Neuroprotective Effect Of(+)-2-(1-hydroxyl-4-oxocyclohexyl)Ethyl Caffeate On APP/PS1 Mice

Alzheimer's disease(AD)is a progressive neurodegenerative disorder.A large number of evidence has demonstrated that neuro-inflammation and oxidative stress are associated with the pathogenesis of AD.Eicosanoida,inflammatory mediators and cytokines can cause neuronal damage.(+)-2-(1-hydroxyl-4-oxocyclohexyl)ethyl caffeate(HOEC),a plant-derived 5-LOX inhibitor,has been proved to possess anti-inflammatory effect.However,little data on neuroprotection was reported in vivo.In this study,we first investigated the effects of HOEC on behavioral performance in APP/PS1 mice using Morris Water maze and fear-conditioning test.And ELISA,Thioflavin S and Western blot were used to detect senile plaques,A?proteins and inflammation mediators and signal pathways related inflammation.APP/PS1 mice were intragastric administrated with different concentrations of HOEC or Zileuton(positive control)for 45 days successively before behavior tests.Results of water maze showed APP/PS1 mice treated with HOEC or Zileuton spend more time in the target quadrant,shorter platform NE latency compared with APP/PS1 treated with vehicle.In fear-conditioning test,APP/PS1 mice were easier or faster to fade fear memory compared to HOEC and Zileuton treated mice.HOEC also led to a decrease in the levels of LTB4 and senile plaque.LTB4 level positively correlated to the escape latency in water maze performance,which might imply LOX pathway play important roles in AD development.JNK is actived in AD,oxidative stress may trigger a series of pathway including JNK,leading to increased production of A? and cognitive dysfunction.We also assessed the changes of MAPKs pathways.Results showed the JNK phosphorylation was declined in mice treated with HOEC.In summary,HOEC can alleviate cognitive dysfunction and memory deficit.The neuroprotective effect of HOEC is not only inhibitor of 5-LOX and anti-inflammatiory effects,but also related to MAPK signaling pathway,effectively alleviating the vicious cycle between inflammation and oxidative stress.The above results indicate that novel 5-LOX inhibitor might be a potential therapeutics for treatment and prevention of Alzheimer's Disease.