Anti-Inflammatory and Antipruritic Effects of Remote Ischaemic Postconditioning in a Mouse Model of Experimental Allergic Contact Dermatitis.

Background and Objectives: Allergic contact dermatitis is a common type IV hypersensitivity reaction characterised by redness, itching, oedema and thickening of the skin. It occurs in about 7% of the population and its incidence is increasing. It has been observed that the preconditioning of tissues by exposing them to transient ischemia increases resistance to subsequent permanent ischemia, and this phenomenon is called ischemic preconditioning. It has been shown that conditioning in one organ can also protect other organs. The protective effect of remote ischemic preconditioning is thought to be based on the induction of anti-inflammatory responses. The aim of this project was to investigate the anti-inflammatory and antipruritic effects of remote ischemic postconditioning in a mouse model of experimental allergic contact dermatitis. Methods: Experimental allergic contact dermatitis was induced with 1-fluoro-2,4-dinitrobenzene. Remote ischemic postconditioning was performed at 3 and 25 h after the challenge. Ear thickness and number of scratches 24 and 48 h after challenge, as well as cytokine levels and the infiltration of mast cells, neutrophils, CD4+ and CD8+ T lymphocytes in serum and ear tissue at 48 h were measured to determine the effect of RIPsC. Results: Remote ischemic postconditioning decreased ear thickness, one of the symptoms of allergic contact dermatitis (p < 0.0001). It had no significant effect on the number of scratches. It reduced serum IL-17 levels (p < 0.01). It alleviated local inflammation by suppressing CD8+ T lymphocyte and neutrophil infiltration. Conclusions: It was concluded that remote ischemic postconditioning may alleviate the symptoms of allergic contact dermatitis by suppressing CD8+ T lymphocyte and neutrophil infiltration and reducing IL-17 secretion.

Does Oral Monosodium Glutamate Have a Cochleotoxic Effect? An Experimental Study.

INTRODUCTION: The effect of orally consumed monosodium glutamate (MSG), which is a common additive in the food industry, on the cochlea has not been investigated. The present study aimed to investigate the possible cochleotoxic effects of oral MSG in guinea pigs using electrophysiological, biochemical, and histopathological methods. METHODS: Thirty guinea pigs were equally divided into control and intervention groups (MSG 100 mg/kg/day; MSG 300 mg/kg/day). At 1 month, 5 guinea pigs from each group were sacrificed; the rest were observed for another month. Electrophysiological measurements (distortion product otoacoustic emission [DPOAE] and auditory brainstem response [ABR]), glutamate levels in the perilymph and blood samples, and histopathological examinations were evaluated at 1 and 2 months. RESULTS: Change in signal-to-noise ratio at 2 months was significantly different in the MSG 300 group at 0.75 kHz and 2 kHz (p = 0.013 and p = 0.044, respectively). There was no statistically significant difference in ABR wave latencies of the guinea pigs given MSG compared to the control group after 1 and 2 months; an increase was noted in ABR thresholds, although the difference was not statistically significant. In the MSG groups, moderate-to-severe degeneration and cell loss in outer hair cells, support cells, and spiral ganglia, lateral surface junction irregularities, adhesions in stereocilia, and partial loss of outer hair cell stereocilia were noted. CONCLUSION: MSG, administered in guinea pigs at a commonly utilized quantity and route of administration in humans, may be cochleotoxic.

Endocannabinoid and N-acylethanolamide levels in rat brain and spinal cord following systemic dipyrone and paracetamol administration.

The cannabinoid system has been suspected to play a role in the mechanisms of action of dipyrone and paracetamol. Our purpose was to measure the local endocannabinoid and N-acylethanolamide levels in the brain and spinal cord of rats following dipyrone and paracetamol administration. Nociception was assessed 1, 5, and 12 h following drug injections in Wistar rats, using tail-flick and hot-plate tests. The antinociceptive effects of dipyrone (150, 300, and 600 mg/kg, i.p.) and paracetamol (30, 100, and 300 mg/kg, i.p.) were observed. After administration of the highest doses of dipyrone and paracetamol, endocannabinoid (N-arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG)) and N-acylethanolamide (palmitoylethanolamide (PEA), oleoylethanolamide (OEA)) levels were measured in the periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and spinal cords of rats using tandem mass spectrometry with liquid chromatography. Increased 2-AG levels were observed in the PAG and the RVM 12 h after paracetamol injection; dipyrone exerted no action on 2-AG levels. Analgesic administrations led to a reduction in AEA levels in the RVM and spinal cord; similar decreases in PEA and OEA levels were observed in the RVM and the spinal cord. Dipyrone and paracetamol administrations appear to exert complicated effects on endocannabinoid and N-acylethanolamide levels in rats.

Could serum endocannabinoid and N-acylethanolamine levels be important in bipolar disorder?

OBJECTIVES: The endocannabinoid system (ECS) is a critical important neuromodulatory system that interacts with many neurohormonal and neurotransmitter systems in the brain. It plays a pivotal role in emotional responses and mood regulation. The ECS is related with psychotic disorders, depression, anxiety and autism. In this study, we aimed to investigate whether there is any relationship between endocannabinoid and N-acylethanolamine levels with bipolar disorder. METHODS: Seventy-nine patients with bipolar disorder diagnosis, who are in the euthymic period, were included in the study. Clinical characteristics, symptoms and serum endocannabinoid and N-acylethanolamine levels were compared. Endocannabinoid and N-acylethanolamine levels were evaluated using liquid chromatography-tandem mass spectrometry. RESULTS: In total of 79 patients, 44 (55.69%) were females and 35 (44.30%) were males. The mean age of the patients was 42.40 ± 1.10 years. Palmitoylethanolamide (PEA) levels were higher and oleoylethanolamide and 2-arachidonyl glycerol levels were lower in patients who had at least one depressive episode during their life-time illness than in patients who had no depressive episode while arachidonyl ethanolamide levels were unchanged. CONCLUSIONS: PEA levels were correlated with the history and frequency of depressive episodes and the history of depressive symptoms in patients with bipolar disorder.

The therapeutic effects of transferring remote ischemic preconditioning serum in rats with neuropathic pain symptoms.

Background and objectives: Neuropathic pain is defined as pain caused by damage to the nerve as a result of a lesion or disease. It has been shown that ischemic preconditioning exerts a protective role in various tissue injuries; however, the effect of transplantation of remote ischemic preconditioning serum (RIPCs) on neuropathic pain symptoms has not been studied. The aim of this project is to investigate the effect of RIPCs transfusion by different routes of administration on neuropathic pain symptoms. Our secondary aim was to demonstrate the role of Schwann cells in the regeneration of sciatic nerve injury and to evaluate the change in the number of glial cells in the spinal cord dorsal horn. Methods: The sciatic nerve partial ligation method was used to induce neuropathic pain. Changes in neuropathic pain symptoms were assessed by measuring thermal hyperalgesia and mechanical allodynia. To determine the possible therapeutic site, alterations in the number of spinal cord lumbar posterior horn microglia and astrocytes were evaluated by ionized calcium-binding adapter molecule 1 (iba1) and glial fibrillary acidic protein (GFAP) immunostaining. Myelin basic protein immunohistochemistry was also used to assess Schwann cell immunoreactivity in the sciatic nerve. Results: In rats that underwent partial sciatic nerve ligation, neuropathic pain symptoms developed on average on day 12 and persisted up to day 21 (p < 0.0001). RIPCs administered intravenously for five days reduced thermal hyperalgesia more than intraperitoneal and subcutaneous administration (p < 0.05). Both central glial cells appear to play a role in the effect of RIPCs. RIPCs treatment increases Schwann cell remyelination. Conclusions: Our results showed that intravenously administered RIPCs remarkably improved the neuropathic pain symptoms, thermal hyperalgesia and mechanical allodynia. Further studies are needed to evaluate the role of RIPCs transfusion on glial cells.

The Effect of Ceftriaxone in Valproic Acid-Induced Mouse Model of Autism.

Purpose: Autism is a multifactorial neurodevelopment disease and it has not been disclosed as a hypoglutamatergic or hyperglutamathergic disease. Ceftriaxone is an antibiotic that increases glutamate transporter-1 (GLT-1) expression in the brain in chronic use. In our study we aimed to investigate the effects of different doses of ceftriaxone in postnatal period in male mice exposed to valproic acid (VPA) at 12.5th day of pregnancy. Methods: A total of 96 BALB/c male mice were divided into 12 groups (n = 8 animals per group). Ceftriaxone (50, 100, 200 mg/kg/d) or saline was given to the male offsprings born from pregnant mice administered VPA and/or saline, between days 47 and 55. Dihydrokainic acid (10 mg/kg), a GLT-1 inhibitor, was administered intraperitoneally to evaluate whether GLT-1 mediates the effect of ceftriaxone. Three chamber sociability and social interaction test and the rota rod test were performed in all groups on days 54 and 55. GLT-1 levels in the hippocampus were measured by immunohistochemistry (IHC) and western blotting (WB). Results: In our study, autism-like behaviors were observed in male offsprings that were exposed to VPA in the intrauterine period. Chronic ceftriaxone administration has no curative effect on behavioral impairment seen in autism. Conclusion: Our results show that ceftriaxone did not exert significant therapeutic effect on VPA-induced mouse model of autism.

The role of endocannabinoid system and TRPV1 receptors in the antidepressant and anxiolytic effects of dipyrone in chronic unpredictable mild stress in mice.

Although dipyrone is a widely used analgesic and antipyretic, its mechanism of action is not fully clarified. Recent studies have drawn attention to its central effects and its relationship with the endocannabinoid system. The endocannabinoid system plays important roles in processes such as anxiety, depression, fear, and learning-memory. In this study, we aimed to investigate whether endocannabinoid levels change in the amygdala in chronic unpredictable mild stress model in mice and whether cannabinoid and TRPV1 receptors mediate antidepressant and anxiolytic effects of dipyrone. Mice were submitted to chronic unpredictable mild stress protocol of 6-weeks, then behavioral test were performed. In the first part of the study, dipyrone was injected at doses of 150, 300, and 600 mg/kg (i.p.) during behavioral tests. In the second part, the CB1 antagonist AM 251 (1 mg/kg, i.p.), the CB2 antagonist AM630 (1 mg/kg, i.p.), and the TRPV1 antagonist capsazepine (3 mg/kg, i.p.) were administered alone or in combination with 300 mg/kg dipyrone to observe if these receptors mediate dipyrone effects. Endocannabinoid and N-acylethanolamines levels were measured by LC-MS/MS in amygdala. Our results showed that there were no changes in AEA, 2-AG, PEA, OAE levels in the amygdala in mice exposed to chronic unpredictable mild stress model; dipyrone exerted antidepressant and anxiolytic effects at doses of 300 and 600 mg/kg; its anxiolytic effect appears to be mediated via CB1 receptors, whereas TRPV1 receptors seems to mediate its antidepressant action.

Effects of hippocampal histone acetylation and HDAC inhibition on spatial learning and memory in the Morris water maze in rats.

In recent years, it has been pointed out that epigenetic changes affect learning and memory formation. Particularly, it has been shown that histone acetylation and DNA methylation work in concert to regulate learning and memory formation. We aimed to examine whether acetylation of H2B within the rat hippocampus alters by trainings in the Morris water maze test. Male, 2-3 months old, Sprague Dawley rats were trained in Morris water maze task. Animals were given four trials per day for five consecutive days to locate a hidden platform. On the sixth day, the platform was removed and the animals were swum for 60 s. The effects of sodium butyrate, histone deacetylase inhibitor, were tested on normal and scopolamine-induced memory-impaired rats. The histone deacetylase inhibitor, sodium butyrate, increased histone H2B acetylation in normal rats. Sodium butyrate had no effect on learning and memory performance of normal rats; however, it partially ameliorated learning and memory disruption induced by scopolamine. So, the histone deacetylase inhibitors can be new treatment agent for cognitive disorders.

Non-opioid Analgesics and the Endocannabinoid System

Non-steroidal anti-inflammatory drugs produce antinociceptive effects mainly through peripheral cyclooxygenase inhibition. In opposition to the classical non-steroidal anti-inflammatory drugs, paracetamol and dipyrone exert weak anti-inflammatory activity, their antinociceptive effects appearing to be mostly due to mechanisms other than peripheral cyclooxygenase inhibition. In this review, we classify classical non-steroidal anti-inflammatory drugs, paracetamol and dipyrone as "non-opioid analgesics" and discuss the mechanisms mediating participation of the endocannabinoid system in their antinociceptive effects. Non-opioid analgesics and their metabolites may activate cannabinoid receptors, as well as elevate endocannabinoid levels through different mechanisms: reduction of endocannabinoid degradation via fatty acid amide hydrolase and/or cyclooxygenase-2 inhibition, mobilization of arachidonic acid for the biosynthesis of endocannabinoids due to cyclooxygenase inhibition, inhibition of endocannabinoid cellular uptake directly or through the inhibition of nitric oxide synthase production, and induction of endocannabinoid release.

Effect of mitomycin-C applied through different approaches following tracheal surgery on development of granulation tissue and level of nephrotoxicity in rats.

BACKGROUND: This study aims to evaluate the effect of mitomycin-C applied through different drug administration approaches on the development of granulation tissue in the field of surgery and renal functions in rats which underwent tracheal surgery. METHODS: Fifty male adult Sprague Dawley rats (weighing mean 200 g to 300 g) were divided into five groups. An incision was performed between the fifth and sixth cartilage ring of the trachea in all groups under anesthesia and the incision was primarily repaired with a 6/0 monofilament absorbable suture. A single dose of mitomycin-C 0.5 mg was applied in the experimental animals appropriate with their assigned groups as topical, intraperitoneal injection, injection to the wound edges, and through inhalation. No mitomycin-C was administered in one group which was accepted as the control group. Rats were sacrificed four weeks after surgery and their tracheas were excised subsequently. Tracheal tissue samples were histopathologically evaluated in terms of epithelization, fibrosis, amount of fibroblasts, angiogenesis, and inflammatory response. Diameter and wall thickness of the tracheas were measured. Blood urea and creatinine levels were evaluated for nephrotoxicity, and the rats were immunohistochemically examined for glomerular pathology. RESULTS: Epithelization was statistically significantly decelerated (p<0.01), diameter of the trachea was statistically significantly larger (p<0.05), and wall thickness of the trachea was significantly thicker in the group with topical mitomycin-C application compared to the control group (p<0.01). CONCLUSION: Topically applied mitomycin-C following tracheal surgery slows down epithelization and, thus, decreases the development of granulation tissue and maintains a wider diameter of the trachea.

Effects of in vitro Amitriptyline, Fluoxetine, Tranylcypromine and Venlafaxine on Saphenous Vein Grafts.

OBJECTIVE: In this study, we aimed to examine the effects of amitriptyline, fluoxetine, tranylcypromine and venlafaxine on saphenous vein grafts in coronary artery bypass graft surgeries. METHODS: 59 patients (40 males and 19 females; mean age 65.1 years, distribution: 45-84 years) who had coronary artery bypass graft surgery between February 2014 and May 2016 were included in the study. After the saphenous vein grafts with intact and denuded endothelium were precontracted with 3×10-6M phenylephrine, amitriptyline, fluoxetine and tranylcypromine were cumulatively added to isolated organ baths in the range of 10-11-3x10-5M, while venlafaxine was added in the range of 10-9-3×10-5M. Then, the antidepressant-induced relaxation responses were recorded isometrically. RESULTS: While the relaxation response of amitriptyline at -6.42 (Log M) was 74.6%, the response at -6.32 (Log M) was 75.5%. While the relaxation response at -6.46 (Log M) of fluoxetine was 68.02%, the response at -6.02 (Log M) was 72.12%. While the relaxation response of tranylcypromine at -7.53 (Log M) was 61.13%, the response at -7.23 (Log M) was 65.53%. While the relaxation response of venlafaxine at -6.21 (Log M) was 29.98%, the response at -5.90 (Log M) was 32.96%. CONCLUSION: The maximum relaxation at minimum and maximum therapeutic concentrations was obtained with amitriptyline, fluoxetine and tranylcypromine, and the minimum relaxation was obtained with venlafaxine. The relaxation responses were independent of the endothelium.

Hemodynamic effects of atrial natriuretic peptide in ischemia-repertusion injury that occurs after exercise.

BACKGROUND/AIM: Atrial natriureticpeptide (ANP) is known as a protective agent against ischemia-reperfusion injuryfor cardiomyocytes. We compared the hemodynamic effects of ANP and isatin, which is known as an ANP receptor blocker, in ischemia followed by reperfusion in exercised rat hearts with nonexercised ones. MATERIALS AND METHODS: Isolated hearts were perfused in 4 exercised (E) groups after a running protocol for 5 days and 4 nonexercised (NE) groups. In the first protocol, ANP was added to the perfusion solution before ischemia in an E and NE group. In the second protocol, different doses of isatin (0.1, 10, 100 µM/L) were added to the perfusion solution before ANP in 3 E and 3 NE groups. Left ventricular developed pressure (LVDP) and maximum and minimum rates of change in left ventricular pressure (dP/dtmax and dP/dtmin) were recorded. RESULTS: Higher LVDP and dP/dtmin values were observed in the E group than the NE group following addition of ANP before ischemia. Values of dP/dtmax were higher in the E group at the first minute of reperfusion period. Hemodynamic difference was not observed between groups given the same amount of isatin before ANP. CONCLUSION: This study indicated that higher ANP concentrations before ischemia were more effective on the left ventricle contractility and relaxation functions in the hearts that were exposed to exercise.

Effects of in vitro amitriptyline, fluoxetine, tranylcypromine and venlafaxine on saphenous vein grafts

Abstract Objective: In this study, we aimed to examine the effects of amitriptyline, fluoxetine, tranylcypromine and venlafaxine on saphenous vein grafts in coronary artery bypass graft surgeries. Methods: 59 patients (40 males and 19 females; mean age 65.1 years, distribution: 45-84 years) who had coronary artery bypass graft surgery between February 2014 and May 2016 were included in the study. After the saphenous vein grafts with intact and denuded endothelium were precontracted with 3×10-6M phenylephrine, amitriptyline, fluoxetine and tranylcypromine were cumulatively added to isolated organ baths in the range of 10-11-3x10-5M, while venlafaxine was added in the range of 10-9-3×10-5M. Then, the antidepressant-induced relaxation responses were recorded isometrically. Results: While the relaxation response of amitriptyline at -6.42 (Log M) was 74.6%, the response at -6.32 (Log M) was 75.5%. While the relaxation response at -6.46 (Log M) of fluoxetine was 68.02%, the response at -6.02 (Log M) was 72.12%. While the relaxation response of tranylcypromine at -7.53 (Log M) was 61.13%, the response at -7.23 (Log M) was 65.53%. While the relaxation response of venlafaxine at -6.21 (Log M) was 29.98%, the response at -5.90 (Log M) was 32.96%. Conclusion: The maximum relaxation at minimum and maximum therapeutic concentrations was obtained with amitriptyline, fluoxetine and tranylcypromine, and the minimum relaxation was obtained with venlafaxine. The relaxation responses were independent of the endothelium.