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Eur J Pharmacol [journal]
- Molecular mechanisms of hyperthermia-induced apoptosis enhanced by withaferin A. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 Dec 7.
Hyperthermia is a good therapeutic tool for non-invasive cancer therapy; however, its cytotoxic effects are not sufficient. In the present study, withaferin A (WA), a steroidal lactone derived from the plant Withania somnifera Dunal, has been investigated for its possible enhancing effects on hyperthermia-induced apoptosis. In HeLa cells, treatment with 0.5 or 1.0μM WA at 44°C for 30min induced significant apoptosis accompanied by decreased intracellular GSH/GSSG ratio and caspase-3 activation, while heat or WA alone did not induce such changes. The upregulation in apoptosis was significantly inhibited by glutathione monoethyl ester, a cell permeable glutathione precursor. Mitochondrial transmembrane potentials were dramatically decreased by the combined treatment, with increases in pro-apoptotic Bcl-2-family proteins tBid and Noxa, and downregulation of antiapoptotic Bcl-2 and Mcl-1. Combined treatment with hyperthermia and WA induced significant increases in JNK phosphorylation (p-JNK), and decreases in the phosphorylation of ERK (p-ERK) compared with either treatment alone. These results suggest that WA enhances hyperthermia-induced apoptosis via a mitochondria-caspase-dependent pathway; its underlying mechanism involves elevated intracellular oxidative stress, mitochondria dysfunction, and JNK activation.
- Calcium channelopathies and Alzheimer's disease: Insight into therapeutic success and failures. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 Dec 6.
Calcium ions are versatile and universal biological signaling factors that regulate numerous cellular processes ranging from cell fertilization, to neuronal plasticity that underlies learning and memory, to cell death. For these functions to be properly executed, calcium signaling requires precise regulation, and failure of this regulation may tip the scales from a signal for life to a signal for death. Disruptions in calcium channel function can generate complex multi-system disorders collectively referred to as "calciumopathies" that can target essentially any cell type or organ. In this review, we focus on the multifaceted involvement of calcium signaling in the pathophysiology of Alzheimer's disease (AD), and summarize the various therapeutic options currently available to combat this disease. Detailing the series of disappointing AD clinical trial results on cognitive outcomes, we emphasize the urgency to design alternative therapeutic strategies if synaptic and memory functions are to be preserved. One such approach is to target early calcium channelopathies centrally linked to AD pathogenesis.
- In vivo administration of ritonavir worsens intestinal damage caused by cyclooxygease inhibitors. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 Dec 4.
The protease inhibitor ritonavir is part of the highly active anti-retroviral therapy (HAART) successfully used in the treatment of human immunodeficiency virus (HIV)-1 infection. There is evidence that ritonavir alters intestinal permeability and induces damage to the small intestine. Because HIV infected patients taking HAART are at high risk for developing cardiovascular complications, there might be a need for the use of low dose of aspirin (ASA) to prevent ischemic events. Similarly, long term survival exposes HIV infected persons to detrimental interactions of ritonavir with non-steroidal anti-inflammatory drugs (NSAIDs). In the present work we tested whether ritonavir worsens intestinal injury caused by NSAIDs and ASA. C57BL6 mice were treated for 25 days with ritonavir and for a further 5 days with the combination of ritonavir plus ASA or ritonavir plus naproxen. In a second set of experiments C57BL6 mice were cotreated with ritonavir plus misoprostol, a PGE1 analog. We found that ritonavir administration caused intestinal damage and its co-administration with naproxen or ASA exacerbated the severity of injury and intestinal inflammation, as assessed by measuring haematocrit, MPO, mucosal levels of PGE2 and mRNA levels of iNOS, MCP-1 and VLA-1. Co-administration of misoprostol protected against intestinal damage induced by naproxen and ritonavir. In conclusion we demonstrated that ritonavir causes intestinal damage and that its association with NSAIDs or ASA worsens the damage caused by COX-inhibitors. Misoprostol rescues from intestinal damage caused by ritonavir. Further studies are need to clarify whether this observation has a clinical readout.
- Effect of curcumin on diabetic peripheral neuropathic pain: Possible involvement of opioid system. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 Dec 4.
Neuropathic pain is one of the most common complications of diabetes mellitus. As efficacy and tolerability of current therapy for neuropathic pain are not ideal, we need to develop the novel drug for better treatment. Curcumin as a natural flavonoid from Curcuma longa has considerable effects on nervous system such as, antidepressant, antinociceptive and neuroprotective effects. The present study was designed to investigate the effect of curcumin on diabetic peripheral neuropathic pain and possible involvement of opioid system. A single dose of 60mg/kg streptozotocin was injected intraperitoneally to induce diabetes in rats. STZ-induced diabetic rats were treated with curcumin (50mg/kg/day) acute and chronically. Thermal hyperalgesia and mechanical allodynia were measured on the days 0, 7, 14 and 21 after diabetes induction as behavioral scores of neuropathic pain. Chronic, but not acute, treatment with curcumin prevents the weight loss and attenuates mechanical allodynia in STZ-induced diabetic rats. Pretreatment with naloxone (1mg/kg) significantly reduced anti-allodynic effect of chronic curcumin in von Frey filament test. Our results suggest that curcumin can be considered as a new therapeutic potential for the treatment of diabetic neuropathic pain and the activation of opioid system may be involved in the antinociceptive effect of curcumin.
- Pyrrolidine dithiocarbamate protects against scopolamine-induced cognitive impairment in rats. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 Dec 3.
Alzheimer's disease (AD) is a chronic neurodegenerative disorder that leads to disturbances of cognitive functions. Although the primary cause of AD remains unclear, brain acetylcholine deficiency, oxidative stress and neuroinflammation may be considered the principal pathogenic factors. The present study was constructed to investigate the anti-amnestic effect of pyrrolidine dithiocarbamate (PDTC) on scopolamine-induced behavioral, neurochemical and biochemical changes in rats. PDTC (50 and 100mg/kg) and donepezil (2.5mg/kg) were orally administered for 14 successive days. Dementia was induced at the end of the treatment period by a single injection of scopolamine (20mg/kg; i.p.), and Y-maze test was conducted 30min thereafter. Rats were then sacrificed and homogenates of cortical and hippocampal tissues were used for the estimation of noradrenaline, dopamine, serotonin and heat shock protein 70 contents along with acetylcholinesterase activity. In addition, certain oxidative stress markers, pro-inflammatory and anti-inflammatory cytokines were assessed. Histological examination of cortical and hippocampal tissues was also performed. Scopolamine resulted in memory impairment that was coupled by alterations in the estimated neurotransmitters, heat shock protein 70, acetylcholinesterase activity, oxidative stress as well as inflammatory biomarkers. Histological analysis revealed serious damaging effects of scopolamine on the structure of cerebral cortex and hippocampus. Pretreatment of rats with PDTC in both doses mitigated scopolamine-induced behavioral, biochemical, neurochemical and histological changes in a manner comparable to donepezil. The observed anti-amnestic effect of PDTC makes it a promising candidate for clinical trials in patients with cognitive impairment.
- The novel dipeptidyl peptidase-4 inhibitor teneligliptin prevents high-fat diet-induced obesity accompanied with increased energy expenditure in mice. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 Dec 3.
Dipeptidyl peptidase-4 (DPP-4)-deficient mice exhibit prevention of obesity with increased energy expenditure, whereas currently available DPP-4 inhibitors do not induce similar changes. We investigated the impact of the novel DPP-4 inhibitor teneligliptin on body weight, energy expenditure, and obesity-related manifestations in diet-induced obese mice. Six-weeks-old C57BL/6N mice were fed a high-fat diet (60%kcal fat) ad libitum and administered teneligliptin (30 or 60mg/kg) via drinking water for 10 weeks. Mice fed a high-fat diet showed accelerated body weight gain. In contrast, compared with the vehicle group, the administration of teneligliptin reduced body weight to 88% and 71% at dose of 30mg/kg/day and 60mg/kg/day, respectively. Although there was no change in locomotor activity, indirect calorimetry studies showed that teneligliptin (60mg/kg) increased oxygen consumption by 22%. Adipocyte hypertrophy and hepatic steatosis induced by a high-fat diet were suppressed by teneligliptin. The mean adipocyte size in the 60-mg/kg treatment group was 44% and hepatic triglyceride levels were 34% of the levels in the vehicle group. Furthermore, treatment with teneligliptin (60mg/kg) reduced plasma levels of insulin to 40% and increased the glucose infusion rate to 39%, as measured in the euglycemic clamp study, indicating its beneficial effect on insulin resistance. We showed for the first time that the DPP-4 inhibitor prevents obesity and obesity-related manifestations with increased energy expenditure. Our findings suggest the potential utility of teneligliptin for the treatment of a broad spectrum of metabolic disorders related to obesity beyond glycemic control.
- Mechanisms involved in increased sensitivity to adenosine A2A receptor activation and hypoxia-induced vasodilatation in porcine coronary arteries. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 Dec 3.
Hypoxia-induced coronary vasorelaxation is a compensatory mechanism increasing blood flow. We hypothesized that hypoxia shares pathways with adenosine and causes vasorelaxation through the adenosine A2A receptor and force suppression by increasing cAMP and phosphorylated heat shock protein (HSP)20. Adenosine receptors in porcine left anterior descending coronary arteries (LAD) were examined by RT-PCR and isometric tension recording in myographs. Vasorelaxation was induced by adenosine, 1% oxygen, or both in the absence or presence of ZM241385, an adenosine A2A receptor antagonist. cAMP was determined by ELISA and p-HSP20/HSP20 and p-MLC/MLC were determined by immunoblotting and densitometric analyses. In coronary arteries exposed to 1% oxygen, there was increased sensitivity to adenosine, the adenosine A2 selective agonist NECA, and the adenosine A2A selective receptor agonist CGS21680. ZM241385 shifted concentration-response curves for CGS21680 to the right, whereas the adenosine A1 antagonist DPCPX, the adenosine A2B receptor antagonist MRS1754 and the adenosine A3 receptor antagonist MRS1523 failed to reduce vasodilatation induced by CGS21680. 1% oxygen or adenosine increased cAMP accumulation and HSP20 phosphorylation without changing T850-MYPT1 and MLC phosphorylation. ZM241385 failed to change 1% oxygen-induced vasodilation, cAMP accumulation, HSP20 phosphorylation and MLC phosphorylation. The PKA inhibitor Rp-8-CPT-cAMPS significantly reduced vasorelaxation induced by 1% oxygen or CGS21680. Our findings suggest that the increased sensitivity to adenosine, NECA, and CGS21680 at 1% oxygen involves adenosine A2A receptors. Adenosine and 1% oxygen induce vasorelaxation in PGF2α-contracted porcine coronary arteries partly by force suppression caused by increased cAMP and phosphorylation of HSP20.
- Intracellular calcium channels: Inositol-1,4,5-trisphosphate receptors. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 Dec 1.
The inositol-1,4,5-trisphosphate receptors (InsP3Rs) are the major intracellular Ca(2+)-release channels in cells. Activity of InsP3Rs is essential for elementary and global Ca(2+) events in the cell. There are three InsP3Rs isoforms that are present in mammalian cells. In this review review we will focus primarily on InsP3R type 1. The InsP3R1 is a predominant isoform in neurons and it is the most extensively studied isoform. Combination of biophysical and structural methods revealed key mechanisms of InsP3R function and modulation. Cell biological and biochemical studies lead to identification of a large number of InsP3R-binding proteins. InsP3Rs are involved in the regulation of numerous physiological processes, including learning and memory, proliferation, differentiation, development and cell death. Malfunction of InsP3R1 play a role in a number of neurodegenerative disorders and other disease states. InsP3Rs represent a potentially valuable drug target for treatment of these disorders and for modulating activity of neurons and other cells. Future studies will provide better understanding of physiological functions of InsP3Rs in health and disease.
- Inhibitory effect of spinal mGlu5 receptor antisense oligonucleotide on the up-regulated expression of spinal G protein associated with chronic morphine treatment. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 Dec 1.
Knockdown of spinal metabotropic glutamate 5 (mGlu5) receptor was shown to inhibit the development of intrathecal morphine antinociceptive tolerance. The present work was designed to evaluate the expression of spinal G-protein during morphine tolerance and knockdown of spinal mGlu5 receptor with antisense oligonucleotide (ODN). Rats were treated with saline, morphine, mGlu5 receptor antisense or mismatch ODN intrathecally. Behavioral tests were employed to test the thermal and mechanical pain thresholds. Five days later, rats were scarified and spinal expression of spinal Gαi, Gαo, Gαq and Gβ were detected. Consistent with the previous results, knockdown of spinal mGlu5 receptor could inhibit spinal morphine antinociceptive tolerance in behavioral tests (P<0.05). The mGlu5 receptor antisense ODN produced a significant reduction in mGlu5 receptor protein of about 56.6% compared with the control group (P<0.05). Expression of spinal Gαi, Gαo, Gαq and Gβ were up-regulated while morphine tolerance developed (P<0.05). Antisense ODN of spinal mGlu5 receptor, but not mismatched ODN, reduced the spinal dorsal horn levels of Gαi, Gαo, Gαs, Gαq and Gβ (P<0.05). We conclude that expression of spinal G (αi, αo, αs, αq and β) protein may be up-regulated after chronic morphine treatment which could be attenuated by knockdown of spinal mGlu5 receptor with antisense ODN.
- Effects of HMG-CoA reductase inhibitors on learning and memory in the guinea pig. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 Dec 1.
Statins reduce the risk of death from cardiovascular disease in millions of people worldwide. Recent pharmacovigilance data has suggested that people taking statins have an increased risk of psychiatric adverse events such as amnesia and anxiety. This study aimed to investigate the possibility of statin-induced amnesia through animal models of memory and learning. We conducted extracellular field recordings of synaptic transmission in area CA1 of hippocampal slices to examine the effects of acute cholesterol lowering with lipid lowering drugs. We also assessed the effect of six weeks of simvastatin (2mg/kg/d) and atorvastatin (1mg/kg/d) treatment using the Morris water maze. Long Term Potentiation (LTP) was significantly diminished in the presence of 3µM atorvastatin or simvastatin and by the cholesterol sequestering agent methyl-β-cyclodextrin (MBCD). The effects were reversed in the MBCD but not the statin treated slices by the addition of cholesterol. In the water maze, statin treatment did not cause any deficits in the first five days of reference memory testing, but statin treated guinea pigs preformed significantly worse than control animals in a working memory test. The deficits observed in our experiments in water maze performance and hippocampal LTP are suggestive of statin induced changes in hippocampal plasticity. The effects on LTP are independent of cholesterol regulation, and occur at concentrations that may be relevant to clinical use. Our results may help to explain some of the behavioural changes reported in some people after beginning statin treatment.