The mechanism of preventive effect of captopril on renal ischemia reperfusion injury is independent of ATP dependent potassium channels

Background: Renal ischemia reperfusion (IR) injury has been a major source of concern during the past decades and angiotensin converting enzyme (ACE) inhibitors have been successfully used to prevent this injury. There have been some controversial reports about the involvement of KATP channels in the mechanism of action of ACE inhibitors. In this study, we examined the effect of KATP channel blocker (Glibenclamide) on preventive effect of captopril on renal IR injury. Methods: Male sprauge-dawley rats were pretreated with glibenclamide (1, 5 and 25 mg/kg) and/or captopril (5 mg/kg). They were anesthetized using ketamine (50 mg/kg) and xylazine (10 mg/kg). The left flank was incised and the left renal artery was clamped for 30 minutes. After that, the kidney was reperfused for 2 hours and then the animal was killed. The Right and left kidneys were removed and evaluated for microscopic damage. Results: Captopril reduced renal IR injury while glibenclamide by itself caused no change. Glibenclamide did not change the preventive effect of captopril. Conclusion: It seems that the preventive effect of captopril is not directly mediated by KATP channels and further attention should be paid to other receptor-mediated angiotensin II effects

Effect of crocus sativus on gentamicin induced nephrotoxicity

Crocus sativus, known as saffron, is used in folk medicine for treatment of different types of diseases, and its anti-inflammatory and free radical scavenging activities have been demonstrated. The present study evaluated gentamicin nephrotoxicity in saffron treated rats. Male Wistar rats (200-250g) were treated with saffron (40 or 80 mg/k/d) for 10 days, or saffron (40 or 80 mg/ kg/d) for 10 days and gentamicin 80 mg/kg/d for five days, starting from day 6. At the end of treatment, blood samples were taken for measurement of serum creatinine (SCr) and BUN. The left kidney was prepared for histological evaluation and the right kidney for Malondialdehyde (MDA) measurement. Gentamicin 80 (mg/k/d) increased SCr, BUN and renal tissue levels of MDA and induced severe histological changes. Saffron at 40 mg/k/d significantly reduced gentamicin-induced increases in BUN and histological scores (p<0.05). Gentamicin-induced increases in BUN, SCr and MDA and histological injury were significantly reduced by treatment with saffron 80 mg/k/d (p<0.05, p<0.001, p<0.05, and p<0.001 respectively). In conclusion, our results suggest that saffron treatment reduces gentamicin induced nephrotoxicity and this effect seems to be dose dependent

Selenium nanoparticles for targeted stroke therapy through modulation of inflammatory and metabolic signaling

Ischemic cerebral stroke is a major cause of death and morbidity. Currently, no neuroprotective agents have been shown to impact the clinical outcomes in cerebral stroke cases. Here, we report therapeutic effects of Se nanoparticles on ischemic stroke in a murine model. Anti-transferrin receptor monoclonal antibody (OX26)-PEGylated Se nanoparticles (OX26-PEG-Se NPs) were designed and synthesized and their neuroprotective effects were measured using in vitro and in vivo approaches. We demonstrate that administration of the biodegradable nanoparticles leads to resolution of brain edema, protection of axons in hippocampus region, and myelination of hippocampal area after cerebral ischemic stroke. Our nanoparticle design ensures efficient targeting and minimal side effects. Hematological and biochemical analyses revealed no undesired NP-induced changes. To gain mechanistic insights into the therapeutic effects of these particles, we characterized the changes to the relevant inflammatory and metabolic signaling pathways. We assessed metabolic regulator mTOR and related signaling pathways such as hippo, Ubiquitin-proteasome system (ERK5), Tsc1/Tsc2 complex, FoxO1, wnt/β-catenine signaling pathway. Moreover, we examined the activity of jak2/stat3 signaling pathways and Adamts1, which are critically involved in inflammation. Together, our study provides a promising treatment strategy for cerebral stroke based on Se NP induced suppression of excessive inflammation and oxidative metabolism. © 2019, The Author(s)

Morphine dependence protects rat kidney against ischaemia-reperfusion injury

1. Ischaemic preconditioning (IPC) protects the heart and kidneys against ischaemia-reperfusion (I/R) injury. It has been shown that opioid receptor activation can mimic cardiac IPC. In a kidney model of I/R, a single dose of morphine failed to mimic IPC. The aim of the present study was to determine the role of chronic morphine (dependence) in protection against renal I/R injury. 2. Male Wistar rats were treated with increasing doses of morphine (20-30 mg/kg per day, s.c., for 5 days) to develop morphine dependence (MD). Three weeks before the I/R procedure, the right kidney was removed. Ischaemia-reperfusion injury was induced by clamping the left renal artery for 45 min, followed by 24 h reperfusion. Some MD rats were pretreated with naloxone (5 mg/kg, s.c.). Twenty-four hours later, creatinine and sodium concentrations were measured in serum and urine, then creatinine clearance (CCr) and the fractional excretion of sodium (FENa) were calculated. Blood urea nitrogen (BUN) was measured only in serum samples. Kidneys were also assessed histologically for evidence of tissue injury. 3. In the present study, MD decreased tissue injury (histological score), serum creatinine and BUN levels, increased CCr and decreased FENa after I/R. Pretreatment with naloxone attenuated the protective effects of MD. Morphine dependence did not have any significant effect on urine volume. 4. In conclusion, it seems that morphine dependence protects the kidney against I/R injury via opioid receptor-dependent pathways. Further studies are required to clearly determine the mechanisms involved. © 2008 The Authors

Pre-medication and renal pre-conditioning: A role for alprazolam, atropine, morphine and promethazine

Four pre-medication drugs are used to relieve pain, allay anxiety, reduce secretion and enhance hypnosis, were evaluated for their effects on ischemia reperfusion (I/R) injury which is one of the major complications of vascular and transplantation surgery. Right kidney was removed from female rats (210-250 g) 3 weeks before surgical procedure. Different doses of morphine (0.5, 2 and 5 mg/kg), promethazine (1, 2 and 5 mg/kg), atropine (0.1, 0.3 and 0.5 mg/kg) and alprazolam (0.08, 0.32 and 0.64 mg/kg) were administered subcutaneously 30 min before left renal artery occlusion and 6 h reperfusion. Left kidneys were processed for histological evaluations. Creatinine and BUN were measured in serum samples. Morphine, promethazine, atropine and alprazolam at all evaluated doses significantly decreased serum creatinine and BUN levels and histopathological scores. The effects of promethazine (1 mg/kg) and all doses of alprazolam were more potent than other pre-medication drugs and doses. This study suggested a protective effect of these pre-medication drugs on I/R injury. Although obvious studies are required, these findings may lead to effective therapies against I/R injury. © 2009 Société Française de Pharmacologie et de Thérapeutique

Design and fabrication of all-polymer transducers with different functional features for basic neuroscience and neuroprosthetics

Neural prostheses aim at recording or altering nervous system activity to partly restore motor, sensory or cognitive modalities that have been lost because of disease or trauma. Where appropriate, microelectrode arrays (MEAs) facilitate high-density recordings and local stimulation of neural activity in the brain. Their body integration, functionality and long-term stability may be improved by resorting to new, more tissue-like materials and conductors with low interface impedance and large charge transfer capacity. Recently, we presented an in vitro prototype of a highly flexible polymeric MEA made of a polydimethylsiloxane (PDMS) scaffold with microchannel tracks and electrodes which were coated with films of organic conductors or filled with a graphite-PDMS composite paste [1]. Here, we present an exemplary design concept for in vivo probes with carbon-PDMS conductors based on the same replica-molding technology. They were fabricated from laser-printed templates and feature a particular squeeze-clamping interconnection scheme based on rubber-like contact pads. This \u201csoft contact\u201d strategy alleviates stress-related twist and break found in classically bonded pads in ribbon cable-type wiring to external electronics

Activation of mitochondrial KATP channels mediates neuroprotection induced by chronic morphine preconditioning in hippocampal CA-1 neurons following cerebral ischemia

Purpose Pharmacologic preconditioning, through activating several mechanisms and mediators, can increase the tolerance of different tissues against ischemia/reperfusion (I/R) injury. Recent studies have shown that morphine preconditioning has protective effects in different organs, especially in the heart. Nevertheless, its mechanisms are not well elucidated in the brain. The present study aimed to clarify whether the activation of mitochondrial KATP (mKATP) channels in chronic morphine (CM) preconditioning could decrease hippocampus damage following I/R injury. Materials and methods CM preconditioning was performed by the administration of additive doses of morphine for 5 days before I/R injury induction. I/R injury was induced by the occlusion of bilateral common carotid arteries. The possible role of mKATP channels was evaluated by the injection of 5-hydroxydecanoate (5-HD) before I/R injury. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) was performed to detect apoptosis in hippocampal neurons. The expressions of B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (BAX) and levels of malondialdehyde (MDA) and catalase (CAT) enzymes were assessed. Results CM attenuated apoptosis in the hippocampal CA1 neurons (P < 0.001 vs I/R), and mKATP channel blocking with 5-HD significantly increased apoptosis (P < 0.001 vs CM + I/R). CM increased CAT activity (P < 0.05 vs I/R) and Bcl-2 protein expression (P < 0.01 vs I/R), while it decreased MDA level (P < 0.05 vs I/R) and BAX protein expression (P < 0.05 vs I/R). Pretreatment with 5-HD abolished all the above-mentioned effects of CM. Conclusions These findings describe novel evidence whereby CM preconditioning in hippocampal CA1 neurons can improve oxidative stress and apoptosis through the activation of mKATP channels and eventually protect the hippocampal tissue against I/R injury. © 2017 Medical University of Bialysto

Nitric oxide and renal protection in morphine-dependent rats

Morphine treatment for 5days protects heart against ischemia-reperfusion (IR) injury. This study evaluated the involvement of nitric oxide (NO) in morphine-induced renal protection. Three weeks after right nephrectomy, increasing doses of morphine were administered (20-30mgkg-1day-1, 5days) to develop dependence in rats. The left kidney underwent 45-min ischemia and 24-h reperfusion. Some rats were pretreated with naloxone (5mgkg-1) or L-NAME (20mgkg-1). In one group, IR was induced 24h after the last dose of morphine during the withdrawal period. Plasma nitrite/nitrate levels and serum creatinine and BUN were measured. Creatinine clearance and fractional excretion of sodium (FENa) were calculated. Myeloperoxidase (MPO) activity, malondialdehyde (MDA) level, and inducible NO synthase (iNOS) expression were determined and histopathology was studied in the left kidney. IR increased serum creatinine and BUN, plasma NO (p&lt;0.01), FENa, iNOS expression (p&lt;0.001), MPO activity, MDA level, and tissue damage and decreased creatinine clearance. Morphine decreased plasma NO (p&lt;0.05 vs IR), serum creatinine and BUN (p&lt;0.01), FENa, MPO activity, MDA level, iNOS expression, and tissue damage (p&lt;0.05), but increased creatinine clearance (p&lt;0.05). Pretreatment with naloxone significantly increased NO production and iNOS expression in morphine-treated rats after IR (p&lt;0.01 vs morphine dependence+IR). Pretreatment with L-NAME in morphine-treated rats decreased NO production (10.7±1.9, p&lt;0.01 vs morphine dependence+IR) but could not change iNOS expression after IR. Both naloxone and L-NAME significantly abolished the protective effects of morphine dependence on functional and histological factors. The protective effect of morphine dependence on serum creatinine, BUN, FENa, and creatinine clearance persisted during the withdrawal period, whereas iNOS expression decreased. NO production was not decreased during the withdrawal period (p&gt;0.1 vs morphine dependence+IR group). Morphine dependence provided renal protection in the acute phase and during withdrawal. Excessive increase or decrease in NO production abolished the effects of morphine, which suggested a role for balanced NO production and iNOS expression. © 2010 Elsevier Inc

Activation of mitochondrial KATP channels mediates neuroprotection induced by chronic morphine preconditioning in hippocampal CA-1 neurons following cerebral ischemia

Purpose Pharmacologic preconditioning, through activating several mechanisms and mediators, can increase the tolerance of different tissues against ischemia/reperfusion (I/R) injury. Recent studies have shown that morphine preconditioning has protective effects in different organs, especially in the heart. Nevertheless, its mechanisms are not well elucidated in the brain. The present study aimed to clarify whether the activation of mitochondrial KATP (mKATP) channels in chronic morphine (CM) preconditioning could decrease hippocampus damage following I/R injury. Materials and methods CM preconditioning was performed by the administration of additive doses of morphine for 5 days before I/R injury induction. I/R injury was induced by the occlusion of bilateral common carotid arteries. The possible role of mKATP channels was evaluated by the injection of 5-hydroxydecanoate (5-HD) before I/R injury. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) was performed to detect apoptosis in hippocampal neurons. The expressions of B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (BAX) and levels of malondialdehyde (MDA) and catalase (CAT) enzymes were assessed. Results CM attenuated apoptosis in the hippocampal CA1 neurons (P < 0.001 vs I/R), and mKATP channel blocking with 5-HD significantly increased apoptosis (P < 0.001 vs CM + I/R). CM increased CAT activity (P < 0.05 vs I/R) and Bcl-2 protein expression (P < 0.01 vs I/R), while it decreased MDA level (P < 0.05 vs I/R) and BAX protein expression (P < 0.05 vs I/R). Pretreatment with 5-HD abolished all the above-mentioned effects of CM. Conclusions These findings describe novel evidence whereby CM preconditioning in hippocampal CA1 neurons can improve oxidative stress and apoptosis through the activation of mKATP channels and eventually protect the hippocampal tissue against I/R injury. © 2017 Medical University of Bialysto