Abstract
Ischemic stroke is a devastating disease with a complex pathophysiology. Galangin is a natural flavonoid isolated from the rhizome of Alpina officinarum Hance, which has been widely used as an antioxidant agent. However, its effects against ischemic stroke have not been reported and its related neuroprotective mechanism has not really been explored. In this study, neurological behavior, cerebral infarct volumes and the improvement of the regional cortical blood flow (rCBF) were used to evaluate the therapeutic effect of galangin in rats impaired by middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia. Furthermore, the determination of mitochondrial function and Western blot of apoptosis-related proteins were performed to interpret the neuroprotective mechanism of galangin. The results showed that galangin alleviated the neurologic impairments, reduced cerebral infarct at 24 h after MCAO and exerted a protective effect on the mitochondria with decreased production of mitochondrial reactive oxygen species (ROS). These effects were consistent with improvements in the membrane potential level (Δψm), membrane fluidity, and degree of mitochondrial swelling in a dose-dependent manner. Moreover, galangin significantly improved the reduced rCBF after MCAO. Western blot analysis revealed that galangin also inhibited apoptosis in a dose-dependent manner concomitant with the up-regulation of Bcl-2 expression, down-regulation of Bax expression and the Bax/Bcl-2 ratio, a reduction in cytochrome c release from the mitochondria to the cytosol, the reduced expression of activated caspase-3 and the cleavage of poly(ADP-ribose) polymerase (PARP). All these data in this study demonstrated that galangin might have therapeutic potential for ischemic stroke and play its protective role through the improvement in rCBF, mitochondrial protection and inhibiting caspase-dependent mitochondrial cell death pathway for the first time.
Highlights
Ischemic stroke is one of the most frequent causes of death and neurological disability [1]
Our results indicated that galangin at doses of 50 and 100 mg·kg−1 exhibited significant neuroprotective activity at 24 h after focal cerebral ischemia in a middle cerebral artery occlusion (MCAO) rat model, both at PM and after MCAO (AM)
When administration of galangin for treatment, there was a remarkable improvement in regional cerebral blood flow (rCBF) after MCAO, which was suspected to be associated with a inhibitor of the vascular Ca(v) 1.2 channels in the literature [13]
Summary
Ischemic stroke is one of the most frequent causes of death and neurological disability [1]. Cerebral ischemia is a common pathological state and has been revealed as one of the causes or key factors contributing to stroke [2]. Restoring the blood supply to the brain as quickly as possible has been considered the most important strategy to treat ischemic stroke. Accumulating evidence has shown that mitochondrial dysfunction plays a pivotal role in cerebral ischemia disorders through its effects on the brain, including energy failure, intracellular calcium overload, oxidative stress and apoptosis. It is essential to evaluate the mitochondrial functions in physiological and pathological conditions to provide more information for the development of new drugs. Scattered regional cerebral blood flow (rCBF) decreases and increases have been reported in mitochondrial disorders [4]. Assays for membrane integrity, membrane fluidity, mitochondrial membrane potential [5] are commonly used for determining mitochondria function
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