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Fatty Acid-Binding Proteins Aggravate Cerebral Ischemia-Reperfusion Injury in Mice
Qingyun Guo1, Ichiro Kawahata1, Tomohide Degawa1
1Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-Ku, Sendai 980-8578, Japan.
Abstract:
Fatty acid-binding proteins (FABPs) regulate the intracellular dynamics of fatty acids, mediate lipid metabolism and participate in signaling processes. However, the therapeutic efficacy of targeting FABPs as novel therapeutic targets for cerebral ischemia is not well established. Previously, we synthesized a novel FABP inhibitor, i.e., FABP ligand 6 [4-(2-(5-(2-chlorophenyl)-1-(4-isopropylphenyl)-1H-pyrazol-3-yl)-4-fluorophenoxy)butanoic acid] (referred to here as MF6). In this study, we analyzed the ability of MF6 to ameliorate transient middle cerebral artery occlusion (tMCAO) and reperfusion-induced injury in mice. A single MF6 administration (3.0 mg/kg, per os) at 0.5 h post-reperfusion effectively reduced brain infarct volumes and neurological deficits. The protein-expression levels of FABP3, FABP5 and FABP7 in the brain gradually increased after tMCAO. Importantly, MF6 significantly suppressed infarct volumes and the elevation of FABP-expression levels at 12 h post-reperfusion. MF6 also inhibited the promotor activity of FABP5 in human neuroblastoma cells (SH-SY5Y). These data suggest that FABPs elevated infarct volumes after ischemic stroke and that inhibiting FABPs ameliorated the ischemic injury. Moreover, MF6 suppressed the inflammation-associated prostaglandin E2 levels through microsomal prostaglandin E synthase-1 expression in the ischemic hemispheres. Taken together, the results imply that the FABP inhibitor MF6 can potentially serve as a neuroprotective therapeutic for ischemic stroke.
Insights
Fatty acid-binding protein (FABP) inhibition with MF6 reduced brain damage and neurological deficits after ischemic stroke. This novel therapeutic approach targets elevated FABP levels, offering potential neuroprotection.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Fatty acid-binding proteins (FABPs) play roles in lipid metabolism and signaling.
- The therapeutic potential of targeting FABPs for cerebral ischemia remains unclear.
- FABP expression increases in the brain following ischemic events.
Purpose of the Study:
- To evaluate the neuroprotective efficacy of a novel FABP inhibitor, MF6, against ischemic stroke.
- To investigate the effect of MF6 on FABP expression and inflammatory pathways post-cerebral ischemia.
Main Methods:
- Transient middle cerebral artery occlusion (tMCAO) model in mice to induce ischemic stroke.
- Administration of MF6 post-reperfusion to assess infarct volume and neurological deficits.
- Analysis of FABP3, FABP5, and FABP7 protein expression levels.
- Investigation of MF6's effect on FABP5 promoter activity in SH-SY5Y neuroblastoma cells.
- Measurement of prostaglandin E2 levels and microsomal prostaglandin E synthase-1 expression.
Main Results:
- Single MF6 administration significantly reduced brain infarct volumes and neurological deficits.
- MF6 suppressed the elevation of FABP3, FABP5, and FABP7 expression in the ischemic brain.
- MF6 inhibited FABP5 promoter activity in human neuroblastoma cells.
- MF6 decreased prostaglandin E2 levels by downregulating microsomal prostaglandin E synthase-1.
Conclusions:
- Elevated FABP levels contribute to infarct volume expansion after ischemic stroke.
- The FABP inhibitor MF6 demonstrates significant neuroprotective effects in a mouse model of cerebral ischemia.
- MF6 represents a promising therapeutic candidate for treating ischemic stroke by modulating FABP activity and inflammation.
