Protective effects of icariin on brain dysfunction induced by lipopolysaccharide in rats
Introduction
Inflammation occurring in pathologically vulnerable regions of the Alzheimer's-diseased (AD) brain, extensive neuronal loss, extracellular deposition of amyloid β-protein (Aβ) and neurofibrillary tangles (NFT) are among the characteristic pathological features of AD (Weninger and Yankner 2001). Neuroinflammation has been known to play a role in the pathogenesis of AD, by which damaged neurons, neurites, highly insoluble Aβ peptide deposits and NFT provide obvious stimuli for inflammation (Akiyama et al. 2000). Likewise, the AD brain shows chronic inflammatory response characterized by an abundance of reactive astrocytes and activated microglia, complement, and cytokines (Fuller et al. 2009). These documented phenomena strongly suggest that AD inflammation contributes significantly to AD pathogenesis.
A longitudinal study showed that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduced the risk of AD dementia (but not of vascular dementia; Szekely et al. 2008), as well as slowing disease progression, and reducing microglial activation in an animal model of AD (Kotilinek et al., 2008, Yan et al., 2003). The safety of long-term use of NSAIDs has, however, been questioned, and providing other potential anti-inflammatory treatments for AD remains essential.
Icariin, a flavonol isolated from Epimedii herba, is considered to be the primary active component of Epimedium extracts. It has been widely used for the treatment of atherosclerosis and neuropathy in Chinese traditional medicine (Zhao et al. 2007) and shares several mechanisms of action with compounds used in Western medicine to treat impotence and improve sexual function. In particular, icariin has been demonstrated to enhance the production of bioactive nitric oxide (Xu and Huang 2007), and to act as an antioxidant (Xie et al., 2007, Zhao et al., 2007) and nootropic (Luo et al., 2007, Zheng et al., 2008) in animal studies. Our previous study indicated that icariin may inhibit beta-amyloid peptide segment 25–35-induced expression of beta-secretase in rat hippocampus (Nie et al. 2010), and it has also reported that icariin attenuates chronic mild stress-induced behavioral and neuroendocrinological alterations in male Wistar rats (Pan et al. 2007). Meanwhile, icariin could pass through the blood–brain barrier into brain tissues (Li and Wang 2008). These results suggest that icariin may have potential as an anti-inflammatory agent.
Therefore, in the present study, a rat model of learning and memory deficit was induced by lipopolysaccharide (LPS), a non-infectious component of Gram-negative bacterial cell walls. LPS provides a potent stimulus for experimental immune activation. Peripheral or central administration of this bacterial endotoxin characteristically leads to behavioral changes including reduced food and water intake, decreased exploration and social interactions (Gasparotto et al., 2007, Sparkman et al., 2005). This study adopted the AD model induced by LPS to examine the anti-inflammatory effect of icariin, in an attempt to find a new multifunctional neuroprotective agent to prevent and treat neurodegenerative diseases.
Section snippets
Drugs and reagents
Icariin (purity coefficient 96%, by HPLC) was isolated from Epimedium acuminatum Franch. by the Key Laboratory of Chemistry for Natural Products of Guizhou Province, the Chinese Academy of Sciences, and its formula structure was as shown in Fig. 1. It was dissolved in distilled water before use. LPS (Escherichia coli; 055:B5) and ibuprofen were purchased from Sigma Chemical Co. (St. Louis, MO, USA). LPS was dissolved in normal saline and ibuprofen dissolved in distilled water. Both the
Behavior examination
Eighty-four qualified rats with similar scores in escape latency and searching distance were then divided randomly into six groups. The brain dysfunction models were established by injecting LPS into the lateral ventricle, by which the escape latency and the searching distance were significantly increased as compared with the control group at day 10. Icariin and ibuprofen can improve spatial learning ability and memory in rats with brain dysfunction induced by LPS, as evidenced by a decrease in
Discussion
Icariin, at doses of 30–120 mg/kg body wt., is beneficial in its broad range of pharmacological and biological activities, including assisting the inhibition of free radical formation, decreased lipid peroxidation and Aβ1–40 deposits, the amelioration of learning and memory deficits in aluminum-intoxicated rats (Luo et al. 2007). Recent research suggested that icariin can also improve spatial learning abilities and memory in vascular dementia model rats (Xu et al. 2009). Overall, ICA is an
Acknowledgement
This work was supported by grant from the Key Projects of Guizhou Science and Technology Department (C-343).
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