Differential hippocampal response to chronic alcohol consumption of young adult and mature adult rats

AIMS Early ethanol consumption could be a risk factor for young brain integrity and its maturation, and also for the development of addictive behaviors in adulthood. Neuronal nitric oxide synthase (nNOS) expressing neurons are specifically located in the subgranular layer (SGL) of dentate gyrus and may be relevant for hippocampal neurogenesis. The focus of this work is aimed to determine local changes in the nNOS-like immunoreactive (nNOS-LIR) cell populations of the SGL after chronic ethanol exposure in young adult and mature adult rats. METHODS We used the nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase (NADPH-d) reaction as a qualitative marker of nNOS enzyme activity. We also analyzed the nNOS-LIR cell density by the nNOS immunocytochemistry in order to compare these two methods of labeling. Dorsal striatum (CPu) was also analyzed in order to compare two neural areas with high nNOS-LIR cell density. RESULTS The young adult group showed less hippocampal NADPH-d(+) cell density than the mature adult group. Interestingly, the NADPH-d(+) cell density was increased in the SGL of the young adult ethanol-treated group, whereas it decreased in the mature adult ethanol-treated group, when compared with their respective controls. No change was observed in any of the groups for the hippocampal nNOS-LIR cell density and no differences could be established in CPu for nNOS-LIR and NADPH-d(+) cell densities in any of the groups studied. CONCLUSION The NADPH-d expression is affected by chronic ethanol exposure in opposite ways between both age groups studied. Further studies are needed to evaluate the relative importance of these findings, especially when considering human subject

Role of hippocampal NF-κB and GluN2B in the memory acquisition impairment of experiences gathered prior to cocaine administration in rats

Cocaine can induce severe neurobehavioral changes, among others, the ones involved in learning and memory processes. It is known that during drug consumption, cocaine-associated memory and learning processes take place. However, much less is known about the effects of this drug upon the mechanisms involved in forgetting.The present report focuses on the mechanisms by which cocaine affects memory consolidation of experiences acquired prior to drug administration. We also study the involvement of hippocampus in these processes, with special interest on the role of Nuclear factor kappa B (NF-κB), N-methyl-D-aspartate glutamate receptor 2B (GluN2B), and their relationship with other proteins, such as cyclic AMP response element binding protein (CREB). For this purpose, we developed a rat experimental model of chronic cocaine administration in which spatial memory and the expression or activity of several proteins in the hippocampus were assessed after 36 days of drug administration. We report an impairment in memory acquisition of experiences gathered prior to cocaine administration, associated to an increase in GluN2B expression in the hippocampus. We also demonstrate a decrease in NF-κB activity, as well as in the expression of the active form of CREB, confirming the role of these transcription factors in the cocaine-induced memory impairment

Cocaine promotes oxidative stress and microglial-macrophage activation in rat cerebellum

Different mechanisms have been suggested for cocaine neurotoxicity, including oxidative stress alterations. Nuclear factor kappa B (NF-κB), considered a sensor of oxidative stress and inflammation, is involved in drug toxicity and addiction. NF-κB is a key mediator for immune responses that induces microglial/macrophage activation under inflammatory processes and neuronal injury/degeneration. Although cerebellum is commonly associated to motor control, muscular tone, and balance. Its relation with addiction is getting relevance, being associated to compulsive and perseverative behaviors. Some reports indicate that cerebellar microglial activation induced by cannabis or ethanol, promote cerebellar alterations and these alterations could be associated to addictive-related behaviors. After considering the effects of some drugs on cerebellum, the aim of the present work analyzes pro-inflammatory changes after cocaine exposure. Rats received daily 15 mg/kg cocaine i.p., for 18 days. Reduced and oxidized forms of glutathione (GSH) and oxidized glutathione (GSSG), glutathione peroxidase (GPx) activity and glutamate were determined in cerebellar homogenates. NF-κB activity, CD68, and GFAP expression were determined. Cerebellar GPx activity and GSH/GSSG ratio are significantly decreased after cocaine exposure. A significant increase of glutamate concentration is also observed. Interestingly, increased NF-κB activity is also accompanied by an increased expression of the lysosomal mononuclear phagocytic marker ED1 without GFAP alterations. Current trends in addiction biology are focusing on the role of cerebellum on addictive behaviors. Cocaine-induced cerebellar changes described herein fit with previosus data showing cerebellar alterations on addict subjects and support the proposed role of cerebelum in addiction

ZnO-mesoporous glass scaffolds loaded with osteostatin and mesenchymal cells improve bone healing in a rabbit bone defect.

The use of 3D scaffolds based on mesoporous bioactive glasses (MBG) enhanced with therapeutic ions, biomolecules and cells is emerging as a strategy to improve bone healing. In this paper, the osteogenic capability of ZnO-enriched MBG scaffolds loaded or not with osteostatin (OST) and human mesenchymal stem cells (MSC) was evaluated after implantation in New Zealand rabbits. Cylindrical meso-macroporous scaffolds with composition (mol %) 82.2SiO2–10.3CaO–3.3P2O5–4.2ZnO (4ZN) were obtained by rapid prototyping and then, coated with gelatin for easy handling and potentiating the release of inorganic ions and OST. Bone defects (7.5 mm diameter, 12 mm depth) were drilled in the distal femoral epiphysis and filled with 4ZN, 4ZN+MSC, 4ZN+OST or 4ZN+MSC+OST materials to evaluate and compare their osteogenic features. Rabbits were sacrificed at 3 months extracting the distal third of bone specimens for necropsy, histological and microtomography (µCT) evaluations. Systems investigated exhibited bone regeneration capability. Thus, trabecular bone volume density (BV/TV) values obtained from µCT showed that the good bone healing capability of 4ZN was significantly improved by the scaffolds coated with OST and MSC. Our findings in vivo suggest the interest of these MBG complete systems to improve bone repair in the clinical practice

Chronic Cocaine Effects in Retinal Metabolism and Electrophysiology: Treatment with Topiramate

Purpose: Cocaine abuse is a major public health problem with multiple-related complications. Indeed, cocaine can affect almost every organ of the human body, but little is known about its effects on the visual system. The main purpose of this work was to study if topiramate was able to reverse changes in retinal metabolism and retinal function induced by chronic cocaine exposure in adult rats. Materials and methods: Sixteen Wistar rats were treated with a daily oral dose of cocaine during 36 days. Sixteen rats receiving NaCl 0.9% served as controls. Eight control and eight cocaine animals were administered topiramate from day 18 to day 36 of the experiment. Malondialdehyde (MDA), glutathione (GSH) and glutamate content, as well as glutathione peroxidase (GPx) activity in retina tissue homogenates were determined. Retinal function was assessed by electroretinogram (ERG). Results: Glutamate concentration was increased in the retinas of cocaine-treated rats. No changes in oxidative stress parameters were observed in the retinas of cocaine-treated rats when compared with the control ones. Cocaine induced a decrease in the a-wave and b-wave ERG amplitude. The administration of topiramate reversed cocaine-induced increase in glutamate concentration and had little effect on a-wave and b-wave ERG amplitude. Topiramate, a drug used during the last decade for the treatment of epileptic seizures, is able to reverse the cocaine-induced alterations observed in retinal glutamate concentration. Conclusions: We can conclude that retinal glutamate metabolism and function may be affected by exposure to cocaine. We confirm that topiramate, a treatment recently proposed for cocaine dependence, is also able to recover partially cocaine-induced changes in the retina

Evolution over Time of Ventilatory Management and Outcome of Patients with Neurologic Disease∗

OBJECTIVES: To describe the changes in ventilator management over time in patients with neurologic disease at ICU admission and to estimate factors associated with 28-day hospital mortality. DESIGN: Secondary analysis of three prospective, observational, multicenter studies. SETTING: Cohort studies conducted in 2004, 2010, and 2016. PATIENTS: Adult patients who received mechanical ventilation for more than 12 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 20,929 patients enrolled, we included 4,152 (20%) mechanically ventilated patients due to different neurologic diseases. Hemorrhagic stroke and brain trauma were the most common pathologies associated with the need for mechanical ventilation. Although volume-cycled ventilation remained the preferred ventilation mode, there was a significant (p < 0.001) increment in the use of pressure support ventilation. The proportion of patients receiving a protective lung ventilation strategy was increased over time: 47% in 2004, 63% in 2010, and 65% in 2016 (p < 0.001), as well as the duration of protective ventilation strategies: 406 days per 1,000 mechanical ventilation days in 2004, 523 days per 1,000 mechanical ventilation days in 2010, and 585 days per 1,000 mechanical ventilation days in 2016 (p < 0.001). There were no differences in the length of stay in the ICU, mortality in the ICU, and mortality in hospital from 2004 to 2016. Independent risk factors for 28-day mortality were age greater than 75 years, Simplified Acute Physiology Score II greater than 50, the occurrence of organ dysfunction within first 48 hours after brain injury, and specific neurologic diseases such as hemorrhagic stroke, ischemic stroke, and brain trauma. CONCLUSIONS: More lung-protective ventilatory strategies have been implemented over years in neurologic patients with no effect on pulmonary complications or on survival. We found several prognostic factors on mortality such as advanced age, the severity of the disease, organ dysfunctions, and the etiology of neurologic disease