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Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic
Yeon Suk Jung1, Jung Hwa Park1,2, Hyunha Kim1,2
1Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
Aim:
Increasing evidence suggests that probucol, a lipid-lowering agent with anti-oxidant activities, may be useful for the treatment of ischemic stroke with hyperlipidemia via reduction in cholesterol and neuroinflammation. In this study we examined whether probucol could protect against brain ischemic injury via anti-neuroinflammatory action in normal and hyperlipidemic mice.
Methods:
Primary mouse microglia and murine BV2 microglia were exposed to lipopolysaccharide (LPS) for 3 h, and the release NO, PGE2, IL-1β and IL-6, as well as the changes in NF-κB, MAPK and AP-1 signaling pathways were assessed. ApoE KO mice were fed a high-fat diet containing 0.004%, 0.02%, 0.1% (wt/wt) probucol for 10 weeks, whereas normal C57BL/6J mice received probucol (3, 10, 30 mg·kg(-1)·d(-1), po) for 4 d. Then all the mice were subjected to focal cerebral ischemia through middle cerebral artery occlusion (MCAO). The neurological deficits were scored 24 h after the surgery, and then brains were removed for measuring the cerebral infarct size and the production of pro-inflammatory mediators.
Results:
In LPS-treated BV2 cells and primary microglial cells, pretreatment with probucol (1, 5, 10 μmol/L) dose-dependently inhibited the release of NO, PGE2, IL-1β and IL-6, which occurred at the transcription levels. Furthermore, the inhibitory actions of probucol were associated with the downregulation of the NF-κB, MAPK and AP-1 signaling pathways. In the normal mice with MCAO, pre-administration of probucol dose-dependently decreased the infarct volume and improved neurological function. These effects were accompanied by the decreased production of pro-inflammatory mediators (iNOS, COX-2, IL-1, IL-6). In ApoE KO mice fed a high-fat diet, pre-administration of 0.1% probucol significantly reduced the infarct volume, improved the neurological deficits following MCAO, and decreased the total- and LDL-cholesterol levels.
Conclusion:
Probucol inhibits LPS-induced microglia activation and ameliorates cerebral ischemic injury in normal and hyperlipidemic mice via its anti-neuroinflammatory actions, suggesting that probucol has potential for the treatment of patients with or at risk for ischemic stroke and hyperlipidemia.
Insights
Probucol reduces brain damage and inflammation in mice with ischemic stroke and hyperlipidemia. This lipid-lowering drug shows potential for treating stroke patients with high cholesterol.
Area of Science:
- Neuroscience
- Pharmacology
- Cardiovascular Medicine
Background:
- Ischemic stroke is a leading cause of death and disability.
- Hyperlipidemia is a significant risk factor for ischemic stroke.
- Probucol, a lipid-lowering agent, possesses antioxidant properties that may offer neuroprotection.
Purpose of the Study:
- To investigate the neuroprotective effects of probucol against ischemic brain injury.
- To determine if probucol's protective action is mediated by anti-neuroinflammatory effects.
- To evaluate probucol's efficacy in both normal and hyperlipidemic mouse models of stroke.
Main Methods:
- In vitro: Microglia exposed to lipopolysaccharide (LPS) to assess inflammatory markers and signaling pathways (NF-κB, MAPK, AP-1).
- In vivo: Normal and ApoE knockout mice (hyperlipidemic model) treated with probucol before middle cerebral artery occlusion (MCAO).
- Assessed neurological deficits, infarct size, and pro-inflammatory mediator production post-MCAO.
Main Results:
- Probucol dose-dependently inhibited LPS-induced release of inflammatory mediators (NO, PGE2, IL-1β, IL-6) in microglia.
- Probucol downregulated key inflammatory signaling pathways (NF-κB, MAPK, AP-1).
- In MCAO models, probucol reduced infarct volume, improved neurological function, and decreased pro-inflammatory mediators. In hyperlipidemic mice, probucol also lowered cholesterol levels.
Conclusions:
- Probucol effectively inhibits microglia activation and reduces cerebral ischemic injury in mice.
- The anti-neuroinflammatory actions of probucol contribute to its neuroprotective effects.
- Probucol demonstrates potential as a therapeutic agent for ischemic stroke, particularly in patients with hyperlipidemia.
