Montelukast targeting the cysteinyl leukotriene receptor 1 ameliorates Aβ1-42-induced memory impairment and neuroinflammatory and apoptotic responses in mice.
Montelukast, known as a cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, is currently used for treatment of inflammatory diseases such as asthma. Here, we investigated effects of montelukast on neuroinflammatory, apoptotic responses, and memory performance following intracerebral infusions of amyloid-β (Aβ). The data demonstrated that intracerebroventrical infusions of aggregated Aβ1-42 (410 pmol/mouse) produced deficits in learning ability and memory, as evidenced by increase in escape latency during acquisition trials and decreases in exploratory activities in the probe trial in Morris water maze (MWM) task, and by decrease in the number of correct choices and increase in latency to enter the shock-free compartment in Y-maze test, and caused significant increases in pro-inflammatory cytokines such as NF-κB p65, TNF-α and IL-1β as well as pro-apoptotic molecule caspase-3 activation and anti-apoptotic protein Bcl-2 downregulation in hippocampus and cortex. Interestingly, this treatment resulted in upregulation of protein or mRNA of CysLT1R in both hippocampus and cortex. Blockade of CysLT1R by repeated treatment with montelukast (1 or 2 mg/kg, ig, 4 weeks) reduced Aβ1-42-induced CysLT1R expression and also suppressed Aβ1-42-induced increments of NF-κB p65, TNF-α, IL-1β and caspase-3 activation, and Bcl-2 downregulation in the hippocampus and cortex. Correspondingly, montelukast treatment significantly improved Aβ1-42-induced memory impairment in mice, but had little effect on normal mice. Our results show that montelukast may ameliorate Aβ1-42-induced memory impairment via inhibiting neuroinflammation and apoptosis mediated by CysLT1R signaling, suggesting that CysLT1R antagonism represents a novel treatment strategy for Alzheimer's disease.
Department of Pharmacology, China Pharmaceutical University, Tong Jiaxiang, Nanjing 210009, China.
Jin'e
J
Lai
Department of Pharmacology, China Pharmaceutical University, Tong Jiaxiang, Nanjing 210009, China.
Meng
M
Hu
Department of Pharmacology, China Pharmaceutical University, Tong Jiaxiang, Nanjing 210009, China.
Hao
H
Wang
Department of Pharmacology, China Pharmaceutical University, Tong Jiaxiang, Nanjing 210009, China.
Mei
M
Hu
Department of Pharmacology, China Pharmaceutical University, Tong Jiaxiang, Nanjing 210009, China.
Yan
Y
Long
Department of Pharmacology, China Pharmaceutical University, Tong Jiaxiang, Nanjing 210009, China.
Ming-xing
MX
Miao
Department of Pharmacology, China Pharmaceutical University, Tong Jiaxiang, Nanjing 210009, China.
Jia-chang
JC
Li
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Xiao-bing
XB
Wang
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Ling-yi
LY
Kong
Department of Pharmacology, China Pharmaceutical University, Tong Jiaxiang, Nanjing 210009, China. Electronic address: haohongchina@hotmail.com.
Hao
H
Hong
D000085:Acetates / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D003521:Cyclopropanes; D016207:Cytokines / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D020024:Leukotriene Antagonists / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D018077:Receptors, Leukotriene / Q000378:metabolism*; D013440:Sulfides
D000085:Acetates; D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003521:Cyclopropanes; D016207:Cytokines; D020024:Leukotriene Antagonists; D016328:NF-kappa B; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; C075222:amyloid beta-protein (1-42); C505409:Casp3 protein, mouse; D053148:Caspase 3; C083169:leukotriene D4 receptor; C093875:montelukast
Amyloid-β; Cysteinyl leukotriene receptor 1; Memory; Montelukast; NF-κB