5-lipoxygenase pathway and its downstream cysteinyl leukotrienes as potential therapeutic targets for Alzheimer's disease.

5-lipoxygenase (ALOX5) is an enzyme involved in arachidonic acid (AA) metabolism, a metabolic pathway in which cysteinyl leukotrienes (CysLTs) are the resultant metabolites. Both ALOX5 and CysLTs are clinically significant in a number of inflammatory diseases, such as in asthma and allergic rhinitis, and drugs antagonizing the effect of these molecules have long been successfully used to counter these diseases. Interestingly, recent advances in 'neuroinflammation' research has led to the discovery of several novel inflammatory pathways regulating many cerebral pathologies, including the ALOX5 pathway. By means of pharmacological and genetic studies, both ALOX5 and CysLTs receptors have been shown to be involved in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative/neurological diseases, such as in Parkinson's disease, multiple sclerosis, and epilepsy. In both transgenic and sporadic models of AD, it has been shown that the levels of ALOX5/CysLTs are elevated, and that genetic/pharmacological interventions of these molecules can alleviate AD-related behavioral and pathological conditions. Clinical relevance of these molecules has also been found in AD brain samples. In this review, we aim to summarize such important findings on the role of ALOX5/CysLTs in AD pathophysiology, from both the cellular and the molecular aspects, and also discuss the potential of their blockers as possible therapeutic choices to curb AD-related conditions.

Mogrol attenuates lipopolysaccharide (LPS)-induced memory impairment and neuroinflammatory responses in mice.

This study aimed to evaluate whether mogrol, a main bioactive ingredient of Siraitia grosvenorii, could attenuate LPS-induced memory impairment in mice. The behavioral tests and immunohistochemical analysis and Western blot were performed. The present results showed that oral administration of mogrol (20, 40, 80 mg/kg) significantly improved LPS-induced memory impairment in mice. The results also indicated that mogrol treatment significantly reduced the number of Iba1-positive cells, the nuclear NF-κB p65 and levels of TNF-α, IL-1ß and IL-6 both in the hippocampus and frontal cortex of LPS-challenged mice. [Formula: see text].

Neuroprotective effect of mogrol against Aß1-42 -induced memory impairment neuroinflammation and apoptosis in mice.

OBJECTIVES: Cognitive impairment is the main character of Alzheimer's disease (AD). This study mainly focused on whether mogrol, a tetracyclic triterpenoids compound of Siraitia grosvenorii Swingle, can ameliorate the memory impairment induced by Aß1-42 . METHODS: Memory impairment mice model was made by stereotactic intra-hippocampal microinjection of Aß1-42 (410 pm/mouse). Mogrol (20, 40, 80 mg/kg) was given to mice by intragastric administration at 3 days after Aß1-42 injection for totally 3 weeks. Morris water maze test and Y-maze test were operated to evaluate the therapeutic effect of morgrol on Aß1-42 -induced memory impairments. Immunohistochemical analyses and Hoechst 33258 assay were used to evaluate effect of morgrol on Aß1-42 -induced microglia overactivation and apoptotic response in hippocampus of mice. Western blotting assay was used to evaluate effect of mogrol on the Aß1-42 -activated NF-κB signaling. KEY FINDINGS: Mogrol could significantly alleviate Aß1-42 -induced memory impairments, inhibit Aß1-42 -induced microglia overactivation and prevent Aß1-42 -triggered apoptotic response in the hippocampus. Mogrol also could suppress Aß1-42 -activated NF-κB signaling, reduce the production of proinflammatory cytokines. CONCLUSIONS: This study suggested that mogrol would ameliorate the memory impairment induced by Aß1-42 , which is involved in anti-inflammation and anti-apoptosis in the brain.