Prostanoid signaling: dual role for prostaglandin E2 in neurotoxicity

The prostanoids, a naturally occurring subclass of eicosanoids, are lipid mediators generated through oxidative pathways from arachidonic acid. These cyclooxygenase metabolites, consisting of the prostaglandins (PG), prostacyclin and tromboxane, are released in response to a variety of physiological and pathological stimuli in almost all organs, including the brain. They are produced by various cell types and act upon targeted cells via specific G protein-coupled receptors. The existence of multiple receptors, cross-reactivity and coupling to different signal transduction pathways for each prostanoid, collectively establish their diverse effects. Notably, these effects can occur in functionally opposing directions within the same cell or organ. Prostaglandin E(2) (PGE(2)) is the most versatile prostanoid because of its receptors, E Prostanoid (EP) receptor subtypes 1 through 4, its biological heterogeneity and its differential expression on neuronal and glial cells throughout the central nervous system. Since PGE(2) plays an important role in processes associated with various neurological diseases, this review focuses on its dual neuroprotective and neurotoxic role in EP receptor subtype signaling pathways in different models of brain injury.     

Disruption of astrocytic glutamine turnover by manganese is mediated by the protein kinase C pathway

Manganese (Mn) is a trace element essential for normal human development and is required for the proper functioning of a variety of physiological processes. Chronic exposure to Mn can cause manganism, a neurodegenerative disorder resembling idiopathic Parkinson's disease (PD). Mn(II) neurotoxicity is characterized by astrocytic impairment both in the expression and activity of glutamine (Gln) transporters. Because protein kinase C (PKC) activation leads to the downregulation of a number of neurotransmitter transporters and Mn(II) increases PKC activity, we hypothesized that the PKC signaling pathway contributes to the Mn(II)-mediated disruption of Gln turnover. Our results have shown that Mn exposure increases the phosphorylation of both the PKCα and PKCδ isoforms. PKC activity was also shown to be increased in response to Mn(II) treatment. Corroborating our earlier observations, Mn(II) also caused a decrease in Gln uptake. This effect was blocked by PKC inhibitors. Notably, PKC activation caused a decrease in Gln uptake mediated by systems ASC and N, but had no effect on the activities of systems A and L. Exposure to α-phorbol 12-myristate 13-acetate significantly decreased SNAT3 (system N) and ASCT2 (system ASC) protein levels. Additionally, a co-immunoprecipitation study demonstrated the association of SNAT3 and ASCT2 with the PKCδ isoform, and Western blotting revealed the Mn(II)-mediated activation of PKCδ by proteolytic cleavage. PKC activation was also found to increase SNAT3 and ubiquitin ligase Nedd4-2 binding and to induce hyperubiquitination. Taken together, these findings demonstrate that the Mn(II)-induced dysregulation of Gln homeostasis in astrocytes involves PKCδ signaling accompanied by an increase in ubiquitin-mediated proteolysis.     

Peaceful use of disastrous neurotoxicants

The increasing exposure to environmental neurotoxicants in the last decades caused serious health problems in the world population. Some of the neurotoxic agents are being used in agriculture and household such as insecticides and rodenticides and others are of natural origin like snake and scorpion venoms. Additional group of harmful substances is the chemical warfare agents including nerve and blistering agents that are known for their disastrous effects on neuronal tissues. The present paper presents a combination of epidemiological/clinical and molecular approaches for investigating the effect of certain groups of neurotoxicants on a variety of pathologies.The work of Finkelstein and coworkers describes epidemiological and clinical studies on acute and chronic organophosphate (OP)-induced neurotoxicity in certain populations in Israel. They mainly investigated the neurotoxic effects of low-level long-term exposure to OP in agricultural areas but also dealt with acute exposures as well. A molecular approach to OP mechanism of neuronal injury was described by Milatovic and coworkers. They demonstrated OP-induced oxidative injury in pyramidal neurons in the CA1 hippocampal area and its suppression by antioxidants. Lecht and coworkers described the novel snake venom angioneurins as important mediators of the physiological cross-talk between the cardiovascular and nervous systems. They also showed that under certain conditions these angioneurins may induce pathologies such as tumor development or disruption of the vascular barrier function during envenomation. Additional mechanistic/therapeutic approach was presented by Brodsky, Rosengarten, Proscura, Shapira and Wormser. They developed a novel anti-inflammatory peptide that reduced skin irritation induced by heat and sulfur mustard (SM) stimuli. Since SM causes neuropsychiatric symptoms and alterations in neurological functions this peptide may serve as a potential treatment of neuronal injuries caused by environmental neurotoxicants.These reviews highlight different aspects of neurotoxicity, addressing epidemiology and mechanisms of toxicity; and identifying novel potential therapies.     

Therapy in type 2 diabetes: insulin glargine vs. NPH insulin both in combination with glimepiride

BACKGROUND: Type 2 diabetes (T2DM) patients often fail to achieve adequate glycemic control with oral antidiabetic drugs (OADs). Insulin has been shown to improve glycemic control in these patients but with increased risk of hypoglycemia. This study compared the efficacy and safety of insulin glargine and NPH insulin, both in combination with a once-daily fixed dose of glimepiride, in terms of glycemic control and incidence of hypoglycemia. METHODS: In this open-label, 24-week randomized trial in ten Latin American countries, T2DM patients poorly controlled on OADs (HbA1c > or = 7.5 and < or = 10.5%) received glimepiride plus insulin glargine (n = 231) or NPH insulin (n = 250) using a forced titration algorithm. The primary endpoint was the equivalence of 24-week mean changes in HbA1c. RESULTS: Insulin glargine and NPH insulin achieved similar HbA1c reductions (adjusted mean difference -0.047; 90% CI -0.232, 0.138; per-protocol analysis). Confirmed nocturnal hypoglycemia was significantly lower with insulin glargine vs. NPH insulin (16.9 vs. 30.0%; p <0.01; safety analysis). Patients receiving insulin glargine were significantly more likely to achieve HbA1c levels < 7.0% without hypoglycemia (27 vs. 17%; p = 0.014; per-protocol analysis). There was a more pronounced treatment satisfaction improvement with insulin glargine vs. NPH insulin (p <0.02; full analysis). The proportion of patients who lost time from work or normal activities due to diabetes was lower with insulin glargine vs. NPH (1.8 vs. 3.3%; full analysis). CONCLUSIONS: In patients with T2DM, inadequately controlled on OADs, once-daily insulin glargine plus glimepiride is effective in improving metabolic control with a reduced incidence of nocturnal hypoglycemia compared with NPH insulin.     

Early prediction of cerebral palsy after neonatal intensive care using motor development trajectories in infancy

Neonatal intensive care unit (NICU) patients are at high risk for developmental disabilities such as cerebral palsy (CP). Early identification of CP is essential to effective rehabilitation, but diagnosis is often delayed, especially in preterm infants. We hypothesized that through the longitudinal evaluation of motor trajectories in the NICU follow-up clinic, we could distinguish infants who develop CP by 3 years of age.     

Alteration of iron homeostasis following chronic exposure to manganese in rats

Recent studies suggest that manganese-induced neurodegenerative toxicity may be partly due to its action on aconitase, which participates in cellular iron regulation and mitochondrial energy production. This study was performed to investigate whether chronic manganese exposure in rats influenced the homeostasis of iron in blood and cerebrospinal fluid (CSF). Groups of 8–10 rats received intraperitoneal injections of MnCl₂ at the dose of 6 mg Mn/kg/day or equal volume of saline for 30 days. Concentrations of manganese and iron in plasma and CSF were determined by atomic absorption spectrophotometry. Rats exposed to manganese showed a greatly elevated manganese concentration in both plasma and CSF. The magnitude of increase in CSF manganese (11-fold) was equivalent to that of plasma (10-fold). Chronic manganese exposure resulted in a 32% decrease in plasma iron (p<0.01) and no changes in plasma total iron binding capacity (TIBC). However, it increased CSF iron by 3-fold as compared to the controls (p<0.01). Northern blot analyses of whole brain homogenates revealed a 34% increase in the expression of glutamine synthetase (p<0.05) with unchanged metallothionein-I in manganese-intoxicated rats. When the cultured choroidal epithelial cells derived from rat choroid plexus were incubated with MnCl₂ (100 μM) for four days, the expression of transferrin receptor mRNA appeared to exceed by 50% that of control (p<0.002). The results indicate that chronic manganese exposure alters iron homeostasis possibly by expediting unidirectional influx of iron from the systemic circulation to cerebral compartment. The action appears likely to be mediated by manganese-facilitated iron transport at brain barrier systems.     

Global status of diabetes prevention and prospects for action: A consensus statement

Primary prevention of type 2 diabetes (T2D) should be achievable through the implementation of early and sustainable measures. Several randomized control studies that found success in preventing the progression to T2D in high‐risk populations have identified early and intensive intervention based on an individualized prevention model as the key factor for participant benefit. The global prevalence of both overweight and obesity has now been widely recognized as the major epidemic of the 21st century. Obesity is a major risk factor for the progression from normal glucose tolerance to prediabetes and then to T2D. However, not all obese individuals will develop prediabetes or progress to diabetes. Intensive, multicomponent behavioural interventions for overweight and obese adults can lead to weight loss. Diabetes medications, including metformin, GLP‐1 agonists, glitazones, and acarbose, can be considered for selected high‐risk patients with prediabetes when lifestyle‐based programmes are proven unsuccessful. Nutrition education is the cornerstone of a healthy lifestyle. Also, physical activity is an integral part of the prediabetes management plan and one of the main pillars in the prevention of diabetes. Mobile phones, used extensively worldwide, can facilitate communication between health professionals and the general population, and have been shown to be helpful in the prevention of T2D. Universal screening is needed. Noninvasive risk scores should be used in all countries, but they should be locally validated in all ethnic populations focusing on cultural differences around the world. Lifestyle interventions reduce the progression to prediabetes and diabetes. Nevertheless, many questions still need to be answered.     

Effects of the combination of insulin and gliclazide compared with insulin alone in type 2 diabetic patients with secondary failure to oral hypoglycemic agents.

Twenty non-insulin-dependent diabetic patients on insulin therapy for more than 2 months due to secondary failure to oral hypoglycemic agents (OHA) were additionally treated with gliclazide, 80 mg b.i.d., for 1 month and 160 mg b.i.d. for a further 2 months, while reducing insulin dose gradually according to glycemic control. At the end of the first month, fasting blood glucose had decreased from 12.8 +/- 0.7 to 9 +/- 0.8 mM (mean +/- standard error; P < 0.005) and thereafter remained stable. Insulin requirements decreased from 34.2 +/- 2.5 to 18.3 +/- 3.2 U/day (P < 0.001). Three patients were able to cease insulin treatment altogether. A direct correlation was found between final insulin dose and previous duration of infusion monotherapy (r = 0.52; P < 0.05). C-peptide/glucose score (fasting C-peptide/fasting BG x 100) increased from 0.11 +/- 0.03 to 0.21 +/- 0.05 (P < 0.05). We conclude that combined therapy reduces insulin requirement by increasing endogenous secretion, which may mainly affect hepatic glucose production as indicated by greater improvement in fasting vs. post-prandial blood glucose. This therapy could avoid hyperinsulinemia, which has been reported to be involved in macrovascular complications, and the additional haemovascular properties of gliclazide could make it more effective in such a combination.