Pretreatment with antiasthmatic drug ibudilast ameliorates Aβ1-42-induced memory impairment and neurotoxicity in mice

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 Aβ1-42-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) Aβ1-42-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 Aβ1-42-injected mice. Taken together, our findings suggest that ibudilast has preventive effects on Aβ-induced cognitive impairment via inhibiting neuroinflammatory and apoptotic responses.