CysLT1R downregulation reverses intracerebroventricular streptozotocin-induced memory impairment via modulation of neuroinflammation in mice

Abstract

Our previous studies showed that cysteinyl leukotrienes receptor 1 (CysLT₁R) is upregulated in amyloid-β (Aβ)-induced neurotoxicity and that administration of CysLT₁R antagonists such as pranlukast or montelukast can ameliorate memory impairment in mice. In the current study, we sought to explore the role of CysLT₁R in intracerebroventricular streptozotocin (STZ-ICV)-induced mouse model of memory impairment and neuroinflammation through shRNA-mediated knockdown of CysLT₁R and also its pharmacological blockade by pranlukast. ICR mice were infused with STZ (3.0mg/kg) by a single bilateral stereotaxic ICV microinjection followed by administration of CysLT₁R-shRNA (intra-hippocampal) or pranlukast (intragastric, IG). After 21days, a set of behavioral and biochemical tests were performed in order to assess the degree of memory impairment and neuroinflammation in mice. STZ-infused mice spent less time in the target quadrant of Morris water maze test and took more time to find the shock-free arm in modified Y-maze test, which were rescued in the CysLT₁R-knockdowned or pranlukast-treated mice. STZ-induced memory impairment was also accompanied by an elevated level of hippocampal CysLT₁R, microglial activation, increased IL-1β, and TNF-α. Such elevation of these factors was found to be mediated through the classical NF-κB pathway and administration of CysLT₁R-shRNA or pranlukast for 21days reversed all these parameters, suggesting a role of CysLT₁R in STZ-induced memory deficit and neuroinflammation.

Keywords: Cysteinyl leukotrienes receptor 1; Memory; Neuroinflammation; Pranlukast; STZ ICV; Stereotaxic injection.