Modulation of Diabetes-Induced Oxidative Stress, Apoptosis, and Ca2+ Entry Through TRPM2 and TRPV1 Channels in Dorsal Root Ganglion and Hippocampus of Diabetic Rats by Melatonin and Selenium

Abstract

Neuropathic pain and hippocampal injury can arise from the overload of diabetes-induced calcium ion (Ca) entry and oxidative stress. The transient receptor potential (TRP) melastatin 2 (TRPM2) and TRP vanilloid type 1 (TRPV1) are expressed in sensory neurons and hippocampus. Moreover, activations of TRPM2 and TRPV1 during oxidative stress have been linked to neuronal death. Melatonin (MEL) and selenium (Se) have been considered potent antioxidants that detoxify a variety of reactive oxygen species (ROS) in neurological diseases. In order to better characterize the actions of MEL and Se in diabetes-induced peripheral pain and hippocampal injury through modulation of TRPM2 and TRPV1, we tested the effects of MEL and Se on apoptosis and oxidative stress in the hippocampal and dorsal root ganglion (DRG) neurons of streptozotocin (STZ)-induced diabetic rats. Fifty-eight rats were divided into six groups. The first group was used as control. The second group was used as the diabetic group. The third and fourth groups received Se and MEL, respectively. Intraperitoneal Se and MEL were given to diabetic rats in the fifth and sixth groups. On the 14th day, hippocampal and DRG neuron samples were freshly taken from all animals. The neurons were stimulated with a TRPV1 channel agonist (capsaicin) and a TRPM2 channel agonist (cumene hydroperoxide). We observed a modulator role of MEL and Se on intracellular free Ca concentrations, current densities of TRPM2 and TRPV1 channels, apoptosis, caspase 3, caspase 9, mitochondrial depolarization, reduced glutathione, glutathione peroxidase, lipid peroxidation, and intracellular ROS production values in the neurons. In addition, procaspase 3 and 9 activities in western blot analyses of the brain cortex were also decreased by MEL and Se treatments. In conclusion, in our diabetes experimental model, TRPM2 and TRPV1 channels are involved in the Ca entry-induced neuronal death and modulation of this channel activity by MEL and Se treatment may account for their neuroprotective activity against apoptosis and Ca entry. Graphical Abstract Possible molecular pathways of involvement of melatonin and selenium in diabetes-induced apoptosis, oxidative stress, and calcium accumulation through TRPM2 and TRPV1 channels in the hippocampus and DRG neurons of rats. The TRPM2 channel is activated by ADP-ribose and oxidative stress although it is inhibited by ACA. The TRPV1 channel is activated by oxidative stress and capsaicin and it is blocked by capsazepine (CPZ). Diabetes can result in augmented ROS release in hippocampal and DRG neurons through polyol reactions, leading to Ca uptake through TRPM2 and TRPV1 channels. Mitochondria were reported to accumulate Ca provided intracellular Ca rises, thereby leading to the depolarization of mitochondrial membranes and release of apoptosis-inducing factors such as caspase 3 and caspase 9. Melatonin and selenium reduce TRPM2 and TRPV1 channel activation through the modulation of polyol oxidative reactions and selenium-dependent glutathione peroxidase (GSH-Px) ...

The neuroprotective action of dexmedetomidine on apoptosis, calcium entry and oxidative stress in cerebral ischemia-induced rats: Contribution of TRPM2 and TRPV1 channels

“…Excessive production of mitochondrial ROS and an overload of Ca 2+ through increased TRPM2 and TRPV1 channel activity are two of the main causes of neurodegenerative diseases in hippocampus and induction of peripheral pain in DRG (Fig. 8)51017. The aim of the study was to evaluate whether DEX functionally interacts with TRPM2 and TRPV1 in the HIPPO and DRG neurons of rats with cerebral ischemia.…”

“…Additionally, the persistent Ca 2+ current contributes to the propagation of brain injury-induced apoptosis, as indicated by the current results. In recent years, it has become clear that several experimental and pathological conditions can significantly increase the persistence of the TRPM2 and TRPV1 channel currents in the brain617. On this basis, DEX’s inhibition of the TRPM2 and TRPV1 currents contributes to the prevention or limitation of brain injuries during cerebral ischemia.…”

“…Mounting evidence indicates that production of free oxygen radicals and stimulation of apoptotic caspase 3 and 9 pathways are increased in the hippocampus and DRG by increased mitochondrial membrane depolarization (Fig. 8)517. This is because the neurons have poor antioxidant content but high oxygen consumption and polyunsaturated fatty acid content.…”

“…We used whole-cell mode of patch-clamp techniques in EPC10 patch-clamp set (HEKA, Lamprecht, Germany)17. Resistances of whole cell recording electrodes were 3–7 MΩ.…”

“…As a result, ADPR production in the brains of cerebral ischemia-induced rats increased16. Prevention of apoptotic cascades through inhibition of the TRPM2 and TRPV1 in the hippocampal (HIPPO) and DRG neurons of rats were more recently reported517. These later results raised the possibility that HIPPO and DRG neuron apoptosis mediated by the TRPM2 and TRPV1 channels could also contribute to cerebral ischemia injuries, as accumulating evidence suggests their involvement in cerebral ischemia and SCI, including oxidative stress induced by the TRPM2 and TRPV1 channels25.…”