Protective Effect of Low-Dose Alcohol Consumption against Post-Ischemic Neuronal Apoptosis: Role of L-PGDS

Chun Li,Hong Sun,Jiyu Li,Ethyn G Loreno,Manikandan Panchatcharam,Sumitra Miriyala

doi:10.3390/ijms23010133

Abstract

Ischemic stroke is one of the leading causes of permanent disability and death in adults worldwide. Apoptosis is a major element contributing to post-ischemic neuronal death. We previously found that low-dose alcohol consumption (LAC) protects against neuronal apoptosis in the peri-infarct cortex following transient focal cerebral ischemia. Lipocalin-type prostaglandin D2 synthase (L-PGDS), which is mainly localized in the central nervous system (CNS), was previously shown to inhibit neuronal apoptosis. Therefore, we determined whether L-PGDS is involved in the protective effect of LAC against post-ischemic neuronal apoptosis. Wild-type (WT), CaMKIIαCreERT2/+/L-PGDS+/+, and CaMKIIαCreERT2/+/L-PGDSflox/flox mice on a C57BL/6J background were gavage fed with ethanol or volume-matched water once a day for 8 weeks. Tamoxifen (2 mg/day) was given intraperitoneally to CaMKIIαCreERT2/+/L-PGDS+/+ and CaMKIIαCreERT2/+/L-PGDSflox/flox mice for 5 days during the fourth week. AT-56 (30 mg/kg/day), a selective inhibitor of L-PGDS, was given orally to AT-56-treated WT mice from the fifth week for four weeks. Cerebral ischemia/reperfusion (I/R) injury, TUNEL-positive neurons, and cleaved caspase-3-positive neurons were measured at 24 h of reperfusion after a 90 min unilateral middle cerebral artery occlusion (MCAO). We found that 0.7 g/kg/day but not 2.8 g/kg/day ethanol significantly upregulated L-PGDS in the cerebral cortex. In addition, 0.7 g/kg/day ethanol diminished cerebral ischemia/reperfusion (I/R) injury and TUNEL-positive and cleaved caspase-3-positive neurons in the peri-infarct cortex in WT and CaMKIIαCreERT2/+/L-PGDS+/+ mice. Furthermore, the neuroprotective effect of 0.7 g/kg/day ethanol was alleviated in AT-56-treated WT and CaMKIIαCreERT2/+/L-PGDSflox/flox mice. Our findings suggest that LAC may protect against cerebral I/R injury by suppressing post-ischemic neuronal apoptosis via an upregulated L-PGDS.

Highlights

Ischemic stroke, which occurs when an artery supplying blood to the brain becomes obstructed, is one of the major causes resulting in permanent disability and death globally [1,2]
Due to the use of tissue-type plasminogen activator and intravascular techniques, transient focal cerebral ischemia has become a common type of ischemic stroke
Since we found that low-dose alcohol consumption (LAC) but not heavy alcohol consumption (HAC), which exacerbates cerebral I/R injury, alters Lipocalin-type prostaglandin D2 synthase (L-PGDS) in the brain, our second goal was to determine whether L-PGDS is involved in LAC-induced suppression of neuronal apoptosis following transient focal cerebral ischemia

Summary

Introduction

Ischemic stroke, which occurs when an artery supplying blood to the brain becomes obstructed, is one of the major causes resulting in permanent disability and death globally [1,2]. Due to the use of tissue-type plasminogen activator (tPA) and intravascular techniques, transient focal cerebral ischemia has become a common type of ischemic stroke. A form of programmed cell death, contributes to a significant proportion of neuron death in the ischemic penumbra during reperfusion [4]. Apoptosis is indicated by a series of typical morphological features, including the formation of apoptotic bodies, chromatin condensation, and cell and nuclear shrinkage. Three apoptotic pathways (the perforin/granzyme, extrinsic (death ligand), and intrinsic (mitochondrial)) have been discovered. Caspase-3 appears the common effector caspase in all three apoptotic pathways [5]. It is activated upon proteolytic cleavage via the intrinsic and extrinsic pathways following ischemic stroke [6]

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Conclusion