Icariin improves brain function decline in aging rats by enhancing neuronal autophagy through the AMPK/mTOR/ULK1 pathway

Abstract

Context: Icariin (ICA) is the main active ingredient of Epimedium brevicornu Maxim (Berberidaceae), which is used in the immune, reproductive, neuroendocrine systems, and anti-aging. Objective: To evaluate the effect of ICA on natural aging rat. Materials and methods: 16-month-old Sprague-Dawley (SD) rats were randomly divided into aging, low and high-dose ICA groups (n ¼ 8); 6-month-old rats were taken as the adult control (n ¼ 8). Rats were fed regular feed (aging and adult control) or feed containing ICA (ICA 2 and 6 mg/kg group) for 4 months. HE and Nissl staining were used to assess pathological changes. Western blot was used to test the expression of autophagy (LC3B, p62, Atg5, Beclin1) and p-AMPK, p-mTOR and p-ULK1 (ser 757). Immunofluorescence was used to detect the co-localization of LC3 and neurons. Results: ICA improved neuronal degeneration associated with aging and increased the staining of Nissl bodies. Western blot showed that ICA up-regulated autophagy-related proteins LC3B (595%), Beclin1 (73.5%), p-AMPK (464%) protein (p < 0.05 vs. 20 M) in the cortex and hippocampus of aging rats, downregulated the expression of p62 (56.9%), p-mTOR (53%) and p-ULK1 (ser 757) (65.4%) protein (p < 0.05 vs. 20 M). Immunofluorescence showed that the fluorescence intensity of LC3 decreased in the aging rat brain, but increased and mainly co-localized with neurons after ICA intervention. Conclusions: Further research needs to verify the expression changes of AMPK/mTOR/ULK1 and the improvement effect of ICA in elderly. These results will further accelerate the applications of ICA and the treatment for senescence.

Neuroinflammation in Alzheimer’s Disease

“…Xia et al have demonstrated that, in aged rats, Epimedium flavonoids and icariin attenuate the proinflammatory response while enhancing an anti-inflammatory response in inter alia the hippocampus, hypothalamus, and hypophysis, and mitigate neuroinflammation in aging [ 512 , 513 ]. Icariin acts via the AMPK/mTOR/ULK1 pathway to increase neuronal autophagy and enhance brain function in aged Sprague–Dawley (SD) rats [ 514 ]. Moreover, in the bilateral common carotid arteries occlusion (BCCAO) rat model of AD, which manifests as neuronal morphological damage along with Aβ deposition in the hippocampus and cognitive deficits of Aβ in rat hippocampus, oral administration of icariin reduces hippocampal expression of APP and BACE1, and induces the expressions of insulin-degrading enzyme (IDE) and a disintegrin and metalloproteinase domain 10 (ADAM10).…”

Dietary Supplements and Natural Products: An Update on Their Clinical Effectiveness and Molecular Mechanisms of Action During Accelerated Biological Aging

“…Icariin, including its active metabolic metabolites and semi-synthetic derivatives, has evolved to be an anti-aging molecule with stimulating effects on age-related diseases. Icariin enhanced brain function in aging rodents by increasing neuronal autophagy ( Zheng et al, 2021 ). This ability of icariin to induce neuronal autophagy/mitophagy was via the AMPK/mTOR/ULK1 pathway, suggesting that it can modulate intrinsic nutrient-sensing signaling to engage the cellular trash management system effectively ( Wang et al, 2021a ; Zheng et al, 2021 ).…”

The neuroprotective effects of icariin on ageing, various neurological, neuropsychiatric disorders, and brain injury induced by radiation exposure

“…In addition, several studies have proved that ageing is accompanied by dysfunctional autophagy [ 118 ]. Icariin reduces neuronal dysfunction in ageing rats by promoting neuronal autophagy through the AMPK/mTOR/ULK1 pathway [ 119 ]. Icariin could ameliorate the motor and learning disabilities of male C57BL/6J ageing mice by activating Akt/Nrf2/NF-ĸB signaling pathway [ 117 ].…”