Modulation of LOX and COX pathways via inhibition of amyloidogenesis contributes to mitoprotection against β-amyloid oligomer-induced toxicity in an animal model of Alzheimer's disease in rats

• ICV amyloid beta produced cognitive deficits and mitochondrial oxidative damage.
• Amyloid beta treated rats showed neuro-inflammation and beta-amyloid deposition.
• Zafirlukast and valdecoxib significantly improved the behavioral performances.
• Both drugs attenuated the mito-oxidative damage declining the β-A deposition.
• Zafirlukast and valdecoxib are found to be neuro-protective through the modulation of LOX and COX pathways.

Several lines of evidence indicate that beta amyloid (β-A) production, neurofibrillary tangles and neuroinflammation are interrelated in the pathogenesis of Alzheimer's disease (AD). AD is associated with enhanced β-A production and accumulation resulting in neuroinflammation probably via activation of lipoxygenase (LOX) and cyclooxygenase (COX) pathways. Therefore, the present study was designed to investigate the role of LOX and COX inhibitors (zafirlukast and valdecoxib) in amyloidogenesis in β-A1–42 oligomer induced experimental AD in rats. The behavioral activities were assessed using actophotometer, novel object recognition test (ORT), Morris water maze (MWM) followed by biochemical assessments, determination of proinflammatory cytokines and mediators (TNF-α, IL-1β and PGE2), β-A1–42 levels and histopathological analysis. ICV administration of β-A1–42 oligomer produced significant impairment in memory consolidation. In addition to this significant increase in mito-oxidative stress, neuroinflammatory markers, acetylcholinesterase (AChE) toxicity, β-A1–42 level, neuronal cell death and neuroinflammation are more profound in β-A1–42 oligomer treated AD rats. Administration of zafirlukast (15 and 30 mg/kg), and valdecoxib (5 and 10 mg/kg) significantly improved the behavioral performances and showed significant reversal of mito-oxidative damage declining the neuroinflammation in β-A1–42 oligomer treated rats. Furthermore, more profound effects were observed at the sub-therapeutic dose combination of zafirlukast (15 mg/kg) and valdecoxib (5 mg/kg). The results of the present study indicate that protective effects of zafirlukast and valdecoxib are achieved through the blockade of release of LOX and COX metabolites therefore, representing a new therapeutic target for treating AD and other neurodegenerative disorders.

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