title: Pretreatment with antiasthmatic drug ibudilast ameliorates Aβ 1-42-induced memory impairment and neurotoxicity in mice.
abstract: Amyloid-β peptide (Aβ) is thought to be associated with the progressive neuronal death observed in Alzheimer's disease (AD). However, effective neuroprotective approaches against Aβ neurotoxicity are unavailable. Here, we investigated possible preventive effects of ibudilast, as a pharmacologic phosphodiesterase inhibitor, currently used for treatment of inflammatory diseases such as asthma, on Aβ 1-42-induced neuroinflammatory, apoptotic responses and memory impairment. We found that pretreatment with ibudilast (4 or 12 mg/kg, i.p.) significantly ameliorated impaired spatial learning and memory in intracerebroventricularly (ICV) Aβ 1-42-injected mice, as evidenced by decrease in escape latency during acquisition trials and increase in exploratory activities in the probe trial in Morris water maze (MWM) task, and by increase in the number of correct choices and decrease in latency to enter the shock-free compartment in Y-maze test. Further study showed that ibudilast prevented generation of pro-inflammatory cytokines such as NF-κB p65 and TNF-α as well as pro-apoptotic molecule caspase-3 activation and anti-apoptotic protein Bcl-2 downregulation in both hippocampus and cortex of ICV Aβ 1-42-injected mice. Taken together, our findings suggest that ibudilast has preventive effects on Aβ-induced cognitive impairment via inhibiting neuroinflammatory and apoptotic responses.
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zhen lin
authors.initials: Zl
authors.lastname: Mei
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Kai Long
authors.initials: KL
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Long
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ming Xing
authors.initials: MX
authors.lastname: Miao
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: tianhua_yan@yahoo.com.cn.
authors.forename: Tian Hua
authors.initials: TH
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: haohongchina@hotmail.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008569:Memory Disorders / Q000517:prevention & control*; D051379:Mice; D008813:Mice, Inbred ICR; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D007212:Indolizines; D011720:Pyrazoles
chemical_list: D016229:Amyloid beta-Peptides; D018927:Anti-Asthmatic Agents; D053148:Caspase 3; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; C075222:amyloid beta-protein (1-42); C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles
keywords: Amyloid-β; Ibudilast; Memory; Neurotoxicity