Diabetes mellitus is known to exacerbate cerebral ischemic injury. In the present study, we investigated antiapoptotic and anti-inflammatory effects of oral supplementation of ascorbic acid (AA) on cerebral injury caused by middle cerebral artery occlusion and reperfusion (MCAO/Re) in rats with streptozotocin-induced diabetes. We also evaluated the effects of AA on expression of sodium-dependent vitamin C transporter 2 (SVCT2) and glucose transporter 1 (GLUT1) after MCAO/Re in the brain. The diabetic state markedly aggravated MCAO/Re-induced cerebral damage, as assessed by infarct volume and edema. Pretreatment with AA (100 mg/kg, p.o.) for two weeks significantly suppressed the exacerbation of damage in the brain of diabetic rats. AA also suppressed the production of superoxide radical, activation of caspase-3, and expression of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) in the ischemic penumbra. Immunohistochemical staining revealed that expression of SVCT2 was upregulated primarily in neurons and capillary endothelial cells after MCAO/Re in the nondiabetic cortex, accompanied by an increase in total AA (AA + dehydroascorbic acid) in the tissue, and that these responses were suppressed in the diabetic rats. AA supplementation to the diabetic rats restored these responses to the levels of the nondiabetic rats. Furthermore, AA markedly upregulated the basal expression of GLUT1 in endothelial cells of nondiabetic and diabetic cortex, which did not affect total AA levels in the cortex. These results suggest that daily intake of AA attenuates the exacerbation of cerebral ischemic injury in a diabetic state, which may be attributed to anti-apoptotic and anti-inflammatory effects via the improvement of augmented oxidative stress in the brain. AA supplementation may protect endothelial function against the exacerbated ischemic oxidative injury in the diabetic state and improve AA transport through SVCT2 in the cortex.
BackgroundGanoderma lucidum is a popular medicinal mushroom used for promoting health and longevity in Asian countries. Previously, we reported that a water-soluble extract from a culture medium of Ganoderma lucidum mycelia (MAK) exerts antioxidative and cerebroprotective effects against ischemia–reperfusion injury in vivo. Here, we evaluated the antidepressant and anxiolytic activities of MAK in rats.MethodsMAK (0.3 or 1 g/kg, p.o.) was administered in the experimental animals 60 min before the forced swimming, open-field, elevated plus-maze, contextual fear-conditioning, and head twitch tests. Additionally, the mechanisms involved in the antidepressant-like action of MAK were investigated by the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP)- or 5-HT2A agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI)-induced head twitch responses.ResultsTreatment with MAK (1 g/kg) exhibited antidepressant-like effects in the forced swimming test, attenuated freezing behavior in the contextual fear-conditioning test, and decreased the number of head twitches induced by DOI, but not with 5-HTP. No significant response was observed in locomotion or anxiety-like behavior, when the animals were evaluated in the open-field or elevated plus-maze test, respectively.ConclusionsThese data suggest that MAK has antidepressant-like potential, which is most likely due to the antagonism of 5-HT2A receptors, and possesses anxiolytic-like effects toward memory-dependent and/or stress-induced anxiety in rats.
The water-soluble extract of Ganoderma lucidum mycelia (WER) is prepared from a solid medium composed of bagasse and rice bran overgrown with Ganoderma lucidum mycelia. Recently, we reported that WER shows a blood glucose-lowering effect in maltose-loaded non-diabetic mice. Here, we investigated the efficacy of WER in type 2 diabetic state using KK-A y mice. Moreover, the food-drug interactions of WER with α-glucosidase inhibitors, voglibose or acarbose were examined using both in vitro and in vivo experiments. Methods: The glucose-lowering effects of oral administration in vivo of WER alone, or concomitant administration of WER with voglibose/acarbose on the elevation of blood glucose levels by sugar-tolerance tests were examined in KK-A y mice. The inhibitory effects on α-glucosidase in vitro were also evaluated. Results: Oral administration of WER (1 g/kg), which did not affect fasting blood glucose, significantly suppressed the hyperglycemia after loading of maltose (18% of decrease in AUC) compared to the water-administrated control mice. In vitro study showed that WER inhibited maltase in concentration-dependent manner. The inhibitory effects of lower concentrations of voglibose or acarbose on α-glucosidase activity were additively enhanced by the presence of WER, but those of higher concentrations were not affected. The glucose-lowering effect of voglibose (0.1 mg/kg) disappeared in maltose-loaded KK-A y mice when the drug was concomitantly administrated with WER (1 g/kg), whereas acarbose (16 mg/kg) with WER showed no significant change in its effect. Conclusion: These results demonstrated that WER shows the glucose-lowering effect in maltose-loaded KK-A y , which may be based on inhibition of the α-glucosidase activity. The present study suggests that concomitant intake of WER with voglibose may override the therapeutic effect of voglibose on postprandial hyperglycemia by food-drug interaction in diabetic state.
Ferulic acid (FA), a phenolic phytochemical, has been reported to exert antioxidative and neuroprotective effects. In this study, we investigated the protective effects of FA against the dysfunction of the swallowing reflex induced by ligation of bilateral common carotid arteries (2VO) in rats. In 2VO rats, topical administration of water or citric acid to the pharyngolaryngeal region evoked a diminished number of swallowing events with prolonged latency compared to sham-operated control rats. 2VO rats had an increased level of superoxide anion radical, and decreased dopamine and tyrosine hydroxylase enzyme levels in the striatum, suggesting that 2VO augmented cerebral oxidative stress and impaired the striatal dopaminergic system. Furthermore, substance P (SP) expression in the laryngopharyngeal mucosa, which is believed to be positively regulated by dopaminergic signaling in the basal ganglia, was decreased in 2VO rats. Oral treatment with FA (30 mg/kg) for 3 weeks (from one week before 2VO to two weeks after) improved the swallowing reflex and maintained levels of striatal dopamine and laryngopharyngeal SP expression in 2VO rats. These results suggest that FA maintains the swallowing reflex by protecting the dopamine-SP system against ischemia-induced oxidative damage in 2VO rats.
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