Protective effect of pranlukast on Aβ₁₋₄₂-induced cognitive deficits associated with downregulation of cysteinyl leukotriene receptor 1.
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.
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Su-Su
SS
Tang
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Miao-jin
MJ
Ji
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Lan
L
Chen
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Mei
M
Hu
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Yan
Y
Long
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Yong-qi
YQ
Li
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Ming-xing
MX
Miao
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Jia-chang
JC
Li
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Ning
N
Li
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Hui
H
Ji
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Xi-jing
XJ
Chen
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Hao
H
Hong
D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000503:physiopathology; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D007858:Learning / Q000187:drug effects; D020024:Leukotriene Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008568:Memory / Q000187:drug effects; D008813:Mice, Inbred ICR; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology; D018077:Receptors, Leukotriene / Q000187:drug effects
D016229:Amyloid beta-Peptides; D002867:Chromones; D020024:Leukotriene Antagonists; D010446:Peptide Fragments; D018077:Receptors, Leukotriene; C075222:amyloid beta-protein (1-42); C083169:leukotriene D4 receptor; C047681:pranlukast