Abstract
The antioxidant properties of alpha-lipoic acid (aLA) correlate with its ability to promote neuroproliferation. However, there have been no comprehensive studies examining the neurorestorative effects of aLA administration after the onset of ischemia. The middle cerebral artery (MCA) of adult rats was occluded for 2 hours and then reperfused. aLA (20 mg/kg) was administered in 71 animals (aLA group) through the left external jugular vein immediately after reperfusion. An equivalent volume of vehicle was administered to 71 animals (control group). Functional outcome, levels of endogenous neural precursors with neurogenesis, glial cell activation, and brain metabolism were evaluated. Immediate aLA administration after reperfusion resulted in significantly reduced mortality, infarct size, and neurological deficit score (NDS) in the test group compared to the control group. Long-term functional outcomes, measured by the rotarod test, were markedly improved by aLA treatment. There was a significant increase in the number of cells expressing nestin and GFAP in the boundary zone and infarct core regions after aLA treatment. Furthermore, significantly more BrdU/GFAP, BrdU/DCX, and BrdU/NeuN double-labeled cells were observed along the boundary zone of the aLA group on days 7, 14, and 28 days, respectively. And brain metabolism using 18F-FDG microPET imaging was markedly improved in aLA group. The effects of aLA was blocked by insulin receptor inhibitor, HNMPA (AM)3. These results indicate that immediate treatment with aLA after ischemic injury may have significant neurorestorative effects mediated at least partially via insulin receptor activation. Thus, aLA may be useful for the treatment of acute ischemic stroke.
Highlights
Stroke is a leading cause of death worldwide and the largest single cause of long-term disability in millions of people in developed countries [1]
To determine whether the early proliferative effects of alpha-lipoic acid (aLA) on post-stroke neurogenesis seen at 2 weeks were sustained, we evaluated the number of cells co-labeled with BrdU and the mature neuronal maker NeuN 4 weeks after stroke. aLA-treated rats showed an increased number of BrdU/NeuN-positive cells in the cerebral cortex (P < 0.001) when compared with control (Figure 10)
We have shown that urgent treatment with aLA (20 mg/ kg) after ischemic injury had long-term (56 days) neurorestorative effects against neural damage caused by cerebral infarction in rats
Summary
Stroke is a leading cause of death worldwide and the largest single cause of long-term disability in millions of people in developed countries [1]. Large hemispheric infarctions due to middle cerebral artery occlusion (MCAO) are a major cause of severe morbidity and mortality. Despite sophisticated medical management and neurosurgical techniques, middle cerebral artery (MCA) territory infarction still results in a high mortality rate of 40% to 80% [2]. There is a considerable body of evidence to suggest that oxidative stress is a fundamental mechanism causing brain damage in stroke and reperfusion ensuing stroke [3]. The brain is highly susceptible to reactive oxygen species (ROS) that induce damage due to low levels of protective antioxidants, high concentrations of peroxidizable lipids, high oxygen consumption, and high iron levels that act as pro-oxidants under pathological conditions [4]. ROS have been implicated as one of the earliest and most important components of tissue injury after reperfusion of an ischemic organ [5]
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