Protective effect of pranlukast on Aβ 1–42-induced cognitive deficits associated with downregulation of cysteinyl leukotriene receptor 1

Abstract

Deposition of extracellular amyloid-β (Aβ) peptide is one of the pathological hallmarks of Alzheimer's disease (AD). Accumulation of Aβ is thought to associate with cognition deficits, neuroinflammation and apoptosis observed in AD. However, effective neuroprotective approaches against Aβ neurotoxicity are unavailable. In the present study, we analysed the effects of pranlukast, a selective cysteinyl leukotriene receptor 1 (CysLT₁R) antagonist, on the impairment of learning and memory formation induced by Aβ and the probable underlying electrophysiological and molecular mechanisms. We found that bilateral intrahippocampal injection of Aβ₁₋₄₂ 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 CysLT₁R expression and subsequent NF-κB 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 Aβ₁₋₄₂-induced impairments of cognitive function and hippocampal LTP in mice. Furthermore, pranlukast reversed Aβ₁₋₄₂-induced CysLT₁R upregulation, and markedly suppressed the Aβ₁₋₄₂-triggered NF-κB 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.

Hippocampal CysLT1R knockdown or blockade represses LPS-induced depressive behaviors and neuroinflammatory response in mice

“…Leukotriene pathway modifiers, including 5-lipoxygenase inhibitor (zileuton) and CysLT 1 R antagonists (montelukast, zafirlukast, and pranlukast), have been used as anti-asthmatic drugs [11][12][13] . Recently, several studies on CysLT 1 R have focused on its novel pathophysiological role in CNS disorders, such as cognitive impairment [14] , cerebral ischemia [15] , brain trauma [16] and experimental autoimmune encephalomyelitis [17] . We recently reported that CysLT 1 R knockdown in the mouse hippocampus prevented the CMS-induced depressive-like phenotype and neuroinflammation [18] .…”

Opposite in vivo effects of agents that stimulate or inhibit the glutamate/cysteine exchanger system on the inhibition of hippocampal LTP by Aß

“…Moreover, microglial oxidative and nitrosative stress have been strongly implicated as being essential contributors to the synaptic plasticity disrupting action of Aß (Wang et al, 2004;Vilhardt et al, in press). Although SAS and its metabolites have other actions, in particular antiinflammatory (Chavez et al, 2012), inhibition of the transcriptional regulator nuclear factor-jB (NF-jB) (Wahl et al, 1998;Kaiser et al, 1999;de la Fuente et al, 2014) and antagonism of NMDA receptors (Ryu et al, 2003), such effects are expected to abrogate, rather than facilitate, the inhibition of LTP by Aß (Wang et al, 2004;Wang et al, 2005;Hu et al, 2009;Klyubin et al, 2011;Chen et al, 2014;Tang et al, 2014). Thus a highly likely, but yet to be proven, explanation for the negative effects of SAS in the present experiments is impeding the production of GSH under conditions of microglial oxidative and nitrosative stress, including those caused by Aß (Almaguer-Melian et al, 2000;Steullet et al, 2006;Albrecht et al, 2010;Patten et al, 2013;Vilhardt et al, in press).…”

Cysteinyl Leukotrienes as Potential Pharmacological Targets for Cerebral Diseases

“…In bilateral i.c.v. A β 1–42 -injected mice, pranlukast and montelukast reversed the A β 1–42 -induced cognitive deficits associated to inflammatory and apoptotic responses, as evidenced by decreased NF-kB p65, TNF- α , IL-1 β , and caspase-3 in the hippocampus and cortex [125, 132]. Moreover, in other studies, montelukast restores learning and memory function in old rats, in which cognition is compromised and the hippocampus concentrations of 5-LOX transcripts and of leukotrienes were increased [27, 133].…”