The extent of brain injury during reperfusion appears to depend on the experimental pattern of ischemia/reperfusion. The goals of this study were: first, to identify the rate of free radicals generation and the antioxidant activity during ischemia and reperfusion by means of biochemical measurement of lipid peroxidation (LPO) and both enzymatic (superoxid dismutase -SOD, catalase -CAT, glutathion peroxidase -GPx) and non-enzymatic antioxidants activity (glutathione -GSH); and second, to try to find out how the pattern of reperfusion may influence the balance between free radical production and clearance. Wistar male rats were subject of four-vessel occlusion model (Pulsinelly & Brierley) cerebral blood flow being controlled by means of two atraumatic arterial microclamps placed on carotid arteries. The level of free radicals and the antioxidant activity were measured in ischemic rat brain tissue homogenate using spectrophotometrical techniques. All groups subjected to ischemia shown an increase of LPO and a reduction of the activity of enzymatic antioxidative systems (CAT, GPx, SOD) and non-enzymatic systems (GSH). For both groups subjected to ischemia and reperfusion, results shown an important increase of LPO but less significant than the levels found in the group with ischemia only. Statistically relevant differences (p<0.01) between continuous reperfusion and fragmented reperfusion were observed concerning the LPO, CAT, SOD and GSH levels, oxidative aggression during fragmented reperfusion being more important.
Attractive therapeutic strategies to enhance post-stroke recovery of aged brains include methods of cellular therapy that can enhance the endogenous restorative mechanisms of the injured brain. Since stroke afflicts mostly the elderly, it is highly desirable to test the efficacy of cell therapy in the microenvironment of aged brains that is generally refractory to regeneration. In particular, stem cells from the bone marrow allow an autologous transplantation approach that can be translated in the near future to the clinical practice. Such a bone marrow-derived therapy includes the grafting of stem cells as well as the delayed induction of endogenous stem cell mobilization and homing by the stem cell mobilizer granulocyte colony-stimulating factor (G-CSF). We tested the hypothesis that grafting of bone marrow-derived pre-differentiated mesenchymal cells (BM-MSCs) in G-CSF-treated animals improves the long-term functional outcome in aged rodents. To this end, G-CSF alone (50 μg/kg) or in combination with a single dose (106 cells) of rat BM MSCs was administered intravenously to Sprague-Dawley rats at 6 h after transient occlusion (90 min) of the middle cerebral artery. Infarct volume was measured by magnetic resonance imaging at 3 and 48 days post-stroke and additionally by immunhistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period of 56 days. Daily treatment for post-stroke aged rats with G-CSF led to a robust and consistent improvement of neurological function after 28 days. The combination therapy also led to robust angiogenesis in the formerly infarct core and beyond in the “islet of regeneration.” However, G-CSF + BM MSCs may not impact at all on the spatial reference-memory task or infarct volume and therefore did not further improve the post-stroke recovery. We suggest that in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time.
Current anti-epileptic medications that boost synaptic inhibition are effective in reducing several types of epileptic seizure activity. Nevertheless, these drugs can generate significant side-effects and even paradoxical responses due to the broad nature of their action. Recently developed chemogenetic techniques provide the opportunity to pharmacologically recruit endogenous inhibitory mechanisms in a selective and circuit-specific manner. Here, we use chemogenetics to assess the potential of suppressing epileptiform activity by enhancing the synaptic output from three major interneuron populations in the rodent hippocampus: parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP) expressing interneurons. To target different neuronal populations, promoter-specific cre-recombinase mice were combined with viral-mediated delivery of chemogenetic constructs. Targeted electrophysiological recordings were then conducted in an in vitro model of chronic, drug-resistant epilepsy. In addition, behavioral video-scoring was performed in an in vivo model of acutely triggered seizure activity. Pre-synaptic and post-synaptic whole cell recordings in brain slices revealed that each of the three interneuron types increase their firing rate and synaptic output following chemogenetic activation. However, the interneuron populations exhibited different effects on epileptiform discharges. Recruiting VIP interneurons did not change the total duration of epileptiform discharges. In contrast, recruiting SST or PV interneurons produced robust suppression of epileptiform synchronization. PV interneurons exhibited the strongest effect per cell, eliciting at least a fivefold greater reduction in epileptiform activity than the other cell types. Consistent with this, we found that in vivo chemogenetic recruitment of PV interneurons suppressed convulsive behaviors by more than 80%. Our findings support the idea that selective chemogenetic enhancement of inhibitory synaptic pathways offers potential as an anti-seizure strategy.
Capsaicin is a widespread spice known for its analgesic qualities. Although a comprehensive body of evidence suggests pleiotropic benefits of capsaicin, including anti-inflammatory, antioxidant, anti-proliferative, metabolic, or cardioprotective effects, it is frequently avoided due to reported digestive side-effects. As the gut bacterial profile is strongly linked to diet and capsaicin displays modulatory effects on gut microbiota, a new hypothesis has recently emerged about its possible applicability against widespread pathologies, such as metabolic and inflammatory diseases. The present review explores the capsaicin–microbiota crosstalk and capsaicin effect on dysbiosis, and illustrates the intimate mechanisms that underlie its action in preventing the onset or development of pathologies like obesity, diabetes, or inflammatory bowel diseases. A possible antimicrobial property of capsaicin, mediated by the beneficial alteration of microbiota, is also discussed. However, as data are coming mostly from experimental models, caution is needed in translating these findings to humans.
The presence of maternal Anti-Ro/Anti-La antibodies causes a passively acquired autoimmunity that may be associated with serious fetal complications. The classic example is the autoimmune-mediated congenital heart block (CHB) which is due in most cases to the transplacental passage of Anti-Ro/Anti-La antibodies. The exact mechanisms through which these pathologic events arise are linked to disturbances in calcium channels function, impairment of calcium homeostasis and ultimately apoptosis, inflammation and fibrosis. CHB still represents a challenging diagnosis and a source of debate regarding the best management. As the third-degree block is usually irreversible, the best strategy is risk awareness and prevention. Although CHB is a rare occurrence, it affects one in 20,000 live births, with a high overall mortality rate (up to 20%, with 70% of in utero deaths). There is also concern over the lifelong consequences, as most babies need a pacemaker. This review aims to offer, apart from the data needed for a better understanding of the issue at hand, a broader perspective of the specialists directly involved in managing this pathology: the rheumatologist, the maternal–fetal specialist and the cardiologist. To better illustrate the theoretical facts presented, we also include a representative clinical case.
Capillary electrophoresis (CE) is a resourceful and versatile separation method for the analysis of complex carbohydrate mixtures. In combination with electrospray ionization (ESI) mass spectrometry (MS), CE enables fast, sensitive, and efficient separations for the accurate identification of a large variety of glycoform mixture types. In this chapter several reliable off- and on-line CE-based methods for the analysis of glycoforms with ESI MS/MS are presented. The first part of this chapter is dedicated to the application of off-line CE/ESI MS to complex mixtures of O-glycopeptides and mixtures of proteoglycan-derived O-glycans, i.e., glycosaminoglycans such as depolymerized hybrid chains of chondroitin sulfate (CS) and dermatan sulfate (DS). Procedures for off-line fractionation of these heterogeneous mixtures followed by ESI MS screening and sequencing of single glycoforms by collision-induced dissociation (CID) at low energies are also described. Ample sections are further devoted to on-line CE/ESI MS technique and its application to separation and identification of O-glycopeptides and CS/DS oligosaccharides. The concept and construction principles of two different sheathless CE/ESI MS interfaces together with the protocols to be applied for successful on-line analysis of O-glycopeptides and CS/DS oligosaccharides are presented in details in the last part of the chapter.
Ischemic preconditioning (IPC) of the brain describes the neuroprotection induced by a short, conditioning ischemic episode (CIE) to a subsequent severe (test) ischemic episode (TIE). Most of the supporting evidence for IPC is based on histological assessment, several days after TIE. The aim of this study is to investigate if changes induced by IPC can be detected within 30 min of reperfusion following the ischemic episode. A rat model of "four-vessel occlusion" transient global cerebral ischemia and parametric analysis of electrocorticogram were used. A control group was subjected directly to a 10 min TIE, and in a preconditioned group TIE was induced 48 h after a 3 min CIE. Quantitative histology was performed 48 h after TIE. Our key finding is that, 30 min after reperfusion, there is a significant increase in the electrocortical slow activity in the control group but not in the preconditioned group. Moreover the increase inversely correlates with the degree of electrocortical suppression during seconds 10 to 15 after the onset of the ischemic episode.The tolerance of the brain to an ischemic injury depends not only on the duration and severity of insufficient blood flow but also on various pre-and post-ischemic factors that are able to influence the post ischemic outcome. There is a lot of interest concerning the postischemic factors that can improve the recovery due to immediate clinical applicability. Nevertheless, recent experimental work focuses on the preischemic factors, that can increase the ischemic tolerance, among which the suppression of metabolic rate, the increase of brain tissue energy reserves and the inhibition of membrane permeability of cations are of particular importance [1].One of the most surprising discoveries in the search for preischemic neuroprotective factors was that exposure to short episodes of sublethal insults like ischemia, hypoxia, hyperthermic stresses and toxic agents results in a subsequent resistance to severe ischemic injury. The phenomenon of
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