Abstract
Single long-chain omega-3 fatty acids (e.g. docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA)) are known for their neuroprotective properties associated with ischemic stroke. This pilot study aimed to test the effectiveness of an acute treatment with a long-chain omega-3 lipid emulsion (Omegaven 10%®, OGV) that contains fish oil (DHA 18 mg/ml; EPA 21 mg/ml) and α-tocopherol (0.2 mg/ml) in a transient middle cerebral artery occlusion (MCAO) model of ischemic stroke in mice. For this purpose, female CD-1 mice were anesthetized and subjected to 90 minutes of MCAO. To reflect a clinically relevant situation for an acute treatment, either after induction of stroke or after reperfusion, a single dose of OGV was injected intravenously into the tail vein (5 ml/kg b.w.). A neurological severity score was used to assess motor function and neurological outcome. Stroke-related parameters were determined 24 hours after MCAO. Microdialysis was used to collect samples from extracellular space of the striatum. Mitochondrial function was determined in isolated mitochondria or dissociated brain cells. Inflammation markers were measured in brain homogenate. According to control experiments, neuroprotective effects could be attributed to the long-chain omega-3 content of the emulsion. Intravenous injection of OGV reduced size and severity of stroke, restored mitochondrial function, and prevented excitotoxic glutamate release. Increases of pro-inflammatory markers (COX-2 and IL-6) were attenuated. Neurological severity scoring and neurochemical data demonstrated that acute OGV treatment shortly after induction of stroke was most efficient and able to improve short-term neurological outcome, reflecting the importance of an acute treatment to improve the outcome. Summarising, acute treatment of stroke with a single intravenous dose of OGV provided strong neuroprotective effects and was most effective when given immediately after onset of ischemia. As OGV is an approved fishoil emulsion for parenteral nutrition in humans, our results may provide first translational data for a possible early management of ischemic stroke with administration of OGV to prevent further brain damage.
Highlights
Ischemic stroke is a major cause of death worldwide and responsible for serious long-time disability in adults
Earlier studies used free docosahexaenoic acid (DHA) dissolved in saline which is less suitable for the intended human use. [9,10,11] Stroke related parameters were investigated 24 hours after reperfusion and showed reduced infarct size and infarct severity, improved neurological outcome and behavior, improved mitochondrial function, enhanced glucose levels, prevention of excitotoxic glutamate release and decreased neuroinflammation
Compared to the stroke control group, Omegaven 10% (OGV) a.r. increased the mitochondrial membrane potential by 20% (MMP; Fig 2A), and ATP levels by 63% (Fig 2B) which were significantly reduced in dissociated brain cells 24 hours after reperfusion
Summary
Ischemic stroke is a major cause of death worldwide and responsible for serious long-time disability in adults. [1] neuroprotection remains a prominent goal for stroke therapy and ischemiarelated damage.[2] Ischemia induces changes in mitochondrial respiration and increased mitochondria-related oxidative stress.[3] mitochondria are an important target for neuroprotection in ischemic stroke.[4] Experimental studies identified intravenous administration of the long-chain omega-3 fatty acid docosahexaenoic acid (DHA)—a major component of fish oil—at least in the 3 hours following initiation of stroke and 1 hour post-reperfusion as a potent neuroprotective agent in ischemic stroke.[5] It was concluded that DHA has the potential for treating focal ischemic stroke in a clinical setting and that acute administration of DHA enriched lipid emulsions may be an effective intervention in pathogenesis of human stroke.[6] Early discovery and prevention of long-term sequelae is the primary task in treating patients with acute ischemic stroke.[7] we aimed to test the effectiveness of an intravenous injection (5 ml/kg b.w.) of OGV shortly after onset of ischemic stroke or after reperfusion in a transient MCAO mouse model This situation should reflect two clinically relevant points in time or situations: First, an early neuroprotective treatment in patients arriving at the hospital with a suspected ischemic stroke (at stroke). Earlier studies used free DHA dissolved in saline which is less suitable for the intended human use. [9,10,11] Stroke related parameters were investigated 24 hours after reperfusion and showed reduced infarct size and infarct severity, improved neurological outcome and behavior, improved mitochondrial function, enhanced glucose levels, prevention of excitotoxic glutamate release and decreased neuroinflammation
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