Mirtazapine may show anti-hyperglycemic effect by decreasing GLUT2 through leptin and galanin expressions in the liver of type 1 diabetic rats.

OBJECTIVES: The aim of this study was to explore the molecular mechanism of mirtazapine with respect to energy metabolism in Streptozotocin-induced diabetic liver of rats by immunohistochemistry and Western blot. MATERIALS AND METHODS: Twenty-one male Sprague-Dawley rats were assigned into 3 groups including control, type 1 diabetes mellitus (T1DM) group (55 mg/kg Streptozocin, IP) and T1DM+mirtazapine (20 mg/kg,PO) group. At the end of the experiment, blood glucose levels were measured and liver tissues were stained by Periodic acid-Schiff. Moreover, leptin and glucose transporter 2 (GLUT2) proteins were analyzed by western blot and immunohistochemistry; however, galanin were analyzed only by immunohistochemistry. RESULTS: At the end of the study, in diabetes group, blood glucose level, GLUT2 and galanin expressions increased, while leptin expression decreased when compared to control group. Mirtazapine treatment restored the decreased leptin expression, and the increased blood glucose level and galanine expression to the level of the control group. It also decreased the GLUT2 expression even below the control group. CONCLUSION: We concluded that mirtazapine may show its anti-hyperglycemic effect by decreasing GLUT2 through altering the leptin and galanin expression in the liver of type 1 diabetic rats. Mirtazapine can be used as an antidepressant for T1DM patients and as a drug to reduce blood glucose level in T1DM.

Beneficial effect of mirtazapine on diabetes-induced hyperalgesia: involvement of TRPV1 and ASIC1 channels in the spinal cord and dorsal root ganglion.

OBJECTIVES: Neuropathic pain reduces the life qualities of patients with Diabetes mellitus. Clinical guidelines recommend relief in diabetic neuropathic pain through the use of some antidepressants, anticonvulsants, opioids as well as capsaicin cream or lidocaine patches. However, since the majority of patients do not or partially respond to current treatments, there is a growing necessity for new drugs increasing the pain relief in patients with diabetes. Therefore, based on the therapeutic potential of antidepressants on neuropathic pain, we investigated the promising antihyperalgesic effect of mirtazapine (MRT) in painful diabetic neuropathy. METHODS: Experimental diabetes was induced in rats by single intraperitoneal injection of 55 mg/kg dose of streptozocin (STZ). After 4 weeks of injection of STZ, MRT was administrated for 14 days at 40 mg/kg dose. Randall-Selitto and Hargreaves tests were applied for paw-withdrawal threshold and paw-withdrawal latency measurement. TRPV1 and ASIC1 expressions measured by Western blot in dorsal root ganglion and spinal cord. RESULTS: Administration of MRT significantly improved both of the decreased paw-withdrawal threshold and shortened the paw-withdrawal latency of diabetic rats, respectively. Besides, increased levels of TRPV1 and ASIC1 channels in dorsal root ganglion and spinal cord of diabetic rats, evaluated by Western blot method, were decreased following the MRT treatment. DISCUSSION: These data show, for the first time, that MRT has beneficial effects against diabetes-induced hyperalgesia, and that suppressive effect of this drug on TRPV1 and ASIC1 levels, which are increased in diabetic rats, may be some of the pharmacological mechanisms underlying the exhibited antihyperalgesic effect of MRT.

Mirtazapine suppresses sterile inflammation through NLRP3-inflammasome in diabetic rat kidney.

AIM: The aim of this study was to investigate the effects of mirtazapine, which is anti-oxidative and antidepressant agent, on the kidney damage caused by diabetes mellitus. MATERIALS AND METHODS: The rats were randomly divided into three groups (n = 7 animals in each group). The group I rats served as control and they received 0.1 mol/L of citric acid buffer (pH = 4.5) as vehicle. The rats in the group II (DM group) and III (DM + Mirtazapine-treated group) were treated intraperitoneally with a single dose of 55 mg/kg streptozotocin dissolved in 0.1 mol/L of citric acid buffer. Group III rats were also received 20 mg/kg/day of mirtazapine for 2 weeks. At the end of the experiment, the rats were sacrificed. Then, the kidneys were excised and prepared for microscopical examination. caspase-1 and NLRP3 proteins were examined using immunohistochemistry and western blotting. The TUNEL assay for apoptosis and ELISA assay for IL-1ß were performed. RESULTS: Histological examination showed that mirtazapine administration has an ameliorative effect on DM-induced kidney damage. Immunohistochemical and western blot analyses showed that NLRP3 and caspase-1 expressions were increased in the DM group according to the control group and the mirtazapine administration decreased these expressions. The intraglomerular and tubular TUNEL-positive cells were numerous in the DM group compared to the mirtazapine-treated group. The level of IL-1ß was highest in the DM group, and decreased significantly in the mirtazapine-treated group. CONCLUSION: In this study, 20 mg/kg/day mirtazapine administration for 2 weeks reduced NLRP3 and caspase-1 expressions and IL-1ß level in the diabetic rat kidneys. These results suggesting that mirtazapine may be useful in the treatment of DM and other metabolic diseases. Advanced molecular studies are needed to elucidate the exact effects of mirtazapine on NLRP3 inflammasome.

Neuroprotective Effect of Genistein in Peripheral Nerve Injury.

AIM: To investigate the effects of genistein in a rat model of sciatic nerve crush injury and complete sciatic nerve transection. The effects of genistein were compared with those of gabapentin, which is widely used in clinical practice for peripheral nerve injury. MATERIAL AND METHODS: Forty-eight rats were randomly divided into six groups (8 rats in each group): group 1 (sham); group 2, sciatic nerve crush injury (control); group 3, sciatic nerve crush injury+genistein 20 mg/kg; group 4, sciatic nerve crush injury+gabapentin 90 mg/kg; group 5, sciatic nerve transection+genistein 20 mg/kg; group 6, sciatic nerve transection+gabapentin 90 mg/kg. The effects of genistein and gabapentin were assessed with immunohistochemical staining for growth associated protein-43 (GAP-43) and myelin basic protein (MBP). Interleukin-1ß and tumor necrosis factor α levels in the injured nerve specimens were assessed as a measure of inflammatory response; walking track analysis and sciatic function index for neurological recovery and the paw mechanical withdrawal threshold were examined for neuropathic pain. RESULTS: On histopathological examination, genistein use was associated with a greater immunoreactivity for GAP-43 and MBP compared with that associated with gabapentin. Genistein and gabapentin had similar effects on anti-inflammatory activity, functional recovery, and neuropathic pain. CONCLUSION: Genistein and gabapentin exhibit positive effects on histopathology, inflammation, and clinical findings of peripheral nerve injury. When the systemic side effects of gabapentin are considered, genistein (a basic soy isoflavone that has no side effects) can be used as an alternative to medical treatment in peripheral nerve injury.

Characterization of dorsal root ganglion neurons cultured on silicon micro-pillar substrates.

Our study focuses on characterization of dorsal root ganglion (DRG) neurons cultured on silicon micro-pillar substrates (MPS) with the ultimate goal of designing micro-electrode arrays (MEAs) for successful electrophysiological recordings of DRG neurons. Adult and neonatal DRG neurons were cultured on MPS and glass coverslips for 7 days in vitro. DRG neuronal distribution and morphometric analysis, including neurite alignment and length, was performed on MPS areas with different pillar width and spacing. We showed that MPS provide an environment for growth of adult and neonatal DRG neurons as permissive as control glass surfaces. Neonatal DRG neurons were present on MPS areas with narrow pillar spacing, while adult neurons preferred wider pillar spacing. Compared to the control glass surfaces the neonatal and adult DRG neurons in regions with narrow pillar spacing range developed a smaller number of longer neurites. In the same area, neurites were preferentially oriented along three directional axes at 30°, 90° and 150°. MPS architecture influenced growth directionality of all main DRG neuronal subtypes. We can conclude that specific micro-pillar substrate topography affects the morphology of DRG neurons. This knowledge can enable development of MEAs with precisely defined physical features for various neuroscience applications.

Resveratrol reduces IL-6 and VEGF secretion from co-cultured A549 lung cancer cells and adipose-derived mesenchymal stem cells.

Stem cell therapies are important treatment methodologies used in many areas of experimental or clinical medicine. In recent studies of cancer models, Mesenchymal stem cells (MSCs) suppressed the growth of cancer cells. However, also in some studies, stem cell treatments have been shown to induce cancer formation, increase tumor volume, induce the formation of new vessels, and lead to cancer invasion. The presence of MSC-secreted cytokines and their effects on cancer cells limits the reliability of MSC-based treatments. Resveratrol (trans-3,5,4'-trihydroxystilbene), an antioxidant found in red wine, has been shown to have therapeutic effects against several cancers. The aim of this study was to co-culture MSCs with A549 cancer cells to suppress the release of cancer-promoting cytokines from MSCs and to increase the applicability and reliability of stem cell therapies with resveratrol. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and neutral red cell viability assays were used to find safety dose of resveratrol. The MSCs secreted the cytokines IL-6 and VEGF, and the effect of resveratrol on these cytokines was analyzed by ELISA and western blot analysis of conditioned medium. One µM of resveratrol was found to be the safety dose for the A549 cancer cells and MSCs. We observed the highest release of IL-6 and VEGF from the co-cultured A549 cells and MSCs, and resveratrol was found to significantly decrease the release of these cytokines. Our study suggests that resveratrol exerts a positive effect on the release of cytokines. The safety dose of resveratrol can be administered together with stem cells during stem cell treatment.

Effects of nonsteroidal anti-inflammatory meloxicam on stomach, kidney, and liver of rats.

Nonsteroidal anti-inflammatory (NSAI) drugs are the most commonly used group of drugs today. Increase in the use of standard NSAI for treating pain and inflammation was restricted by the fact that these drugs were proven to possibly cause gastrointestinal and renal toxicity. Meloxicam is a NSAI that has anti-inflammatory, analgesic, and antipyretic effects. This study aims to investigate the effects of meloxicam on stomach, kidney, and liver of rats under light microscopy level. Based on the light microscopic observations, mononuclear cell infiltration and pseudolobular formation was established in liver samples of animals in the experimental group. Metaplasia in surface and glandular epithelia and atrophy were observed in stomach samples. Glomerular stasis-related hypertrophy and focal interstitial nephritis were found in kidneys. It was concluded in this study that meloxicam might cause hepatotoxicity, nephrotoxicity, and gastric metaplasia in rats at a used dose and duration.