Protective effect of pranlukast on A beta sub(1-42)-induced cognitive deficits associated with downregulation of cysteinyl leukotriene receptor 1

Deposition of extracellular amyloid- beta (A beta ) peptide is one of the pathological hallmarks of Alzheimer's disease (AD). Accumulation of A beta is thought to associate with cognition deficits, neuroinflammation and apoptosis observed in AD. However, effective neuroprotective approaches against A beta neurotoxicity are unavailable. In the present study, we analysed the effects of pranlukast, a selective cysteinyl leukotriene receptor 1 (CysLT sub(1)R) antagonist, on the impairment of learning and memory formation induced by A beta and the probable underlying electrophysiological and molecular mechanisms. We found that bilateral intrahippocampal injection of A beta sub(1-42) resulted in a significant decline of spatial learning and memory of mice in the Morris water maze (MWM) and Y-maze tests, together with a serious depression of in vivo hippocampal long-term potentiation (LTP) in the CA1 region of the mice. Importantly, this treatment caused significant increases in CysLT sub(1)R expression and subsequent NF- Kappa B signaling, caspase-3 activation and Bcl-2 downregulation in the hippocampus or prefrontal cortex. Oral administration of pranlukast at 0.4 or 0.8 mg/kg for 4 wk significantly reversed A beta sub(1-42)-induced impairments of cognitive function and hippocampal LTP in mice. Furthermore, pranlukast reversed A beta sub(1-42)-induced CysLT sub(1)R upregulation, and markedly suppressed the A beta sub(1-42)-triggered NF- Kappa B pathway, caspase-3 activation and Bcl-2 downregulation in the hippocampus and prefrontal cortex in mice. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay confirmed its presence in the brain after oral administration of pranlukast in mice. These data disclose novel findings about the therapeutic potential of pranlukast, revealing a previously unknown therapeutic possibility to treat memory deficits associated with AD.