Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity.

Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostanoid synthesis, has been implicated in the neurotoxicity resulting from hypoxia-ischemia, and its inhibition has therapeutic potential for ischemic stroke. However, COX-2 inhibitors increase the risk of cardiovascular complications. We therefore sought to identify the downstream effectors of COX-2 neurotoxicity, and found that prostaglandin E(2) EP1 receptors are essential for the neurotoxicity mediated by COX-2-derived prostaglandin E(2). EP1 receptors disrupt Ca(2+) homeostasis by impairing Na(+)-Ca(2+) exchange, a key mechanism by which neurons cope with excess Ca(2+) accumulation after an excitotoxic insult. Thus, EP1 receptors contribute to neurotoxicity by augmenting the Ca(2+) dysregulation underlying excitotoxic neuronal death. Pharmacological inhibition or gene inactivation of EP1 receptors ameliorates brain injury induced by excitotoxicity, oxygen glucose deprivation and middle cerebral artery (MCA) occlusion. An EP1 receptor inhibitor reduces brain injury when administered 6 hours after MCA occlusion, suggesting that EP1 receptor inhibition may be a viable therapeutic option in ischemic stroke.

Type 2 Diabetes: Also a "Clock Matter"?

BACKGROUND: We investigated whether chronotype is associated with glycemic control, antidiabetic treatment, and risk of developing complications in patients with type 2 diabetes (T2DM). METHODS: The diabetologists filled out an online questionnaire on the Google Form platform to collect the following parameters of subjects with T2DM: body mass index (BMI), fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), diabetes history, antidiabetic treatment, diabetic complications, and chronotype categories. RESULTS: We enrolled 106 subjects with T2DM (M/F: 58/48; age: 63.3 ± 10.4 years; BMI: 28.8 ± 4.9 kg/m2). Thirty-five point eight% of the subjects showed a morning chronotype (MC), 47.2% an intermediate chronotype (IC), and 17% an evening chronotype (EC). EC subjects reported significantly higher HbA1c (p < 0.001) and FPG (p = 0.004) values, and higher prevalence of cardiovascular complications (CVC) (p = 0.028) and of subjects taking basal (p < 0.001) and rapid insulin (p = 0.01) compared to MC subjects. EC subjects reported significantly higher HbA1c (p < 0.001) and FPG (p = 0.015) than IC subjects. An inverse association was found between chronotype score, HbA1c (r = -0.459; p < 0.001), and FPG (r = -0.269; p = 0.05), remaining significant also after adjustment for BMI, age, and disease duration. CONCLUSIONS: EC is associated with higher prevalence of CVC and poorer glycemic control independently of BMI and disease duration in subjects with T2DM.

Metabolic and cardiopulmonary effects of detraining after a structured exercise training programme in young PCOS women.

OBJECTIVE: The aim of the present study was to determine if the favourable cardiopulmonary and metabolic benefits induced by exercise training (ET) programme are maintained after its cessation. PATIENTS: Thirty-two young overweight polycystic ovary syndrome (PCOS) women matched for age and body mass index (BMI) with other 32 PCOS patients was enrolled. The first group [PCOS-T (trained)] underwent 24-week ET programme, whereas the second [PCOS-DT (detrained)] underwent 12-week ET programme followed by 12-week detraining period. METHODS: At baseline, after 12- and 24-week follow-up, all PCOS women were studied for their hormonal (ovarian and adrenal androgens), metabolic (glucose and insulin) and lipid profile, and underwent cardiopulmonary exercise test. RESULTS: After the initial 12-week ET programme, both PCOS-T and PCOS-DT groups, without differences between groups, showed a similar significant (P < 0.05) improvement in BMI, fasting insulin, areas under curve insulin (AUC(INS)), glucose and insulin AUC (AUC(GLU/INS)), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and maximal oxygen consumption at cardiopulmonary exercise test (VO2max). At 24-week follow-up, PCOS-T group showed a significant (P < 0.05) improvement in BMI, fasting insulin, AUC(INS), AUC(GLU/INS), LDL-C, HDL-C and VO2max, in comparison to baseline and 12-week follow-up. At same follow-up visit, the all parameters resulted significantly (P < 0.05) worsened in PCOS-DT group in comparison to 12-week follow-up and PCOS-T group. In PCOS-DT group, no parameter assessed at 24-week follow-up was significantly different in comparison with baseline. CONCLUSION: In young PCOS women, 12-week detraining resulted in a complete loss of the favourable adaptations obtained after ET.

Lipopolysaccharide induces early tolerance to excitotoxicity via nitric oxide and cGMP.

BACKGROUND AND PURPOSE: Sublethal injury induces tolerance to a subsequent lethal insult, a phenomenon termed preconditioning (PC). PC occurs within hours (early tolerance) or days (delayed tolerance) after the inducing stimulus. In the brain, delayed tolerance has been studied extensively, but very little is known about early tolerance. We investigated whether the proinflammatory agent lipopolysaccharide (LPS), a well-established inducer of delayed tolerance, can also induce early tolerance and, if so, whether nitric oxide (NO) is involved in its mechanisms. METHODS: In C57BL/6 mice, LPS was administered and N-methyl-D-aspartate (NMDA) was microinjected into the neocortex 30 minutes to 24 hours later. Lesion volume was assessed 24 hours after NMDA administration in thionine-stained sections. RESULTS: LPS reduced NMDA lesions when administered 1 hour (-25+/-1%; P<0.05, n=5 per group) or 24 hours (-25+/-4%; P<0.05, n=5 per group) before NMDA application. LPS administration 30 minutes or 2 to 4 hours before NMDA administration was not neuroprotective (P>0.05). The protection at 1 hour was independent of protein synthesis and was blocked by inhibition of neuronal NO synthase or soluble guanylyl cyclase. Furthermore, early protection was not observed in neuronal or endothelial NO synthase-null mice, but it was present in inducible NO synthase-null mice. CONCLUSIONS: The data demonstrate that LPS induces both early and late tolerance. At variance with delayed tolerance, which depends on inducible NO synthase and peroxynitrite, early tolerance is mediated by endothelial and neuronal NO through production of cGMP. The findings suggest that LPS can trigger signaling between endothelial cells and neurons, leading to NO production and cGMP-dependent neuroprotection.

Cyclooxygenase-2 does not contribute to postischemic production of reactive oxygen species.

We sought to determine whether reactive oxygen species (ROS) derived from cyclooxygenase-2 (COX-2) are involved in ischemic brain injury. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in C57BL/6 mice. The time course of neocortical ROS production was assessed in vivo using hydroethidine as a marker. The same brain sections were used for infarct volume measurements. Transient middle cerebral artery occlusion led to a biphasic increase in ROS production with peaks 2 and 72 h after reperfusion. The COX-2 inhibitor NS398 (10 mg/kg) attenuated the production of COX-2-derived prostaglandin E(2) and reduced brain injury, but did not affect ROS production at 2 and 72 h. Similarly, ROS production was not reduced in COX-2-null mice. In contrast, ROS production and brain injury were reduced in mice lacking the nox2 subunit of the superoxide-producing enzyme nicotinamide adenine dinucleotide phosphate (reduced form) oxidase. The data suggest that COX-2 is not a major source of oxygen radicals after cerebral ischemia and raise the possibility that other COX-2 reaction products, including prostanoids or nonoxygen-based radicals, mediate the COX-2-dependent component of the injury.

Lifestyle changes in the management of adulthood and childhood obesity.

Adulthood and childhood obesity is rapidly becoming an epidemic problem and it has a short and long-term impact on health. Short-term consequences are mostly represented by psychological effects; in fact obese children have more chances to develop psychological or psychiatric problems than non-obese children. The main long-term effect is represented by the fact that childhood obesity continues into adulthood obesity and this results in negative effects in young adult life, since obesity increases the risk to develop morbidity and premature mortality. The obesity-related diseases are mostly represented by hypertension, type 2 diabetes, dyslipidemia, cardiovascular diseases. Medical treatment should be discouraged in childhood because of the side effects and it should be only reserved for obese children with related medical complications. Lifestyle changes should be encouraged in both adulthood and childhood obesity. This review focuses on the management of obesity both in adulthood and in childhood, paying particular attention to lifestyle changes that should be recommended.

Variable phenotype in a P102L Gerstmann-Sträussler-Scheinker Italian family.

BACKGROUND: Gerstmann-Sträussler-Scheinker disease is an autosomal dominant prion disease. The clinical features include ataxia, dementia, spastic paraparesis and extrapyramidal signs. METHODS: We report a new large Italian family affected by Gerstmann-Sträussler-Scheinker disease. RESULTS: The four generation pedigree includes 11 patients. The mean age at onset +/- SD was 41.4 +/- 16.2 years. Mean disease duration to death in four patients was 5.5 +/- 1.7 years. Two clinical patterns were evident: cognitive impairment with scarce neurological features or ataxia followed by cognitive impairment. Molecular analysis showed P102L mutation in PRNP gene. CONCLUSION: Three Italian families have been reported to date. The variable phenotype has already been reported, and does not appear related to the codon 129 polymorphism.

The risk of a persistent glucose metabolism impairment after gestational diabetes mellitus is increased in patients with polycystic ovary syndrome.

OBJECTIVE: To test the hypothesis that the risk of persistent glucose impairment after gestational diabetes mellitus (GDM) is increased in patients with polycystic ovary syndrome (PCOS). RESEARCH DESIGN AND METHODS: The prospective case-control study included 42 pregnant patients with PCOS and GDM and 84 pregnant control patients with GDM but without clinical and biochemical hyperandrogenism, polycystic ovaries, and oligo-anovulation. The case and control subjects were matched one to two for age and BMI. The glycemic profiles were studied in all subjects 6 weeks, 12 weeks, and 18 months after delivery. The incidence and the relative risk (RR) were calculated for overall persistence of an abnormal glycemic pattern and for each specific alteration, i.e., impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and diabetes mellitus (DM). RESULTS: At 18 months after delivery, the incidences of IFG, IGT, and IFG-IGT were significantly (P < 0.05) higher in the cases than in the controls. At the 18-month follow-up, the RR for the composite outcome of glucose metabolism impairment in PCOS women was 3.45 (95% CI 1.82-6.58). CONCLUSIONS: Patients with PCOS are at increased risk for a persistent impaired glucose metabolism after GDM.

Purinergic signaling induces cyclooxygenase-1-dependent prostanoid synthesis in microglia: roles in the outcome of excitotoxic brain injury.

Cyclooxygenases (COX) are prostanoid synthesizing enzymes constitutively expressed in the brain that contribute to excitotoxic neuronal cell death. While the neurotoxic role of COX-2 is well established and has been linked to prostaglandin E(2) synthesis, the role of COX-1 is not clearly understood. In a model of N-Methyl-D-aspartic acid (NMDA) induced excitotoxicity in the mouse cerebral cortex we found a distinctive temporal profile of COX-1 and COX-2 activation where COX-1, located in microglia, is responsible for the early phase of prostaglandin E(2) synthesis (10 minutes after NMDA), while both COX-1 and COX-2 contribute to the second phase (3-24 hours after NMDA). Microglial COX-1 is strongly activated by ATP but not excitatory neurotransmitters or the Toll-like receptor 4 ligand bacterial lipopolysaccharide. ATP induced microglial COX-1 dependent prostaglandin E(2) synthesis is dependent on P2X7 receptors, extracellular Ca(2+) and cytoplasmic phospholipase A2. NMDA receptor activation induces ATP release from cultured neurons leading to microglial P2X7 receptor activation and COX-1 dependent prostaglandin E(2) synthesis in mixed microglial-neuronal cultures. Pharmacological inhibition of COX-1 has no effect on the cortical lesion produced by NMDA, but counteracts the neuroprotection exerted by inhibition of COX-2 or observed in mice lacking the prostaglandin E(2) receptor type 1. Similarly, the neuroprotection exerted by the prostaglandin E(2) receptor type 2 agonist butaprost is not observed after COX-1 inhibition. P2X7 receptors contribute to NMDA induced prostaglandin E(2) production in vivo and blockage of P2X7 receptors reverses the neuroprotection offered by COX-2 inhibition. These findings suggest that purinergic signaling in microglia triggered by neuronal ATP modulates excitotoxic cortical lesion by regulating COX-1 dependent prostanoid production and unveil a previously unrecognized protective role of microglial COX-1 in excitotoxic brain injury.