Capsicum baccatum Red Pepper Prevents Cardiometabolic Risk in Rats Fed with an Ultra-Processed Diet.

Metabolic syndrome is a serious health condition reaching epidemic proportions worldwide and is closely linked to an increased risk of cardiovascular problems. The lack of appropriate treatment paves the way for developing new therapeutic agents as a high priority in the current research. In this study, we evaluated the protective effects of Capsicum baccatum red pepper on metabolic syndrome scenarios induced by an ultra-processed diet in rats. After four months, the ultra-processed diet increased central obesity, triglycerides, total cholesterol, LDL-cholesterol plasma levels, and impaired glucose tolerance. The oral administration of C. baccatum concomitantly with the ultra-processed diet avoided the accumulation of adipose tissue in the visceral region, reduced the total cholesterol and LDL fraction, and improved glucose homeostasis, factors commonly associated with metabolic syndrome. The data presented herein reveal an important preventive action of C. baccatum in developing metabolic disorders among animals fed a hypercaloric diet, significantly reducing their cardiometabolic risk. Allied with the absence of toxic effects after chronic use, our study suggests C. baccatum red pepper as a secure and enriched source of bioactive compounds promising to protect against pathological processes associated with metabolic syndrome.

Pre- and early postnatal enriched environmental experiences prevent neonatal hypoxia-ischemia late neurodegeneration via metabolic and neuroplastic mechanisms.

Prenatal and early postnatal periods are important for brain development and neural function. Neonatal insults such as hypoxia-ischemia (HI) causes prolonged neural and metabolic dysregulation, affecting central nervous system maturation. There is evidence that brain hypometabolism could increase the risk of adult-onset neurodegenerative diseases. However, the impact of non-pharmacologic strategies to attenuate HI-induced brain glucose dysfunction is still underexplored. This study investigated the long-term effects of early environmental enrichment in metabolic, cell, and functional responses after neonatal HI. Thereby, male Wistar rats were divided according to surgical procedure, sham, and HI (performed at postnatal day 3), and the allocation to standard (SC) or enriched condition (EC) during gestation and lactation periods. In-vivo cerebral metabolism was assessed by means of [18 F]-FDG micro-positron emission tomography, and cognitive, biochemical, and histological analyses were performed in adulthood. Our findings reveal that HI causes a reduction in glucose metabolism and glucose transporter levels as well as hyposynchronicity in metabolic brain networks. However, EC during prenatal or early postnatal period attenuated these metabolic disturbances. A positive correlation was observed between [18 F]-FDG values and volume ratios in adulthood, indicating that preserved tissue by EC is metabolically active. EC promotes better cognitive scores, as well as down-regulation of amyloid precursor protein in the parietal cortex and hippocampus of HI animals. Furthermore, growth-associated protein 43 was up-regulated in the cortex of EC animals. Altogether, results presented support that EC during gestation and lactation period can reduce HI-induced impairments that may contribute to functional decline and progressive late neurodegeneration.

Long-term changes in metabolic brain network drive memory impairments in rats following neonatal hypoxia-ischemia.

BACKGROUND AND PURPOSE: Hypoxia and cerebral ischemia (HI) events are capable of triggering important changes in brain metabolism, including glucose metabolism abnormalities, which may be related to the severity of the insult. Using positron emission microtomography (microPET) with [18F]fluorodeoxyglucose (18F-FDG), this study proposes to assess abnormalities of brain glucose metabolism in adult rats previously submitted to the neonatal HI model. We hypothesize that cerebral metabolic outcomes will be associated with cognitive deficits and magnitude of brain injury. METHODS: Seven-day-old rats were subjected to an HI model, induced by permanent occlusion of the right common carotid artery and systemic hypoxia. 18F-FDG-microPET was used to assess regional and whole brain glucose metabolism in rats at 60 postnatal days (PND 60). An interregional cross-correlation matrix was utilized to construct metabolic brain networks (MBN). Rats were also subjected to the Morris Water Maze (MWM) to evaluate spatial memory and their brains were processed for volumetric evaluation. RESULTS: Brain glucose metabolism changes were observed in adult rats after neonatal HI insult, limited to the right brain hemisphere. However, not all HI animals exhibited significant cerebral hypometabolism. Hippocampal glucose metabolism was used to stratify HI animals into HI hypometabolic (HI-h) and HI non-hypometabolic (HI non-h) groups. The HI-h group had drastic MBN disturbance, cognitive deficit, and brain tissue loss, concomitantly. Conversely, HI non-h rats had normal brain glucose metabolism and brain tissue preserved, but also presented MBN changes and spatial memory impairment. Furthermore, data showed that brain glucose metabolism correlated with cognitive deficits and brain volume outcomes. CONCLUSIONS: Our findings demonstrated that long-term changes in MBN drive memory impairments in adult rats subjected to neonatal hypoxic ischemia, using in vivo imaging microPET-FDG. The MBN analyses identified glucose metabolism abnormalities in HI non-h animals, which were not detected by conventional 18F-FDG standardized uptake value (SUVr) measurements. These animals exhibited a metabolic brain signature that may explain the cognitive deficit even with no identifiable brain damage.

In vivo characterization of metabotropic glutamate receptor type 5 abnormalities in behavioral variant FTD.

Although the pathogenesis underlying behavioral variant frontotemporal dementia (bvFTD) has yet to be fully understood, glutamatergic abnormalities have been hypothesized to play an important role. The aim of the present study was to determine the availability of the metabotropic glutamate receptor type 5 (mGluR5) using a novel positron emission tomography (PET) radiopharmaceutical with high selectivity for mGluR5 ([(11)C]ABP688) in a sample of bvFTD patients. In addition, we sought to determine the overlap between availability of mGluR5 and neurodegeneration, as measured using [(18)F]FDG-PET and voxel-based morphometry (VBM). Availability of mGluR5 and glucose metabolism ([(18)F]FDG) were measured in bvFTD (n = 5) and cognitively normal (CN) subjects (n = 10). [(11)C]ABP688 binding potential maps (BPND) were calculated using the cerebellum as a reference region, with [(18)F]FDG standardized uptake ratio maps (SUVR) normalized to the pons. Grey matter (GM) concentrations were determined using VBM. Voxel-based group differences were obtained using RMINC. BvFTD patients showed widespread decrements in [(11)C]ABP688 BPND throughout frontal, temporal and subcortical areas. These areas were likewise characterized by significant hypometabolism and GM loss, with overlap between reduced [(11)C]ABP688 BPND and hypometabolism superior to that for GM atrophy. Several regions were characterized only by decreased binding of [(11)C]ABP688. The present findings represent the first in vivo report of decreased availability of mGluR5 in bvFTD. This study suggests that glutamate excitotoxicity may play a role in the pathogenesis of bvFTD and that [(11)C]ABP688 may prove a suitable marker of glutamatergic neurotransmission in vivo.

A new device for step-down inhibitory avoidance task--effects of low and high frequency in a novel device for passive inhibitory avoidance task that avoids bioimpedance variations.

BACKGROUND: Step-down inhibitory avoidance task has been widely used to evaluate aversive memory, but crucial parameters inherent to traditional devices that may influence the behavior analysis (as stimulus frequency, animal's bioimpedance) are frequently neglected. NEW METHOD: We developed a new device for step-down inhibitory avoidance task by modifying the shape and distribution of the stainless steel bars in the box floor where the stimuli are applied. The bars are 2 mm wide, with rectangular shape, arranged in pairs at intervals of 1cm from the next pairs. Each pair makes an electrical dipole where the polarity inverts after each pulse. This device also presents a component that acquires and records the exact current received by the animal foot and precisely controls the frequency of stimulus applied during the entire experiment. RESULT: Different from conventional devices, this new apparatus increases the contact surface with bars and animal's paws, allowing the electric current pass through the animal's paws only, drastically reducing the influence of animal's bioimpedance. The analysis of recorded data showed that the current received by the animal was practically the same as applied, independent of the animal's body composition. Importantly, the aversive memory was observed at specific stimuli intensity and frequency (0.35 or 0.5 mA at 62 and 125 Hz but not at 0.20 mA or 20 Hz). Moreover, with this device it was possible to observe the well-known step-down inhibitory avoidance task memory impairment induced by guanosine. CONCLUSION: This new device offers a substantial improvement for behavioral analysis in step-down inhibitory avoidance task and allows us to precisely compare data from different animals with distinct body composition.

Changes in Brain 14-3-3 Proteins in Response to Insulin Resistance Induced by a High Palatable Diet.

The 14-3-3 protein family takes part in a wide range of cellular processes and is expressed in all eukaryotic organisms. In mammals, seven isoforms (ß, ε, η, γ, τ, ζ, and σ) have been identified. 14-3-3 proteins are suggested to modulate the insulin-signaling cascade in the brain. The aim of this study was to investigate whether insulin resistance state induced by high palatable diet modulates expression of the 14-3-3 proteins in brain. Wistar male rats (n = 8) were divided into two experimental groups: insulin resistant (IR), induced by high palatable diet, and control (CO) group. Biochemical parameters (glucose tolerance test and plasma lipid profile) were evaluated after 130 days. Brain structures (cortex and hippocampus) were dissected for evaluation of messenger RNA (mRNA) and protein levels of different 14-3-3 proteins. Statistical analyses included Student t test and Pearson correlation. Significant decrease was observed in Ywhah and in Ywahq mRNA levels in the cortex of IR group, while no changes were observed in the hippocampus. Significant increase of θ isoform was observed in hippocampus IR group by immunodetection, while no differences were detected in the remaining isoforms. Inverse correlation was observed between blood glucose levels in cortex IR group and both Ywhah and Ywhaq mRNA levels. Protein levels of Creb and phosphatidylinositide 3-kinases (PI3K) showed to be increased in the hippocampus. These alterations may be due to a compensatory effect of impaired insulin signaling. We demonstrated differential expression of 14-3-3 isoforms throughout brain regions of rats with IR. As a whole, our results indicate that brain 14-3-3 levels are influenced by different diets.

Intracerebroventricular metformin decreases body weight but has pro-oxidant effects and decreases survival.

Metformin (Met), which is an insulin-sensitizer, decreases insulin resistance and fasting insulin levels. The precise molecular target of Met is unknown; however, several reports have shown an inhibitory effect on mitochondrial complex I of the electron transport chain (ETC), which is a related site for reactive oxygen species production. In addition to peripheral effects, Met is capable of crossing the blood-brain barrier, thus regulating the central mechanism involved in appetite control. The present study explores the effects of intracerebroventricular (i.c.v.) infusion of Met on ROS production on brain, insulin sensitivity and metabolic and oxidative stress outcomes in CF1 mice. Metformin (Met 50 and 100 µg) was injected i.c.v. in mice daily for 7 days; the brain mitochondrial H2O2 production, food intake, body weight and fat pads were evaluated. The basal production of H2O2 of isolated mitochondria from the hippocampus and hypothalamus was significantly increased by Met (100 µg). There was increased peripheral sensitivity to insulin (Met 100 µg) and glucose tolerance tests (Met 50 and 100 µg). Moreover, Met decreased food intake, body weight, body temperature, fat pads and survival rates. Additionally, Met (1, 4 or 10 mM) decreased mitochondrial viability and increased the production of H2O2 in neuronal cell cultures. In summary, our data indicate that a high dose of Met injected directly into the brain has remarkable neurotoxic effects, as evidenced by hypothermia, hypoglycemia, disrupted mitochondrial ETC flux and decreased survival rate.

Developments in Tau PET Imaging.

ABSTRACT The presence of neurofibrillary tangles in the brain is a hallmark feature of several neurodegenerative diseases termed "tauopathies," including Alzheimer's disease (AD) and the tau molecular subgroup of frontotemporal lobar degeneration (FTLD-tau). Recently, several positron emission tomography (PET) radiopharmaceuticals targeting abnormal conformations of the tau protein have been developed. To date, six novel tau imaging agents-[18F]THK523, [18F]THK5105, [18F]THK5117, [18F]T807, [18F]T808, and [11C]PBB3-have been described and are considered promising as potential tau radioligands. Tau imaging agents offer the opportunity of in vivo topographical mapping and quantification of tau aggregates in parallel with clinical and cognitive assessments. As such, tau imaging is considered of key importance for progress toward earlier and more accurate diagnosis of tauopathies as well as for the monitoring of therapeutic interventions and drug development. Here, we shed light on the most important developments in tau radiopharmaceuticals, highlighting challenges, possibilities and future directions.

Tracking neuroinflammation in Alzheimer's disease: the role of positron emission tomography imaging.

Alzheimer's disease (AD) has been reconceptualized as a dynamic pathophysiological process, where the accumulation of amyloid-beta (Aß) is thought to trigger a cascade of neurodegenerative events resulting in cognitive impairment and, eventually, dementia. In addition to Aß pathology, various lines of research have implicated neuroinflammation as an important participant in AD pathophysiology. Currently, neuroinflammation can be measured in vivo using positron emission tomography (PET) with ligands targeting diverse biological processes such as microglial activation, reactive astrocytes and phospholipase A2 activity. In terms of therapeutic strategies, despite a strong rationale and epidemiological studies suggesting that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the prevalence of AD, clinical trials conducted to date have proven inconclusive. In this respect, it has been hypothesized that NSAIDs may only prove protective if administered early on in the disease course, prior to the accumulation of significant AD pathology. In order to test various hypotheses pertaining to the exact role of neuroinflammation in AD, studies in asymptomatic carriers of mutations deterministic for early-onset familial AD may prove of use. In this respect, PET ligands for neuroinflammation may act as surrogate markers of disease progression, allowing for the development of more integrative models of AD, as well as for the measuring of target engagement in the context of clinical trials using NSAIDs. In this review, we address the biological basis of neuroinflammatory changes in AD, underscore therapeutic strategies using anti-inflammatory compounds, and shed light on the possibility of tracking neuroinflammation in vivo using PET imaging ligands.

Nandrolone-induced aggressive behavior is associated with alterations in extracellular glutamate homeostasis in mice.

Nandrolone decanoate (ND), an anabolic androgenic steroid (AAS), induces an aggressive phenotype by mechanisms involving glutamate-induced N-methyl-d-aspartate receptor (NMDAr) hyperexcitability. The astrocytic glutamate transporters remove excessive glutamate surrounding the synapse. However, the impact of supraphysiological doses of ND on glutamate transporters activity remains elusive. We investigated whether ND-induced aggressive behavior is interconnected with GLT-1 activity, glutamate levels and abnormal NMDAr responses. Two-month-old untreated male mice (CF1, n=20) were tested for baseline aggressive behavior in the resident-intruder test. Another group of mice (n=188) was injected with ND (15mg/kg) or vehicle for 4, 11 and 19days (short-, mid- and long-term endpoints, respectively) and was evaluated in the resident-intruder test. Each endpoint was assessed for GLT-1 expression and glutamate uptake activity in the frontoparietal cortex and hippocampal tissues. Only the long-term ND endpoint significantly decreased the latency to first attack and increased the number of attacks, which was associated with decreased GLT-1 expression and glutamate uptake activity in both brain areas. These alterations may affect extracellular glutamate levels and receptor excitability. Resident males were assessed for hippocampal glutamate levels via microdialysis both prior to, and following, the introduction of intruders. Long-term ND mice displayed significant increases in the microdialysate glutamate levels only after exposure to intruders. A single intraperitoneal dose of the NMDAr antagonists, memantine or MK-801, shortly before the intruder test decreased aggressive behavior. In summary, long-term ND-induced aggressive behavior is associated with decreased extracellular glutamate clearance and NMDAr hyperexcitability, emphasizing the role of this receptor in mediating aggression mechanisms.

Use of amyloid PET across the spectrum of Alzheimer's disease: clinical utility and associated ethical issues.

Abstract Recent advances have made possible the in vivo detection of beta-amyloid (Aß) pathology using positron emission tomography. While the gold standard for amyloid imaging, carbon-11 labeled Pittsburgh compound B is increasingly being replaced by fluorine-18 labeled radiopharmaceuticals, with three already approved for clinical use by US and European regulatory bodies. Appropriate use criteria proposed by an amyloid imaging taskforce convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging recommend restricting use of this technology to the evaluation of patients with mild cognitive impairment or atypical dementia syndromes. While use among asymptomatic individuals is currently viewed as inappropriate due prognostic uncertainty, elevated levels of brain Aß among asymptomatic individuals may represent preclinical Alzheimer's disease. Amyloid imaging is likewise expected to play a role in the design of clinical trials. Though preliminary results suggest amyloid imaging to possess clinical utility and cost-effectiveness, both domains have yet to be assessed systematically. As the field moves toward adoption of a pro-disclosure stance for amyloid imaging findings, it is imperative that a broad range of stakeholders be involved to ensure the appropriateness of emerging policies and protocols.

In vivo tracking of tau pathology using positron emission tomography (PET) molecular imaging in small animals.

Hyperphosphorylation of the tau protein leading to the formation of neurofibrillary tangles (NFTs) is a common feature in a wide range of neurodegenerative diseases known as tauopathies, which include Alzheimer's disease (AD) and the frontotemporal dementias (FTDs). Although heavily investigated, the mechanisms underlying the pathogenesis and progression of tauopathies have yet to be fully understood. In this context, several rodent models have been developed that successfully recapitulate the behavioral and neurochemical features of tau pathology, aiming to achieve a better understanding of the link between tau and neurodegeneration. To date, behavioral and biochemical parameters assessed using these models have been conducted using a combination of memory tasks and invasive methods such as cerebrospinal fluid (CSF) sampling or post-mortem analysis. Recently, several novel positron emission tomography (PET) radiopharmaceuticals targeting tau tangles have been developed, allowing for non-invasive in vivo quantification of tau pathology. Combined with tau transgenic models and microPET, these tracers hold the promise of advancing the development of theoretical models and advancing our understanding of the natural history of AD and non-AD tauopathies. In this review, we briefly describe some of the most important insights for understanding the biological basis of tau pathology, and shed light on the opportunity for improved modeling of tau pathology using a combination of tau-radiopharmaceuticals and animal models.

Serum S100B level increases after running but not cycling exercise.

The objective of this study was to investigate the effect of running versus cycling exercises upon serum S100B levels and typical markers of skeletal muscle damage such as creatine kinase (CK), aspartate aminotransferase (AST) and myoglobin (Mb). Although recent work demonstrates that S100B is highly expressed and exerts functional properties in skeletal muscle, there is no previous study that tries to establish a relationship between muscle damage and serum S100B levels after exercise. We conducted a cross-sectional study on 13 male triathletes. They completed 2 submaximal exercise protocols at anaerobic threshold intensity. Running was performed on a treadmill with no inclination (RUN) and cycling (CYC) using a cycle-simulator. Three blood samples were taken before (PRE), immediately after (POST) and 1 h after exercise for CK, AST, Mb and S100B assessments. We found a significant increase in serum S100B levels and muscle damage markers in RUN POST compared with RUN PRE. Comparing groups, POST S100B, CK, AST and Mb serum levels were higher in RUN than CYC. Only in RUN, the area under the curve (AUC) of serum S100B is positively correlated with AUC of CK and Mb. Therefore, immediately after an intense exercise such as running, but not cycling, serum levels of S100B protein increase in parallel with levels of CK, AST and Mb. Additionally, the positive correlation between S100B and CK and Mb points to S100B as an acute biomarker of muscle damage after running exercise.

Assessment of the dimensions and surface characteristics of orthodontic wires and bracket slots.

OBJECTIVE: The purpose of this study was to evaluate the dimensions and surface characteristics of orthodontic wires and bracket slots of different commercial brands. METHODS: Thirty metallic brackets (0.022 x 0.028-in and 0.022 x 0.030-in) were divided into three groups: DYN/3M group = Dyna-Lock, 3M/Unitek (stainless steel, or SS); STD/MO group = Slim Morelli (SS); and Ni-Free/MO group = Slim Morelli (Ni-Free). The stainless steel wires (0.019 x 0.025-in) were divided into two groups: MO group = Morelli; and 3M group = 3M/Unitek. The bracket and wire measurements were done by two methods: (a) Surface Electron Microscopy (SEM), and (b) Profile Projection. The surface analysis was done qualitatively, based on SEM images and/or by a rugosimeter. The quantitative results were analyzed by ANOVA with Tukey's test (p < 0.05) and Student's t test. RESULTS: A significant difference in the dimensions of slots was observed, and the NiFree/MO group showed the greatest changes when compared to the other groups. The analysis of surface topography of the brackets indicated greater homogeneity of the metallic matrix for DYN/3M and STD/MO groups. As for the dimensions of the wires, groups showed statistically different mean heights. CONCLUSIONS: It was concluded that wires and brackets slots can present altered dimensions, which might directly and unintentionally affect the planned tooth movement.

Assessment of the dimensions and surface characteristics of orthodontic wires and bracket slots

OBJECTIVE: The purpose of this study was to evaluate the dimensions and surface characteristics of orthodontic wires and bracket slots of different commercial brands. METHODS: Thirty metallic brackets (0.022 x 0.028-in and 0.022 x 0.030-in) were divided in three groups: DYN/3M group = Dyna-Lock, 3M/Unitek (stainless steel, or SS); STD/MO group = Slim Morelli (SS); and Ni-Free/MO group = Slim Morelli (Ni-Free). The stainless steel wires (0.019 x 0.025in) were divided into two groups: MO group = Morelli; and 3M group = 3M/Unitek. The bracket and wire measurements were done by two methods: (a) Surface Electron Microscopy (SEM), and (b) Profile projection. The surface analysis was done qualitatively, based on SEM images and/or by a rugosimeter. The quantitative results were analyzed by ANOVA with Tukey's test (p < 0.05) and Student's t test. RESULTS: A significant difference in the dimensions of slots was observed, and the NiFree/MO group showed the greatest changes when compared to the other groups. The analysis of surface topography of the brackets indicated greater homogeneity of the metallic matrix for DYN/3M and STD/MO groups. As for the dimensions of the wires, groups showed statistically different mean heights. CONCLUSIONS: It was concluded that wires and brackets slots can present altered dimensions, which might directly and unintentionally affect the planned tooth movement.

OBJETIVO: o objetivo desse estudo é avaliar as dimensões e as características superficiais de fios retangulares e slots de braquetes de diferentes marcas comerciais. MÉTODOS: trinta braquetes metálicos (0,022" x 0,028" e 0,022" x 0,030") foram divididos em três grupos: Grupo DYN/3M = Dyna-Lock, 3M/Unitek, aço inoxidável (AI); Grupo STD/MO = Slim Morelli (AI); e Grupo NiFree/MO = Slim Morelli (Ni-Free). Já os fios retangulares (0,019" x 0,025"), de aço inoxidável, foram divididos em 2 grupos: Grupo MO = Morelli; Grupo 3M = 3M/Unitek. As mensurações dos slots dos braquetes e dos fios foram realizadas por dois métodos: (a) microscopia eletrônica de varredura (MEV), e (b) projeção de perfil. A análise da topografia superficial foi realizada qualitativamente, baseada em imagens microscópicas (MEV) e/ou por meio de um rugosímetro. Os resultados quantitativos foram submetidos à análise de variância (ANOVA) com o teste de Tukey (p < 0,05) ou o teste t de Student. RESULTADOS: observou-se diferença significativa entre as dimensões dos slots dos braquetes, sendo que o Grupo NiFree/MO apresentou a maior alteração quando comparado aos demais Grupos. A análise da topografia superficial dos braquetes indicou maior homogeneidade da matriz metálica nos Grupos DYN/3M e STD/MO. Quanto às dimensões dos fios, os grupos tiveram alturas médias estatisticamente diferentes entre si. CONCLUSÃO: concluiu-se que a conformação dos fios e dos slots dos braquetes pode apresentar alterações dimensionais, o que afetará direta e indesejavelmente o movimento dentário planejado.

Insulin prevents mitochondrial generation of H2O2 in rat brain.

The mitochondrial electron transport system (ETS) is a main source of cellular ROS, including hydrogen peroxide (H2O2). The production of H2O2 also involves the mitochondrial membrane potential (ΔΨm) and oxygen consumption. Impaired insulin signaling causes oxidative neuronal damage and places the brain at risk of neurodegeneration. We evaluated whether insulin signaling cross-talks with ETS components (complexes I and F0F1ATP synthase) and ΔΨm to regulate mitochondrial H2O2 production, in tissue preparations from rat brain. Insulin (50 to 100 ng/mL) decreased H2O2 production in synaptosomal preparations in high Na(+) buffer (polarized state), stimulated by glucose and pyruvate, without affecting the oxygen consumption. In addition, insulin (10 to 100 ng/mL) decreased H2O2 production induced by succinate in synaptosomes in high K(+) (depolarized state), whereas wortmannin and LY290042, inhibitors of the PI3K pathway, reversed this effect; heated insulin had no effect. Insulin decreased H2O2 production when complexes I and F0F1ATP synthase were inhibited by rotenone and oligomycin respectively suggesting a target effect on complex III. Also, insulin prevented the generation of maximum level of ∆Ψm induced by succinate. The PI3K inhibitors and heated insulin maintained the maximum level of ∆Ψm induced by succinate in synaptosomes in a depolarized state. Similarly, insulin decreased ROS production in neuronal cultures. In mitochondrial preparations, insulin neither modulated H2O2 production or oxygen consumption. In conclusion, the normal downstream insulin receptor signaling is necessary to regulate complex III of ETS avoiding the generation of maximal ∆Ψm and increased mitochondrial H2O2 production.

Physical exercise exacerbates memory deficits induced by intracerebroventricular STZ but improves insulin regulation of H2O2 production in mice synaptosomes.

Insulin brain resistant state is associated with cognitive deficits and Alzheimer's disease by mechanisms that may involve mitochondrial damage and oxidative stress. Conversely, physical exercise improves cognitive function and brain insulin signaling. The intracerebroventricular (i.c.v.) administration of streptozotocin (STZ) in rodents is an established model of insulin-resistant brain state. This study evaluates the effects of physical exercise on memory performance of i.c.v., STZ-treated mice(1 and 3 mg/kg) and whether insulin (50 and 100 ng/ml) modulates mitochondrial H2O2 generation in synaptosomes. S100B levels and SOD and CAT activities were assessed as markers of brain damage caused by STZ. Sedentary and exercise vehicle-treated mice demonstrated similar performance in object recognition memory task. In the water maze test, exercise vehicle-treated mice showed improvement performance in the acquisition and retrieval phases. The administration of STZ (1 mg/kg) before thirty days of voluntary physical exercise protocol impaired recognition and spatial memory only in exercised mice, whereas STZ (3 mg/kg) impaired the performance of sedentary and exercise groups. Moreover, STZ (3 mg/kg) increased hippocampal S100B levels in both groups and SOD/CAT ratio in the sedentary animals. Insulin decreased synaptosomal H2O2 production in exercised compared to sedentary mice; however, both STZ doses abolished this effect. Normal brain insulin signaling is mechanistically involved in the improvement of cognitive function induced by exercise through the regulation of mitochondrial H2O2 production. However, a prior blockade of brain insulin signaling with STZ abolished the benefits of exercise on memory performance and mitochondrial H2O2 regulation.

Pretreatment with memantine prevents Alzheimer-like alterations induced by intrahippocampal okadaic acid administration in rats.

Cerebral okadaic acid (OA) administration induces Alzheimer's disease (AD)-like phenotype in rats. Alterations in glutamate levels associated with hyperactivation of cyclin dependent kinase 5 (Cdk5) signaling pathway downstream Tau phosphorylation may participate in the genesis of this pathological phenotype. Here, we examined the efficacy of memantine (MN) pretreatment on reducing OA-induced AD-like phenotypes in rats. Wistar rats were given daily intraperitoneal injections of MN for 3 days and then given an intrahippocampal infusion of OA. Animals were divided into four groups: control (CO), MN, OA and MN/OA. Spontaneous locomotion and spatial memory performance were assessed by open field and Morris water maze respectively. Additionally, we measured glutamate levels in the cerebrospinal fluid (CSF) and the immunocontent of Cdk5, p35, p25 and phosphorylated Tau (pTauSer199/202) in the hippocampus. Spontaneous locomotion did not differ between groups. The OA group showed a significant decrease in spatial memory performance compared to all groups. The OA infusion also increased CSF glutamate levels and the immunocontents of Cdk5, p25 and pTauSer199/202 in the hippocampus. Conversely, pretreatment with MN prevented OA-induced spatial memory deficits and the increment of CSF glutamate level; which paralleled with normal immunocontents of Cdk5, p25 and pTau- Ser199/202 proteins. There were positive correlations between spatial memory performance and the neurochemical parameters. In summary, pretreatment with MN prevents spatial memory deficits induced by intrahippocampal OA administration in rats. The prevention of increase CSF glutamate levels, along with the reduced hippocampal phosphorylation of TauSer199/202 by Cdk5/p25 signaling pathway, are the mechanisms proposed to participate in the prophylactic effects of MN in this AD-like model.

Long-Term Oral Administration of Capsicum baccatum Extracts Does Not Alter Behavioral, Hematological, and Metabolic Parameters in CF1 Mice.

Our group showed that crude ethanol (CE) and butanol (BUT) extracts of Capsicum baccatum presented anti-inflammatory and antioxidant properties. Furthermore, the flavonoid and total phenolic contents were positively correlated with both of these properties observed for C. baccatum extracts. The present study demonstrated that 60 days of oral administration of CE and BUT (200 mg/kg) in mice did not cause significant differences in the following parameters evaluated: hematological profile, body weight and relative weight of visceral organs, systemic lipid profile, glucose homeostasis (GTT), kidney and hepatic biochemical markers, and spontaneous locomotion and anxiety-like behavior. Altogether, these results indicate for the first time that the long-term oral administration of C. baccatum extracts does not affect specific aspects of CF1 mice physiology, suggesting their safety, building up the venue to test their efficacy in animal models underlying persistent activation of oxidative and inflammatory pathways.