Novel Probucol Analogue, 4,4'-Diselanediylbis (2,6-Di-tert-Butylphenol), Prevents Oxidative Glutamate Neurotoxicity In Vitro and Confers Neuroprotection in a Rodent Model of Ischemic Stroke.

Oxidative glutamate toxicity is regarded as one of the injurious mechanisms associated with ischemic stroke, which represents a major health problem and requires improved pharmacological treatments. We designed and synthesized two new probucol analogues [2,6-di-tert-butyl-4-selenocyanatophenol (C1) and 4,4'-diselanediylbis (2,6-di-tert-butylphenol) (C2)] and investigated their effects against glutamate-induced neuronal oxidative toxicity in vitro in cultured HT22 cells, compared with their parental compound (probucol). In addition, C2, which exhibited the lowest toxicity, was investigated in an in vivo rodent model of ischemic stroke. Glutamate caused concentration- and time-dependent cytotoxicity in HT22 neuronal cells, which was preceded by increased levels of oxidants and depletion of the antioxidant glutathione. The analogues (C1 and C2), but not probucol, significantly decreased the levels of oxidants (including mitochondrial superoxide anion and lipid reactive oxygen species (ROS)) and protected against glutamate-induced cytotoxicity. In the in vivo model of ischemic stroke, which was based on central injections of the vasoconstrictor agent endothelin-1 (800 pmol/site), C2 (20 or 50 mg/kg/day, intraperitoneally, for 4 consecutive days after stroke) displayed significant beneficial effects against ischemic injury in vivo, improving rats' motor-related behavioral skills and decreasing stroke-related striatal gliosis. This is the first study to design, synthesize, and present a probucol analogue (C2) with in vivo beneficial effects against ischemic stroke. This novel compound, which was able to mitigate glutamate-induced oxidative toxicity in vitro, represents a promising neuroprotective drug.

Temporal and contextual binding in episodic memory in younger and older adults.

Episodic memory (EM) is a subsystem responsible for storing and recalling information about the basic elements of an event in a binding manner. Some approaches consider the temporal element to be one of the basic components of EM (WWWhen paradigm), while others consider that the contextual component is able in practice to better represent this cognitive ability (WWWhich paradigm). The relationship of both paradigms simultaneously with other instruments for measuring EM has not been investigated in healthy older adults. Thus, the present study examined the performance of young and older adults on questions based on the WWWhen and WWWhich paradigms, investigating the relationship of these questions with episodic (Remember) and non-episodic (Know) strategies. The results showed that for the younger adults both the questions demonstrated to only be significantly related with the "remember" strategy. On the other hand, older adults presented a response pattern in which the "WWWhich" questions used only episodic strategies for their correct resolution. Aging appears to promote a substantial reduction in both "Remember" and "Know" strategies, mainly those associated with solving tasks based on the temporal element of EM.

Selenium-Derivative Compounds: A Review of New Perspectives in the Treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is one of the most prevalent types of dementia, affecting millions of older people worldwide. AD is stimulating efforts to develop novel molecules targeting its main features associated with a decrease in acetylcholine levels, an increase in oxidative stress and depositions of amyloid-ß (Aß) and tau protein. In this regard, selenium-containing compounds have been demonstrated as potential multi-targeted compounds in the treatment of AD. These compounds are known for their antioxidant and anticholinesterase properties, causing a decrease in Aß aggregation. OBJECTIVE: In this review, we approach structure-activity relationships of each compound, associating the decrease of ROS activity, an increase of tau-like activity and inhibition of AChE with a decrease in the self-aggregation of Aß. METHODS: We also verify that the molecular descriptors apol, nHBAcc and MlogP may be related to optimized pharmacokinetic properties for anti-AD drugs. RESULTS: In our analysis, few selenium-derived compounds presented similar molecular features to FDA-approved drugs. CONCLUSION: We suggest that unknown selenium-derived molecules with apol, nHBAcc and MlogP like FDA-approved drugs may be better successes with optimized pharmacokinetic properties in future studies in AD.

Assessing episodic memory in rodents using spontaneous object recognition tasks.

Models of episodic memory are successfully established using spontaneous object recognition tasks in rodents. In this review, we present behavioral techniques devised to investigate this type of memory, emphasizing methods based on associations of places and temporal order of items explored by rats and mice. We also provide a review on the areas and circuitry of the medial temporal lobe underlying episodic-like memory, considering that a large number of neurobiology data derived from these protocols. Although spontaneous recognition tasks are commonplace in this field, there is need for careful evaluation of factors affecting animal performance. Such as the ongoing development of tools for investigating the neural basis of memory, efforts should be put in the refinement of experimental designs, in order to provide reliable behavioral evidence of this complex mnemonic system.

Post-learning caffeine administration improves 'what-when' and 'what-where' components of episodic-like memory in rats.

Episodic-like memory (ELM) consists in the capacity of nonhuman animals to remember 'where' and 'when' a specific episode occurred ('what'). Previous studies have showed that Wistar rats can form an ELM, but not after a 24 h retention delay. On the other hand, it has been demonstrated that caffeine can improve episodic memory consolidation in humans. Therefore, we verified whether acute post-sample caffeine administration could improve ELM consolidation in Wistar rats, as well if it could be related to neurochemical changes in the prefrontal cortex and hippocampus - regions related to episodic-like memory processing. 46 Male Wistar Rats, approximately 3 months-old, were divided into four groups as follows: untreated (n = 11), saline (n = 11), caffeine 10 mg ∕kg i.p (n = 12); caffeine 15 mg∕kgi.p (n = 12) and tested in WWWhen/ELM task. The animals treated with caffeine in different dosages (10 mg/kg and 15 mg/kg) discriminated temporally and spatially the objects, respectively. These groups also showed a dopamine renewal rate in the hippocampus, suggesting that there was an increase in the turnover compared with the groups with no caffeine administration. We can conclude that caffeine leads to an improvement in the consolidation of the temporal ('what-when') and spatial ('what-where') aspects of episodic-like memory.

Anticonvulsant Activity of trans-Anethole in Mice.

Epilepsy is a chronic neurological disorder affecting 1-2% of world population, and one-third of patients are refractory to pharmacological treatment. This fact has stimulated research for new antiepileptic drugs and natural products have been an important source. trans-Anethole (TAN) is a phenylpropanoid, component of some essential oils, extracted from plants, and its effects have been little studied. Therefore, this study is aimed at investigating the TAN effect in classic seizure models and evaluate the electroencephalographic (EEG) profile of animals treated with this substance. For this, Swiss male mice (Mus musculus) were used, and the lethal dose was evaluated and subsequently submitted to the test maximal electroshock (MES), the pentylenetetrazole- (PTZ) induced seizure test, and the EEG profile. Initially, the LD50 for TAN was estimated in 1000 mg/kg (i.p.) dose and there was no sign of acute toxicity or death. In the MES test, TAN 300, i.p. (12.00 ± 2.9 s) and 400 mg/kg, i.p. (9.00 ± 4.4 s) doses was able to decrease tonic seizures duration induced by electric discharge (0.5 mA, 150 pulses/s, for 0.5 s). In the PTZ test (75 mg/kg, i.p.), TAN 400 mg/kg, i.p. increased the latency to myoclonic jerks (80.0 (56.0-134.0)), the latency totonic-clonic seizures (900.0 (861.0-900.0) and decrease seizure duration (0.0 (0.0-10.0)). No deaths were found in this groups compared to vehicle. EEG analysis showed an amplitude decrease of waves (ratio of baseline) in TAN 300 (1.82 ± 0.23) and 400 mg/kg (1.06 ± 0.16) groups. In this way, TAN at 400 mg/kg was able to inhibit and/or attenuate seizures by increasing the time for the onset of spasms and convulsions, as reducing the duration of seizures. The EEG profile corroborate with this results showing a reduction in the amplitude of waves compared to the PTZ group. Thus, TAN showed an anticonvulsant effect in all experimental models performed, behavioral and electroencephalographic.

A Novel Diselenide-Probucol-Analogue Protects Against Methylmercury-Induced Toxicity in HT22 Cells by Upregulating Peroxide Detoxification Systems: a Comparison with Diphenyl Diselenide.

Methylmercury (MeHg) is a ubiquitous environmental neurotoxicant whose mechanisms of action involve oxidation of endogenous nucleophilic groups (mainly thiols and selenols), depletion of antioxidant defenses, and disruption of neurotransmitter homeostasis. Diphenyl diselenide-(PhSe)2-a model diaryl diselenide, has been reported to display significant protective effects against MeHg-induced neurotoxicity under both in vitro and in vivo experimental conditions. In this study, we compared the protective effects of (PhSe)2 with those of RC513 (4,4'-diselanediylbis(2,6-di-tert-butylphenol), a novel diselenide-probucol-analog) against MeHg-induced toxicity in the neuronal (hippocampal) cell line HT22. Although both (PhSe)2 and RC513 significantly mitigated MeHg- and tert-butylhydroperoxide (t-BuOOH)-cytotoxicity, the probucol analog exhibited superior protective effects, which were observed earlier and at lower concentrations compared to (PhSe)2. RC513 treatment (at either 0.5 µM or 2 µM) significantly increased glutathione peroxidase (GPx) activity, which has been reported to counteract MeHg-toxicity. (PhSe)2 was also able to increase GPx activity, but only at 2 µM. Although both compounds increased the Gpx1 transcripts at 6 h after treatments, only RC513 was able to increase mRNA levels of Prx2, Prx3, Prx5, and Txn2, which are also involved in peroxide detoxification. RC513 (at 2 µM) significantly increased GPx-1 protein expression in HT22 cells, although (PhSe)2 displayed a minor (nonsignificant) effect in this parameter. In agreement, RC513 induced a faster and superior capability to cope with exogenously-added peroxide (t-BuOOH). In summary, when compared to the prototypical organic diaryl diselenide [(PhSe)2], RC513 displayed superior protective properties against MeHg-toxicity in vitro; this was paralleled by a more pronounced upregulation of defenses related to detoxification of peroxides, which are well-known MeHg-derived intermediate oxidant species.

Uso de aterectomia rotacional para tratamento de reestenose intra-stent com subexpansão de dupla malha de stents coronarianos. Relato de caso / Use of rotational atherectomy for treatment of in-stent restenosis with coronary double-mesh stent underexpansion. Case report

O tratamento de lesões reestenóticas intra-stent, principalmente as calcificadas, com subexpansão do stent, geralmente requer o uso de técnicas mais complexas para sua execução, como a aterectomia rotacional. O caso se trata de um paciente do sexo masculino com lesão reestenótica focal intra-stent de 99% na origem do primeiro ramo diagonal, local onde foram implantados dois stents há 14 anos. Após falha da angioplastia apenas com balões, realizou-se a ablação da placa e de parte das hastes dos stents pela técnica de aterectomia rotacional, o que possibilitou o implante de novo stent com sua expansão total.

Treatment of in-stent restenosis lesions, especially calcified lesions, with stent underexpansion, generally requires more complex techniques, such as rotational atherectomy. The case reported is a male patient with a 99% in-stent focal restenosis lesion at the origin of the first diagonal branch, where two stents were implanted 14 years ago. After failure of balloon angioplasty alone, ablation of the plaque and part of the stent struts was performed using the rotational atherectomy technique, which allowed the implantation of a new stent which was totally expanded.

Análise dos desfechos em intervenção coronária percutânea de tronco de coronária esquerda não protegido / Analysis of percutaneous coronary intervention outcomes in unprotected left main coronary artery lesions

Introdução: Lesões significativas no tronco de coronária esquerda são encontradas em aproximadamente 5% dos pacientes submetidos à coronariografia, sendo a maioria dos casos multiarteriais e com envolvimento do tronco distal. A cirurgia de revascularização do miocárdio é considerada o tratamento preferencial para lesões de tronco de coronária esquerda não protegido. No entanto, com o avanço de técnicas e a introdução dos novos stents liberadores de fármacos, a intervenção coronariana percutânea tem sido considerada estratégia viável, apresentando resultados favoráveis. O objetivo deste estudo foi analisar os desfechos em pacientes com lesões de tronco de coronária esquerda não protegido submetidos à intervenção coronariana percutânea. Métodos: Foram analisados dados eletrônicos de pacientes submetidos à intervenção coronariana percutânea entre dezembro de 2017 e janeiro de 2020 em um único centro, com o objetivo de avaliar características clínicas, angiográficas e os desfechos clínicos. Resultados: Foram incluídos 103 pacientes portadores de lesões significativas de tronco não protegido, 66% eram do sexo masculino, 88,3% eram hipertensos, e 87,4% possuíam função ventricular normal. Lesões envolvendo a bifurcação foram identificadas em 73,8% dos pacientes, 36,9% apresentavam lesões concomitantes nos três grandes vasos epicárdicos e 42,7% com escore SYNTAX intermediário (23 a 32 pontos). O sucesso angiográfico foi obtido em 100% dos casos, com quatro (3,9%) eventos cardíacos e cerebrovasculares adversos, sendo 2,9% de mortalidade. Conclusão: Os resultados hospitalares sustentam a intervenção coronariana percutânea como um procedimento seguro, de excelente resultado angiográfico e eventos cardíacos e cerebrovasculares adversos comparáveis aos da cirurgia de revascularização do miocárdio, configurando opção bastante viável em relação ao tratamento cirúrgico.

Background: Significant lesions in the left main coronary artery are found in approximately 5% of patients undergoing coronary angiography, with most cases involving multiple vessels and affecting the distal bifurcation. A coronary artery bypass graft surgery is considered the preferred treatment for unprotected left main coronary artery lesions. However, with the advancement of techniques and the introduction of new drug-eluting stents, percutaneous coronary intervention has been considered a viable strategy, with favorable results. The objective of this study was to analyze the outcomes in patients with unprotected left main coronary artery lesions undergoing percutaneous coronary intervention. Methods: Electronic data from patients undergoing percutaneous coronary intervention between December 2017 and January 2020 at a single center were analyzed to assess clinical and angiographic characteristics and clinical outcomes. Results: A total of 103 patients with significant unprotected left main coronary artery lesions were included; in that, 66% were male, 88.3% were hypertensive, and 87.4% had normal ventricular function. Lesions involving the bifurcation were identified in 73.8% of patients, 36.9% had concomitant lesions in the three major epicardial vessels, and 42.7% had an intermediate SYNTAX score (23 to 32 points). Angiographic success was achieved in 100% of cases, with four (3.9%) adverse cardiac and cerebrovascular events, with 2.9% mortality. Conclusion: Hospital results support percutaneous coronary intervention as a safe procedure, with excellent angiographic results and low rates of adverse cardiac and cerebrovascular events. We concluded that percutaneous coronary intervention is an option to coronary artery bypass graft surgery and is a very viable option for surgical treatment of unprotected left main coronary artery lesions.

Docking and molecular dynamics predicted B-DNA and dihydropyrimidinone selenoesters interactions elucidating antiproliferative effects on breast adenocarcinoma cells.

Dihydropyrimidinones have demonstrated different biological activities including anticancer properties. Cytotoxic potential and antiproliferative potential of new dihydropyrimidinone-derived selenoesters (Se-DHPM) compounds were assessed in vitro against the breast adenocarcinoma cells (MCF-7). Among the eight Se-DHPM compounds tested just 49A and 49F were the most cytotoxic for MCF-7 and the most selective for the non-tumor strain (McCoy) and reduced cell viability in a time- and concentration-dependent manner. Compounds 49A and 49F increased the rate of cell death due to apoptosis and necrosis comparatively to the control, however only the 49F showed antiproliferative potential, reducing the number of colonies formed. In the molecular assay 49A interacts with CT-DNA and caused hyperchromism while 49F caused a hypochromic effect. The intercalation test revealed that the two compounds caused destabilization in the CT-DNA molecule. This effect was evidenced by the loss of fluorescence when the compounds competed and caused the displacement of propidium iodide. Simulations (docking and molecular dynamics) using B-DNA brought a greater understanding of ligand-B-DNA interactions. Furthermore, they predicted that the compounds act as minor groove ligands that are stabilized through hydrogen bonds and hydrophobic interactions. However, the form of interaction foreseen for 49A was more energetically favorable and had more stable hydrogen bonds during the simulation time. Despite some violations foreseen in the ADMET for 49F, the set of other results point to this Se-DHPM as a promising leader compound with anti-tumor potential for breast cancer.Communicated by Ramaswamy H. Sarma.

Dihydropyrimidinone-derived selenoesters efficacy and safety in an in vivo model of Aß aggregation.

In a previous in vitro study, dihydropyrimidinone-derived selenoesteres demonstrated antioxidant properties, metal chelators and inhibitory acetylcholinesterase (AChE) activity, making these compounds promising candidates for Alzheimer's Disease (AD) treatment. However, these effects have yet to be demonstrated in an in vivo animal model; therefore, this study aimed to evaluate the safety and efficacy of eight selenoester compounds in a Caenorhabditis elegans model using transgenic strains for amyloid-beta peptide (Aß) aggregation. The L1 stage worms were acutely exposed (30 min) to the compounds at concentrations ranging from 5 to 200 µM and after 48 h the maintenance temperature was increased to 25 ° C for Aß expression and aggregation. After 48 h, several parameters related to phenotypic manifestations of Aß toxicity and mechanistic elucidation were analyzed. At the concentrations tested no significant toxicity of the compounds was found. The selenoester compound FA90 significantly reduced the rate of paralyzed worms and increased the number of swimming movements compared to the untreated worms. In addition, FA90 and FA130 improved egg-laying induced by levamisole and positively modulated HSP-6 and HSP-4 expression, thereby increasing reticular and mitochondrial protein folding response in C. elegans, which could attenuate Aß aggregation in early exposure. Therefore, our initial screening using an alternative model demonstrated that FA90, among the eight selenoesters evaluated, was the most promising compound for AD evaluation screening in more complex animals.

Theta and gamma oscillations in the rat hippocampus support the discrimination of object displacement in a recognition memory task.

Episodic memory depends on the recollection of spatial and temporal aspects of past experiences in which the hippocampus plays a critical role. Studies on hippocampal lesions in rodents have shown that dentate gyrus (DG) and CA3 are necessary to detect object displacement in memory tasks. However, the understanding of real-time oscillatory activity underlying memory discrimination of subtle and pronounced displacements remains elusive. Here, we chronically implanted microelectrode arrays in adult male Wistar rats to record network oscillations from DG, CA3, and CA1 of the dorsal hippocampus while animals executed an object recognition task of high and low spatial displacement tests (HD: 108 cm, and LD: 54 cm, respectively). Behavioral analysis showed that the animals discriminate between stationary and displaced objects in the HD but not LD conditions. To investigate the hypothesis that theta and gamma oscillations in different areas of the hippocampus support discrimination processes in a recognition memory task, we compared epochs of object exploration between HD and LD conditions as well as displaced and stationary objects. We observed that object exploration epochs were accompanied by strong rhythmic activity in the theta frequency (6-12 Hz) band in the three hippocampal areas. Comparison between test conditions revealed higher theta band power and higher theta-gamma phase-amplitude coupling in the DG during HD than LD conditions. Similarly, direct comparison between displaced and stationary objects within the HD test showed higher theta band power in CA3 during exploration of displaced objects. Moreover, the discrimination index between displaced and stationary objects directly correlated with CA1 gamma band power in epochs of object exploration. We thus conclude that theta and gamma oscillations in the dorsal hippocampus support the successful discrimination of object displacement in a recognition memory task.

Prevention of ferroptosis in acute scenarios: an in vitro study with classic and novel anti-ferroptotic compounds.

Ferroptosis, an iron-dependent form of cell death, has critical roles in diverse pathologies. Data on the temporal events mediating the prevention of ferroptosis are lacking. Focused on temporal aspects of cytotoxicity/protection, we investigated the effects of classic (Fer-1) and novel [2,6-di-tert-butyl-4-(2-thienylthio)phenol (C1) and 2,6-di-tert-butyl-4-(2-thienylselano)phenol (C2)] anti-ferroptotic agents against RSL3-, BSO- or glutamate-induced ferroptosis in cultured HT22 neuronal cell line, comparing their effects with those of the antioxidants trolox, ebselen and probucol. Glutamate (5 mM), BSO (25 µM) and RSL3 (50 nM) decreased approximately 40% of cell viability at 24 h. At these concentrations, none of these agents changed cell viability at 6 h after treatments; RSL3 increased lipoperoxidation from 6 h, although BSO and glutamate only did so at 12 h after treatments. At similar conditions, BSO and glutamate (but not RSL3) decreased GSH levels at 6 h after treatments. Fer-1, C1 and C2 exhibited similar protective effects against glutamate-, BSO- and RSL3-cytotoxicity, but this protection was limited when the protective agents were delivered to cells at time-points characterized by increased lipoperoxidation (but not glutathione depletion). Compared to Fer-1, C1 and C2, the anti-ferroptotic effects of trolox, ebselen and probucol were minor. Cytoprotective effects were not associated with direct antioxidant efficacies. These results indicate that the temporal window is central in affecting the efficacies of anti-ferroptotic drugs in acute scenarios; ferroptosis prevention is improbable when significant rates of lipoperoxidation were already achieved. C1 and C2 displayed remarkable cytoprotective effects, representing a promising new class of compounds to treat ferroptosis-related pathologies.

Catalytic Antioxidant Activity of Bis-Aniline-Derived Diselenides as GPx Mimics.

Herein, we describe a simple and efficient route to access aniline-derived diselenides and evaluate their antioxidant/GPx-mimetic properties. The diselenides were obtained in good yields via ipso-substitution/reduction from the readily available 2-nitroaromatic halides (Cl, Br, I). These diselenides present GPx-mimetic properties, showing better antioxidant activity than the standard GPx-mimetic compounds, ebselen and diphenyl diselenide. DFT analysis demonstrated that the electronic properties of the substituents determine the charge delocalization and the partial charge on selenium, which correlate with the catalytic performances. The amino group concurs in the stabilization of the selenolate intermediate through a hydrogen bond with the selenium.

Stress, memory, and implications for major depression.

The stress response comprises a phylogenetically conserved set of cognitive, physiological, and behavioral responses that evolved as a survival strategy. In this context, the memory of stressful events would be adaptive as it could avoid re-exposure to an adverse event, otherwise the event would be facilitated in positively stressful or non-distressful conditions. However, the interaction between stress and memory comprises complex responses, some of them which are not yet completely understood, and which depend on several factors such as the memory system that is recruited, the nature and duration of the stressful event, as well as the timing in which this interaction takes place. In this narrative review, we briefly discuss the mechanisms of the stress response, the main memory systems, and its neural correlates. Then, we show how stress, through the action of its biochemical mediators, influences memory systems and mnemonic processes. Finally, we make use of major depressive disorder to explore the possible implications of non-adaptive interactions between stress and memory to psychiatric disorders, as well as possible roles for memory studies in the field of psychiatry.

Novel Dihydropyrimidinone-Derived Selenoesters as Potential Cytotoxic Agents to Human Hepatocellular Carcinoma: Molecular Docking and DNA Fragmentation.

BACKGROUND AND OBJECTIVE: Evidence point out promising anticancer activities of Dihydropyrimidinones (DHPM) and organoselenium compounds. This study aimed to evaluate the cytotoxic and antiproliferative potential of DHPM-derived selenoesters (Se-DHPM), as well as their molecular mechanisms of action. METHODS: Se-DHPM cytotoxicity was evaluated against cancer lines (HeLa, HepG2, and MCF-7) and normal cells (McCoy). HepG2 clonogenic assay allowed verifying antiproliferative effects. The propidium iodide/ orange acridine fluorescence readings showed the type of cell death induced after treatments (72h). Molecular simulations with B-DNA and 49H showed docked positions (AutoDock Vina) and trajectories/energies (GROMACS). In vitro molecular interactions used CT-DNA and 49H applying UV-Vis absorbance and fluorescence. Comet assay evaluated DNA fragmentation of HepG2 cells. Flow cytometry analysis verified HepG2 cell cycle effects. Levels of proteins (ß-actin, p53, BAX, HIF-1α, γH2AX, PARP-1, cyclin A, CDK-2, and pRB) were quantified by immunoblotting. RESULTS: Among Se-DHPM, 49H was selectively cytotoxic to HepG2 cells, reduced cell proliferation, and increased BAX (80%), and p53 (66%) causing apoptosis. Molecular assays revealed 49H inserted in the CT-DNA molecule causing the hypochromic effect. Docking simulations showed H-bonds and hydrophobic interactions, which kept the ligand partially inserted into the DNA minor groove. 49H increased the DNA damage (1.5 fold) and γH2AX level (153%). Besides, treatments reduced PARP-1 (60%) and reduced pRB phosphorylation (21%) as well as decreased cyclin A (46%) arresting cell cycle at the G1 phase. CONCLUSION: Together all data obtained confirmed the hypothesis of disruptive interactions between Se-DHPM and DNA, thereby highlighting its potential as a new anticancer drug.

Rats recognize spatial and temporal attributes in a new object recognition memory task with multiple trials.

BACKGROUND: Episodic-like memory tasks based on the spontaneous exploration of objects are commonly applied in one-trial protocols. However, multiple-trial designs are known to reduce animal numbers and data variance, providing faster accumulation of data. NEW METHOD: In this study, we devised a new object recognition memory task for rats that carry out multiple trials per session. We developed three types of continual trial tasks: a longer protocol, a shorter protocol, and a protocol in which the experimental session was divided into two days. RESULTS: In our design, rats expressed temporal and spatial memory, but not what-where-when content integration. We found that shorter protocols were more efficient to evaluate memory capabilities. COMPARISON WITH EXISTING METHODS: To the best of our knowledge, it is the first object recognition task with multiple trials that simultaneously assess the temporal and spatial aspects of episodic-like memory. CONCLUSIONS: We suggest that our task is suitable for the simultaneous measurements of brain functions related to spatial and temporal attributes in rats.

Rescue of trapped Rotablator with knuckle technique for chronic total occlusion.

A 71-year-old man with Chagas disease and stable angina on minimum exertion underwent coronary computed tomography angiography and cine angiography that revealed heavily calcified multivessel disease involving the left main artery (LM). Due to the degree of calcification, it was decided to perform rotablation. The first-stage percutaneous coronary intervention (PCI) with rotablation was performed on the LM, left anterior descending artery and second diagonal branch without complications. Almost 30 days later he returned for right coronary artery (RCA) PCI. The proposed strategy was rotational atherectomy in the posterior descending artery (PDA) and right posterolateral artery (RPLA) with a 1.5 mm burr, followed by implantation of two drug-eluting stents (DES). Through right femoral artery access the RPLA lesion was ablated with success. As there were no signs of dissection and TIMI 3 flow was maintained, the 0.009″ RotaWire was repositioned to cross the PDA lesion and debulking of the lesion was performed. After two attempts we succeeded in crossing the lesion with the 1.5 mm burr, however entrapment of the burr ensued. The system was pulled back until the guiding catheter penetrated deep into the RCA, and attempts were made to release the Rotablator by moving it forward and backward, but the burr did not even spin. The contralateral femoral artery was therefore punctured and a 6F JR guiding catheter was inserted, in order to move a guidewire and small angioplasty balloon tangentially to the burr, but without success. Finally we advanced the guidewire using the 'knuckle' technique, taking advantage of the kinking of the distal portion of the PT2 guidewire, performing a subintimal dissection and re-entry, and could then easily cross the balloon, inflate it and release the trapped burr. Through the 6F system, two programmed and one bailout DES were successfully implanted in the PDA, RPLA and RCA, obtaining final TIMI 3 flow without complications.

New Probucol Analogues Inhibit Ferroptosis, Improve Mitochondrial Parameters, and Induce Glutathione Peroxidase in HT22 Cells.

Probucol, a hypocholesterolemic compound, is neuroprotective in several models of neurodegenerative diseases but has serious adverse effects in vivo. We now describe the design and synthesis of two new probucol analogues that protect against glutamate-induced oxidative cell death, also known as ferroptosis, in cultured mouse hippocampal (HT22) cells and in primary cortical neurons, while probucol did not show any protective effect. Treatment with both compounds did not affect glutathione depletion but still significantly decreased glutamate-induced production of oxidants, mitochondrial superoxide generation, and mitochondrial hyperpolarization in HT22 cells. Both compounds increase glutathione peroxidase (GPx) 1 levels and GPx activity, also exhibiting protection against RSL3, a GPx4 inactivator. These two compounds are therefore potent activators of GPx activity making further studies of their neuroprotective activity in vivo worthwhile.