Menthol is a common compound in pharmaceutical and commercial products and a popular additive to cigarettes. The molecular targets of menthol remain poorly defined. In this study we show an effect of menthol on the α7 subunit of the nicotinic acetylcholine (nACh) receptor function. Using a two-electrode voltage-clamp technique, menthol was found to reversibly inhibit α7-nACh receptors heterologously expressed in Xenopus oocytes. Inhibition by menthol was not dependent on the membrane potential and did not involve endogenous Ca2+-dependent Cl− channels, since menthol inhibition remained unchanged by intracellular injection of the Ca2+ chelator BAPTA and perfusion with Ca2+-free bathing solution containing Ba2+. Furthermore, increasing ACh concentrations did not reverse menthol inhibition and the specific binding of [125I] α-bungarotoxin was not attenuated by menthol. Studies of α7- nACh receptors endogenously expressed in neural cells demonstrate that menthol attenuates α7 mediated Ca2+ transients in the cell body and neurite. In conclusion, our results suggest that menthol inhibits α7-nACh receptors in a noncompetitive manner.

Ischemic stroke is characterized by permanent or transient obstruction of blood flow, which initiates a cascading pathological process, starting from acute ATP loss and ionic imbalance to subsequent membrane depolarization, glutamate excitotoxicity, and calcium overload. These initial events are followed by neuroinflammation and oxidative stress, eventually causing neuronal neurosis and apoptosis. Complicated interplays exist between these steps happening across various stages, which not only represent the complicated nature of ischemic pathology but also warrant a detailed delineation of the underlying molecular mechanisms to develop better therapeutic options. In the present study, we examined the neuroprotective effects of polydatin against ischemic brain injury using a rat model of permanent middle cerebral artery occlusion (MCAO). Our results demonstrated that polydatin treatment reduced the infarction volume and mitigated the neurobehavioral deficits, sequentially rescued neuronal apoptosis. Ischemic stroke induced an elevation of neuroinflammation and reactive oxygen species, which could be attenuated by polydatin via the reduced activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase. In addition, polydatin upregulated the endogenous antioxidant nuclear factor erythroid 2-related factor 2, heme oxygenase-1, the thioredoxin pathway, and eventually reversed ischemic-stroke-induced elevation of ROS and inflammation in ischemic cortical tissue. The diverse and broad actions of polydatin suggested that it could be a multiple targeting neuroprotective agent in ameliorating the detrimental effects of MCAO, such as neuroinflammation, oxidative stress, and neuronal apoptosis. As repetitive clinical trials of neuroprotectants targeting a single step of stroke pathological process have failed previously, our results suggested that a neuroprotective strategy of acting at different stages may be more advantageous to intervene in the vicious cycles in MCAO.

In the heart, the left ventricle pumps blood at higher pressure than the right ventricle. Within the left ventricle, the electromechanical properties of ventricular cardiac myocytes vary transmurally and this may be related to the gradients of stress and strain experienced in vivo across the ventricular wall. Diabetes is also associated with alterations in hemodynamic function. The aim of this study was to investigate shortening and Ca2+ transport in epicardial (EPI) and endocardial (ENDO) left ventricular myocytes in the streptozotocin (STZ)‐induced diabetic rat. Shortening, intracellular Ca2+ and L‐type Ca2+ current (I Ca,L) were measured by video detection, fura‐2 microfluorimetry, and whole‐cell patch clamp techniques, respectively. Time to peak (TPK) shortening was prolonged to similar extents in ENDO and EPI myocytes from STZ‐treated rats compared to ENDO and EPI myocytes from controls. Time to half (THALF) relaxation of shortening was prolonged in ENDO myocytes from STZ‐treated rats compared to ENDO controls. TPK Ca2+ transient was prolonged in ENDO myocytes from STZ‐treated rats compared to ENDO controls. THALF decay of the Ca2+ transient was prolonged in ENDO myocytes from STZ‐treated rats compared to ENDO controls. Sarcoplasmic reticulum (SR) fractional release of Ca2+ was reduced in EPI myocytes from STZ‐treated rats compared to EPI controls. IC a,L activation, inactivation, and recovery from inactivation were not significantly altered in EPI and ENDO myocytes from STZ‐treated rats or controls. Regional differences in Ca2+ transport may partly underlie differences in ventricular myocyte shortening across the wall of the healthy and the STZ‐treated rat left ventricle.

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Diabetic cardiomyopathy is considered to be one of the major diabetes-associated complications, and the pathogenesis of cardiac dysfunction is not well understood. The electromechanical properties of cardiac myocytes vary across the walls of the chambers. The aim of this study was to investigate shortening and Ca transport in epicardial (EPI) and endocardial (ENDO) left ventricular myocytes in the Goto-Kakizaki (GK) type 2 diabetic rat heart. Shortening and intracellular Ca transients were measured by video edge detection and fluorescence photometry. Myocyte surface area was increased in EPI-GK and ENDO-GK compared with control EPI-CON and ENDO-CON myocytes. Time to peak shortening was prolonged in EPI-GK compared with EPI-CON and in ENDO-CON compared with EPI-CON myocytes. Time to half-relaxation of shortening and time to peak Ca transient were prolonged in EPI-GK compared with EPI-CON myocytes. Time to half-decay of the Ca transient was prolonged in EPI-CON compared with EPI-GK and in EPI-CON compared with ENDO-CON myocytes. The amplitude of shortening and the Ca transient were unaltered in EPI-GK and ENDO-GK compared with their respective controls. Sarcoplasmic reticulum Ca and myofilament sensitivity to Ca were unaltered in EPI-GK and ENDO-GK compared with their respective controls. Regional differences in Ca signalling in healthy and diabetic myocytes might account for variation in the dynamics of myocyte shortening. Further studies will be required to clarify the mechanisms underlying regional differences in the time course of shortening and the Ca transient in EPI and ENDO myocytes from diabetic and control hearts.

Diabetes mellitus is a major global health disorder and, currently, over 450 million people have diabetes with 90% suffering from type 2 diabetes. Left untreated, diabetes may lead to cardiovascular diseases which are a leading cause of death in diabetic patients. Calcium is the trigger and regulator of cardiac muscle contraction and derangement in cellular Ca homeostasis, which can result in heart failure and sudden cardiac death. It is of paramount importance to investigate the regional involvement of Ca in diabetes-induced cardiomyopathy. Therefore, the aim of this study was to investigate the voltage dependence of the Ca transients in endocardial (ENDO) and epicardial (EPI) myocytes from the left ventricle of the Goto-Kakizaki (GK) rats, an experimental model of type 2 diabetes mellitus. Simultaneous measurement of L-type Ca currents and Ca transients was performed by whole-cell patch clamp techniques. GK rats displayed significantly increased heart weight, heart weight/body weight ratio, and non-fasting and fasting blood glucose compared to controls (CON). Although the voltage dependence of L-type Ca current was unaltered, the voltage dependence of the Ca transients was reduced to similar extents in EPI-GK and ENDO-GK compared to EPI-CON and ENDO-CON myocytes. TPK L-type Ca current and Ca transient were unaltered. THALF decay of L-type Ca current was unaltered; however, THALF decay of the Ca transient was shortened in ENDO and EPI myocytes from GK compared to CON rat hearts. In conclusion, the amplitude of L-type Ca current was unaltered; however, the voltage dependence of the Ca transient was reduced to similar extents in EPI and ENDO myocytes from GK rats compared to their respective controls, suggesting the possibility of dysfunctional sarcoplasmic reticulum Ca transport in the GK diabetic rat hearts.

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