Icariside II ameliorates ibotenic acid-induced cognitive impairment and apoptotic response via modulation of MAPK pathway in rats.

BACKGROUND: Excitotoxicity is extensively recognized as a major pathological process of neuronal death and has been proved to play a key role in Alzheimer's disease (AD). ICS II, a flavonoid compound from Herba Epimedii Maxim, is attracting great interests due to its neuroprotective properties. PURPOSE: The present study was aimed to explore the effects of ICS II on cognitive dysfunction and apoptotic response induced by excitatory neurotoxin ibotenic acid (IBO) injection in rats. METHODS: Rats subjected to bilateral hippocampal injection of IBO were intragastrically administered with 4, 8 and 16 mg/kg ICS II or 0.6 mg/kg donepezil once a day for continuous 20 days. Learning and memory functions were tested by Morris water maze. The neuronal morphology in hippocampus was examined by HE staining and Nissl staining, respectively. Neuronal apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. The expression of apoptosis-related proteins and the activation of mitogen-activated protein kinase (MAPK) pathway were detected by Western blot. RESULTS: It was uncovered that hippocampal injection of IBO caused learning and memory impairment, neuronal damage and loss, as well as pro-apoptotic response. ICS II administrated at doses of 8 and 16 mg/kg not only rescued behavioral performance, but also protected hippocampal neurons against neurotoxicity via suppressing the elevation of Bax/Bcl-2 ratio and the activation of caspase-3. Meanwhile, ICS II repressed the down-regulation of calbindin protein induced by IBO. Additionally, ICS II exerted an inhibitory effect on MAPK (p38, ERK1/2 and JNK) pathway phosphorylation. CONCLUSION: These results suggest that ICS II attenuates IBO-induced cognitive deficits, possibly via the regulation of calbindin expression and the inhibition of apoptotic response. In addition, the MAPK signaling pathway is implicated in the potential mechanisms of ICS II against IBO-induced excitotoxicity, indicating that ICS II is a promising compound for treatment of excitotoxicity-related diseases, including AD.

Icariside II, a Broad-Spectrum Anti-cancer Agent, Reverses Beta-Amyloid-Induced Cognitive Impairment through Reducing Inflammation and Apoptosis in Rats.

Beta-amyloid (Aß) deposition, associated neuronal apoptosis and neuroinflammation are considered as the important factors which lead to cognitive deficits in Alzheimer's disease (AD). Icariside II (ICS II), an active flavonoid compound derived from Epimedium brevicornum Maxim, has been extensively used to treat erectile dysfunction, osteoporosis and dementia in traditional Chinese medicine. Recently, ICS II attracts great interest due to its broad-spectrum anti-cancer property. ICS II shows an anti-inflammatory potential both in cancer treatment and cerebral ischemia-reperfusion. It is not yet clear whether the anti-inflammatory effect of ICS II could delay progression of AD. Therefore, the current study aimed to investigate the effects of ICS II on the behavioral deficits, Aß levels, neuroinflammatory responses and apoptosis in Aß25-35-treated rats. We found that bilateral hippocampal injection of Aß25-35 induced cognitive impairment, neuronal damage, along with increase of Aß, inflammation and apoptosis in hippocampus of rats. However, treatment with ICS II 20 mg/kg could improve the cognitive deficits, ameliorate neuronal death, and reduce the levels of Aß in the hippocampus. Furthermore, ICS II could suppress microglial and astrocytic activation, inhibit expression of IL-1ß, TNF-α, COX-2, and iNOS mRNA and protein, and attenuate the Aß induced Bax/Bcl-2 ratio elevation and caspase-3 activation. In conclusion, these results showed that ICS II could reverse Aß-induced cognitive deficits, possibly via the inhibition of neuroinflammation and apoptosis, which suggested a potential protective effect of ICS II on AD.