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Although stress is one of the risk factors of diabetes, few studies have assessed the effects of stress on diabetic rats. This study, therefore, analyzed differences in cardiovascular-related factors among control, nonstressed diabetic, and stressed diabetic rats as well as assessed the effects of linalyl acetate (LA) on stressed diabetic rats. Male Sprague-Dawley rats were subjected to immobilization stress throughout the experimental period, and diabetes was induced on day 15 by a single injection of streptozotocin. After confirming the induction of diabetes, stressed diabetic rats were administered LA (10 or 100 mg/kg) or metformin (500 mg/kg) for the last 7 days. Compared with nonstressed diabetic rats, stressed diabetic rats had significantly lower body weight, body fat percentage, ACh-induced vasorelaxation, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and NF-κB expression as well as increased serum nitrite concentration. Although metformin increased serum insulin concentration significantly, 100 mg/kg LA showed only an increasing tendency. However, treatment with 100 mg/kg LA not only reduced serum glucose and NF-κB expression, but also restored ACh-induced vasorelaxation, SBP, DBP, HR, AMP-activated protein kinase expression, and serum nitrite almost to control levels. Importantly, 100 mg/kg LA was more effective than metformin in ameliorating serum glucose, endothelial nitric oxide synthase expression, HR, and serum nitrite. These findings suggest that chronic stress can aggravate endothelial dysfunction and hemodynamic alterations in diabetes and that LA may have potent therapeutic efficacy in diabetic patients with cardiovascular disease complications or chronic stress. NEW & NOTEWORTHY To our knowledge, this is the first study to assess the effects of linalyl acetate (LA) on cardiovascular-related factors in diabetic rats exposed to chronic stress. Treatment with LA restored acetylcholine-induced vasorelaxation, blood pressure, heart rate, and AMP-activated protein kinase and serum nitrite levels. The present results suggest that LA may have potent therapeutic efficacy in diabetic patients with complications of cardiovascular disease or chronic stress.

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Calcium-related ischemic injury (CRII) can damage cells of the neurovascular unit (NVU). Here, we investigate the protective effects of linalyl acetate (LA) against CRII-induced NVU damage and evaluate the underlying mechanisms. The protective effects of LA in cell lines representative of NVU components (BEND, SH-SY5Y, BV2, and U373 cells) were evaluated following exposure to oxygen-glucose deprivation/reoxygenation alone (OGD/R-only) or OGD/R in the presence of 5 mM extracellular calcium ([Ca2+]o) to mimic CRII. LA reversed damage under OGD/R-only conditions by blocking p47phox/NADPH oxidase (NOX) 2 expression, reactive oxygen species (ROS) production, nitric oxide (NO) abnormality, and lactate dehydrogenase (LDH) release only in the BEND cells. However, under CRII-mimicking conditions, LA reversed NO abnormality and matrix metalloproteinase (MMP)-9 activation in the BEND murine brain endothelial cells; inhibited p47phox expression in the human SH-SY5Y neural-like cells; decreased NOX2 expression and ROS generation in the BV2 murine microglial cells; and reduced p47phox expression in the U373 human astrocyte-like cells. Importantly, LA protected against impairment of the neural cells, astrocytes, and microglia, all of which are cellular components of the NVU induced by exposure to CRII-mimicking conditions, by reducing LDH release. We found that LA exerted a protective effect in the BEND cells that may differ from its protective effects in other NVU cell types, following OGD/R-induced damage in the context of elevated [Ca2+]o.