n-oleoylethanolamine and Brain-Ischemia

Our previous study has revealed that OEA promotes motor function recovery in the chronic stage of ischemic stroke. However, the neuroprotective mechanism of OEA on motor function recovery after stroke still is unexplored. Therefore, the aim of this study was to explore the effects of OEA treatment on angiogenesis, neurogenesis, and white matter repair in the peri-infarct region after cerebral ischemia.. The adult male rats were subjected to 2 h of middle cerebral artery occlusion. The rats were treated with 10 and 30 mg/kg OEA or vehicle daily starting from day 2 after ischemia induction until they were sacrificed.. The results revealed that OEA increased cortical angiogenesis, neural progenitor cells (NPCs) proliferation, migration, and differentiation. OEA treatment enhanced the survival of newborn neurons and oligodendrogenesis, which eventually repaired the cortical neuronal injury and improved motor function after ischemic stroke. Meanwhile, OEA treatment promoted the differentiation of oligodendrocyte progenitor cells (OPCs) and oligodendrogenesis by activating the PPARα signaling pathway. Our results showed that OEA restores motor function by facilitating cortical angiogenesis, neurogenesis, and white matter repair in rats after ischemic stroke. Therefore, we demonstrate that OEA facilitates functional recovery after ischemic stroke and propose the hypothesis that the long-term application of OEA mitigates the disability after stroke.

Topics: Animals; Brain Ischemia; Cell Differentiation; Ischemic Stroke; Male; Neurogenesis; Oligodendroglia; PPAR alpha; Rats; Stroke; White Matter

Glial activation and scar formation impede the neurological function recovery after cerebral ischemia. Oleoylethanolamide (OEA), a bioactive lipid mediator, shows neuroprotection against acute brain ischemia, however, its long-term effect, especially on glial scar formation, has not been characterized. In this research, we investigate the effect of OEA on glial activation and scar formation after cerebral ischemia in vitro and in vivo experiments. Glial scar formation in vitro model was induced by transforming growth factor β1 (TGF-β1) in C6 glial cell culture, and experiment model in vivo was induced by middle cerebral artery occlusion (MCAO) in mice. The protein expressions of the markers of glial activation (S100β, GFAP, or pSmads) and glial scar (neurocan) were detected by Western blot and/or immunofluorescence staining; To evaluate the role of PPARɑ in the effect of OEA on glial activation, the PPARɑ antagonist GW6471 was used. Behavior tests were used to assay the effect of OEA on motor function recovery 14 days after brain ischemia in mice. Our results show that OEA (10-50 μM) concentration-dependently inhibited the upregulation of S100β, GFAP, pSmads and neurocan induced by TGF-β1 in C6 glial cells. At the same time, OEA promoted the protein expression and nuclear transportation of PPARɑ in glial cells. PPARα antagonist GW6471 abolished the effect of OEA on glial activation. In addition, we found that delay administration of OEA inhibited the astrocyte activation and promoted the recovery of motor function after brain ischemia in mice. These results indicate that OEA may be developed into a new candidate for attenuating astrocytic scar formation and improving motor function after ischemic stroke.

Topics: Animals; Brain Ischemia; Cell Line; Endocannabinoids; Hand Strength; Infarction, Middle Cerebral Artery; Male; Mice; Neuroglia; Neuroprotective Agents; Oleic Acids; PPAR alpha; Rats; Recovery of Function; Walking

Oleoylethanolamide (OEA) is a high-affinity agonist of peroxisome proliferator-activated receptor α (PPARα) which may act as an endogenous neuroprotective factor. However, it is not clear whether orally administered OEA is effective against ischemic brain injury. In our study, transient focal cerebral ischemia was induced by middle cerebral artery occlusion for 90 min followed by reperfusion. To evaluate its preventive effects, OEA (10, 20 or 40 mg/kg, ig) was administered for 3 days before ischemia. To evaluate its therapeutic effects, OEA (40 mg/kg, ig) was administered at 0.5 or 1h before reperfusion or at 0 or 1h after reperfusion. In some experiments, the PPARα antagonist MK886 (10mg/kg, ig) was administered 0.5h before OEA. Neurological deficit score, infarct volume and brain edema degree were determined at 24h after reperfusion. Blood-brain barrier (BBB) disruption was evaluated by Evans blue (EB) leakage at 6h after reperfusion. Real-time RT-PCR and western blot were performed to detect PPARα mRNA and protein expression. Oral OEA pretreatment improved neurological dysfunction reduced infarct volume and alleviated brain edema in a dose-dependent manner; the most effective dose was 40 mg/kg. The therapeutic time is within 1h after reperfusion. OEA also increased PPARα mRNA and protein expression in the ischemic brain. The PPARα antagonist MK886 abolished the protective effects of OEA. In conclusion, our results indicate that orally administered OEA protects against acute cerebral ischemic injury in mice, at least in part by activating PPARα.

Topics: Administration, Oral; Animals; Blood-Brain Barrier; Brain; Brain Edema; Brain Ischemia; Dose-Response Relationship, Drug; Drug Evaluation; Endocannabinoids; Male; Mice; Oleic Acids; PPAR alpha; Reperfusion Injury

Excitotoxic insults such as stroke may induce release of fatty acid ethanolamides (FAEs), contributing to the downstream events in the ischemic cascade. We therefore studied release of FAEs such as anandamide, palmitylethanolamide (PEA), and oleylethanolamide (OEA) in the brain of a patient suffering from malignant hemispheric infarction treated with hypothermia.. A patient with life-threatening hemispheric stroke was treated with moderate hypothermia (33 degrees C) that was maintained for 3 days, followed by a 3-day rewarming period. Microdialysis was applied to measure glutamate, lactate, and glycerol by using a microdialysis analyzer. FAEs were measured by microdialysis coupled with high-performance liquid chromatography/mass spectrometry. Release of neuroprotective fatty amides occurred within the first day after ischemia and reached high concentrations for all 3 substances in tissue surrounding the primary ischemic lesion: anandamide up to 42 pmol/mL, PEA up to 120 pmol/mL, and OEA up to 242 pmol/mL. There was a significant correlation with elevation of lactate as early marker for the hypoxic insult.. This is the first report demonstrating release of FAEs in vivo during human stroke and may suggest contribution of the FAE signaling system to the pathophysiological events after ischemia.

Topics: Aged; Amides; Arachidonic Acids; Brain; Brain Chemistry; Brain Ischemia; Endocannabinoids; Ethanolamines; Extracellular Space; Glutamic Acid; Glycerol; Hemiplegia; Humans; Hypothermia, Induced; Lactic Acid; Male; Microdialysis; Monitoring, Physiologic; Oleic Acid; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; Sleep Stages; Stroke