, an increase of neural-microglial density, and thickness of the pyramidal-molecular layer in the hippocampus. In addition, Ex + UD caused a rise of GAP-43 protein levels, a reduction of CAP-1 protein levels, improved hippocampal structure, and improved learning and memory function. CONCLUSIONS: These results show that Ex, along with the UD extract, may decrease levels of the central neural complications of diabetes. Given the importance of recognizing non-pharmacological complementary therapies in this field, future studies are warranted.