Dendrobium nobile Lindl. Alkaloids Ameliorate Cognitive Dysfunction in Senescence Accelerated SAMP8 Mice by Decreasing Amyloid-β Aggregation and Enhancing Autophagy Activity

Background: Dendrobium nobile is a well-known traditional Chinese herbal medicine used for age-related diseases. Dendrobium nobile Lindl. alkaloid (DNLA) is the active ingredient to improve learning and memory deficits in laboratory animals. Objective: The aim of the present study was to examine the anti-aging effects of long-term administration of DNLA and metformin during the aging process in senescence-accelerated mouse-prone 8 (SAMP8) mice. Methods: SAMP8 mice were orally given DNLA (20 and 40 mg/kg) or metformin (80 mg/kg) starting at 6 months of age until 12 months of age. Age-matched SAMR1 mice were used as controls. DNLA and metformin treatments ameliorated behavioral deficits of 12-month-old SAMP8 mice, as determined by Rotarod, Y-maze, and Open-field tests. Results: DNLA and metformin treatments prevented brain atrophy and improved morphological changes in the hippocampus and cortex, as evidenced by Nissl and H&E staining for neuron damage and loss, and by SA-beta-gal staining for aging cells. DNLA and metformin treatments decreased amyloid-beta(1-42), A beta PP, PS1, and BACE1, while increasing IDE and neprilysin for A beta clearance. Furthermore, DNLA and metformin enhanced autophagy activity by increasing LC3-II, Beclin1, and Klotho, and by decreasing p62 in the hippocampus and cortex. Conclusion: The beneficial effects of DNLA were comparable to metformin in protecting against aging-related cognitive deficits, neuron aging, damage, and loss in SAMP8 mice. The mechanisms could be attributed to increased A beta clearance, activation of autophagy activity, and upregulation of Klotho.