Impairment In Animals Research Articles

FTY720 attenuates iron deposition and glial responses in improving delayed lesion and long-term outcomes of collagenase-induced intracerebral hemorrhage

Most intracerebral hemorrhage (ICH) survivors have poor long-term outcomes, such as cognitive deficits and depression. Delayed lesions of ICH include neuron loss and white matter injury and the pathology of the lesions involves iron deposition and glial responses, which contribute to depressive-like behavior and cognitive impairment in animals. This study aimed to investigate the effects of FTY720 (0.3 mg/kg/day for 4 weeks) on iron deposition, glial responses, histological abnormalities and behavioral dysfunction in mice with ICH. The primary adverse long-term outcomes in our study of ICH mice were depressive-like behavior and impaired recognition memory. We found that FTY720 safely ameliorated depressive-like behavior and impaired recognition without affecting recovery of grip function and locomotor activity 28 days post-ICH. Moreover, we measured neuron loss, white matter lesions, lesion volume and iron deposition at day 28, which were attenuated in the FTY720-treated group compared to the ICH-control group, without changing initial hematoma volume on day 1 post-ICH. Long-term elevation of glial responses, including microglia activity and astrogliosis with tumor necrosis factor alpha (TNFα) expression was demonstrated by Western blot and immunofluorescence staining, which we found was attenuated by FTY720 treatment. Hence, FTY720 could become a novel therapeutic agent for improving long-term outcomes after ICH.

Systematically Characterize the Anti-Alzheimer's Disease Mechanism of Lignans from S. chinensis based on In-Vivo Ingredient Analysis and Target-Network Pharmacology Strategy by UHPLC⁻Q-TOF-MS.

Lignans from Schisandra chinensis (Turcz.) Baill can ameliorate cognitive impairment in animals with Alzheimer’s disease (AD). However, the metabolism of absorbed ingredients and the potential targets of the lignans from S. chinensis in animals with AD have not been systematically investigated. Therefore, for the first time, we performed an in-vivo ingredient analysis and implemented a target-network pharmacology strategy to assess the effects of lignans from S. chinensis in rats with AD. Ten absorbed prototype constituents and 39 metabolites were identified or tentatively characterized in the plasma of dosed rats with AD using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Based on the results of analysis of the effective constituents in vivo, the potential therapeutic mechanism of the effective constituents in the rats with AD was investigated using a target-network pharmacology approach and independent experimental validation. The results showed that the treatment effects of lignans from S. chinensis on cognitive impairment might involve the regulation of amyloid precursor protein metabolism, neurofibrillary tangles, neurotransmitter metabolism, inflammatory response, and antioxidant system. Overall, we identified the effective components of lignans in S. chinensis that can improve the cognitive impairment induced by AD and proposed potential therapeutic metabolic pathways. The results might serve as the basis for a fundamental strategy to explore effective therapeutic drugs to treat AD.

Mitigating effect of biotin against irradiation-induced cerebral cortical and hippocampal damage in the rat brain tissue.

Radiation-induced brain injury is common and mainly occurs in patients receiving radiotherapy for malignant head and neck tumors. The brain is oversensitive to oxidant injury induced by radiation. Biotin is a member of the vitamin B complex family and its deficiency has been associated with neurogenesis impairment in animals and humans. The present study was undertaken to investigate the mitigating effect of biotin on the cerebral cortical and hippocampal damage induced by radiation exposure. Animals were exposed to radiation in the presence or absence of biotin and sacrificed on day 10. The results demonstrated that the administration of biotin 2mg to irradiated rats had no significant effect on the radiation-induced damage of the cerebral cortex and the hippocampus, while the administration of biotin 6mg has significantly attenuated oxidative stress in the hippocampus, manifested by a reduction of 4-hydroxynonenal (4HNE), total nitrate/nitrite (NOx), and xanthine oxidase (XO) levels associated with an elevation of glutathione (GSH) content as well as superoxide dismutase (SOD) and catalase (CAT) activities. In addition, biotin decreased the pro-inflammatory cytokines (interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrotic factor alpha (TNF-α)), caspase-3, poly(ADP-ribose) polymerase 1 (PARP1) level, and PARP1 gene expression. Moreover, biotin 6mg treatment diminished serum S100 protein (S100B) and neuron-specific enolase (NSE) levels. In conclusion, biotin treatment at high dose post-irradiation has efficiently neutralized the effect of free radicals in the hippocampal region of rats. Thus, it could be applicable as a radio-mitigator for reducing or delayed radiation-induced brain injury in patients post-radiotherapy.

Age-related changes in the shell gland and duodenum in relation to shell quality and bone strength in commercial laying hen hybrids

BackgroundDuring the production period of laying hens, the number of cracked eggshells increases and the skeleton becomes brittle. Both these problems are related to ageing of the hen and cause economic problems for egg producers and impaired animal welfare. This study investigated key factors in the shell gland and duodenum related to eggshell quality and bone strength in laying hens during the production period. Five Lohmann Selected Leghorn (LSL) and five Lohmann Brown (LB), common hybrids in commercial egg production, were euthanized at 21, 29, 49 and 70 weeks (wk) of age. Blood samples for analysis of total calcium were taken at euthanization. Right femur and humerus were used for bone strength measurements and tissue samples from shell gland and duodenum were processed for morphology, immunohistochemical localisation of oestrogen receptors (ERα, ERβ), plasma membrane calcium ATPase (PMCA) and histochemical localisation of carbonic anhydrases (CA). Eggs were collected for shell quality measurements.ResultsAt age 49 week, shell and bone strength had both deteriorated, but the hens were then able to maintain the level until 70 week of age and femur bone strength even improved. The main physiological findings associated with the effects seen at 49 week were reduced gland density and a shift in balance between ERα and ERβ in the shell gland, which coincided with a reduction in CA activity in the duodenum. Somewhat surprisingly, capillary density and capillaries with CA activity both increased in the shell gland over time, the latter possibly mediated via ERβ. These findings were independent of hybrid. PMCA was found in both shell gland and duodenum, but appeared unrelated to the age-related changes in shell and bone quality.ConclusionsIn hens around half-way through the production period, both shell quality and bone strength had deteriorated. Decreased gland density and a shift in the balance between ERα and ERβ in the shell gland, co-occurring with a dramatic drop in duodenal CA activity, are suggested as possible factors involved in age-related changes in shell and bone quality.

Preliminary study on the mechanism underlying the interaction of balance dysfunction and anxiety disorder.

This study aims to explore the anxiety-related behavioral changes and the concentration alterations of monoamine neurotransmitters in balance/anxiety-related nuclei of intratympanic gentamicin (GT)-induced balance disorder models. GT was administrated intratympanically in the adult male Sprague-Dawley rats to establish the vestibular impaired animal model. Rotarod was applied to test the vestibular function, and elevated plus maze and open field test were harnessed to evaluate the anxiety level. Monoamines and their metabolites were assayed by high-performance liquid chromatography. Rotarod test revealed that 6 days after GT administration, the average latency decreased significantly compared with the control group. Three days after GT administration, the travel distance and the central zone time obtained from open field and the duration of open arm stay and the times of open arm entries from elevated plus maze were apparently lower than those of the control group, whereas no significant differences were noted between 2-week group and the control group. Three days after GT administration, the concentration of norepinephrine (NE) and 5-hydroxyindoleacetic acid (5-HIAA) within medial vestibular nucleus (MVN); the concentration of NE, serotonin (5-HT), and 5-HIAA within locus coeruleus (LC); and the concentration of NE, 5-HT, 5-HIAA, and 3,4-dihydroxyphenylacetic acid within dorsal raphe nucleus (DRN) increased significantly compared with the control group. Two weeks after the administration, the concentrations of part of the neurotransmitters were lower than those of the 3-day group, indicating the rapid activation and slow deactivation of MVN-LC and MVN-DRN pathways. Vestibular impairment could lead to elevated anxiety level. The elevated anxiety levels might be attributed to increased monoamine concentrations within MVN, LC, and DRN.

Cinnamaldehyde improves methamphetamine-induced spatial learning and memory deficits and restores ERK signaling in the rat prefrontal cortex.

Objective(s):Methamphetamine is a stimulant compound that penetrates readily into the central nervous system. Repeated exposure to methamphetamine leads to damage in the dopaminergic and serotonergic axons of selected brain regions. Previous studies showed that cinnamaldehyde improved memory impairment in animals. In the present study, we aimed to elucidate the effects of cinnamaldehyde on methamphetamine-induced memory impairment in rats. Materials and Methods:Male Wistar rats received methamphetamine (10 mg/kg, intraperitoneally) for 7 days. Thirty minutes before each injection, animals were given cinnamaldehyde (20, 40, or 80 mg/kg) or rivastigmine (1 mg/kg). The spatial learning and memory were examined using the Morris water maze test. The expression of extracellular signal-regulated kinase (ERK) phosphorylation in the frontal cortex and hippocampus was also detected by immunohistochemical method.Results:Administration of methamphetamine increased the latency to find the platform in the learning phase, while administration of cinnamaldehyde (40 mg/kg) or rivastigmine before methamphetamine reversed the increased latency. Administration of cinnamaldehyde, at the dose of 40 mg/kg with methamphetamine, increased the time and distance traveled in the target quadrant in comparison with the amphetamine group. Moreover, the methamphetamine and cinnamaldehyde-treated group had higher expression of phosphorylated ERK1/2 in the prefrontal cortex in comparison with the methamphetamine-treated animals.Conclusion:The present data demonstrated that repeated METH administration impaired cognitive performance through the ERK pathway and decreased the phosphorylation of ERK1/2 in the prefrontal cortex while administration of cinnamaldehyde restored both effects. Accordingly, cinnamaldehyde may be a valuable therapeutic tool for the treatment of cognitive deficits associated with methamphetamine consumption.

Predictors of dementia misclassification when using brief cognitive assessments.

Brief cognitive assessments can result in false-positive and false-negative dementia misclassification. We aimed to identify predictors of misclassification by 3 brief cognitive assessments; the Mini-Mental State Examination (MMSE), Memory Impairment Screen (MIS) and animal naming (AN). Participants were 824 older adults in the population-based US Aging, Demographics and Memory Study with adjudicated dementia diagnosis (DSM-III-R and DSM-IV criteria) as the reference standard. Predictors of false-negative, false-positive and overall misclassification by the MMSE (cut-point <24), MIS (cut-point <5) and AN (cut-point <9) were analysed separately in multivariate bootstrapped fractional polynomial regression models. Twenty-two candidate predictors included sociodemographics, dementia risk factors and potential sources of test bias. Misclassification by at least one assessment occurred in 301 (35.7%) participants, whereas only 14 (1.7%) were misclassified by all 3 assessments. There were different patterns of predictors for misclassification by each assessment. Years of education predicts higher false-negatives (odds ratio [OR] 1.23, 95% confidence interval [95% CI] 1.07-1.40) and lower false-positives (OR 0.77, 95% CI 0.70-0.83) by the MMSE. Nursing home residency predicts lower false-negatives (OR 0.15, 95% CI 0.03-0.63) and higher false-positives (OR 4.85, 95% CI 1.27-18.45) by AN. Across the assessments, false-negatives were most consistently predicted by absence of informant-rated poor memory. False-positives were most consistently predicted by age, nursing home residency and non-Caucasian ethnicity (all p < 0.05 in at least 2 models). The only consistent predictor of overall misclassification across all assessments was absence of informant-rated poor memory. Dementia is often misclassified when using brief cognitive assessments, largely due to test specific biases.

Diosmin is neuroprotective in a rat model of scopolamine-induced cognitive impairment.

Scopolamine, a muscarinic cholinergic receptor antagonist, is used as a standard pharmaceutical model for inducing cognitive impairment in animals. Several cognitive behaviors, such as motor function, anxiety, short-term memory, attention are affected by injections of scopolamine. In this study, we have assessed the effects of administration of the diosmin (DM, 50 and 100 mg/kg), before injection of 0.4 mg/kg of scopolamine on memory and motor function, the hippocampal dentate gyrus (DG) electrophysiological activity as well as brain inflammation. Eighty male rats were randomly divided into five groups (Control, Veh + scopolamine, DM (50) + scopolamine and DM (100) + scopolamine, donepezil (DP) + scopolamine, n = 16). Scopolamine (0.4 mg/kg, i.p.) is used, in order to induce an animal model of cognitive impairment. Rats pretreated with doses of 50 and 100 mg/kg of DM, 3 mg/kg of DP and/or normal saline for 7 days, before injection of scopolamine. Long-term potentiation (LTP) recording was done for electrophysiological activity assessment. Passive avoidance task (PAT), rotarod and spatial memory tests were evaluated, using a shuttle box, rotarod apparatus and Morris water maze (MWM), respectively. Results indicated that DM at doses of 50 and 100 mg/kg, significantly reversed the LTP (amplitude and slope) impairment of the hippocampal DG neurons, induced by scopolamine. Also, DM at doses of 50 and 100 mg/kg increased the percent of the total time that animals spent in goal quarter, the step-through latency (s) and bar latency time in an animal model of cognitive impairment (p < 0.01 and p < 0.001), respectively. The concentrations of TNF-α in hippocampus of the DM and donepezil groups was significantly lower than the Veh + scopolamine group (p < 0.01). This study revealed that the DM is effective in preventing the disruption of synaptic plasticity and cognitive impairments, induced by scopolamine. The positive effects of DM may be mediated through a decline in the TNF- α concentrations in hippocampus as a pro-inflammatory cytokine. Thus, the acquired results suggested that the DM can be used, as a useful and suitable agent for memory restoration, in the treatment of dementia, seen in elderlies.

Impact of autologous whole blood administration upon experimental mouse models of acute Trypanosoma cruzi infection

BackgroundAutologous whole blood (AWB) administration is described as alternative/complementary medical practice widely employed in medical and veterinary therapy against infections, chronic pathologies and neoplasias. Our aim is to investigate in vivo biological effect of AWB using healthy murine models under the course of Trypanosoma cruzi acute infection.MethodsThe first set of studies consisted of injecting different volumes of AWB and saline (SAL) into the posterior region of quadriceps muscle of healthy male Swiss mice under distinct therapeutic schemes evaluating: animal behavior, body and organ weight, hemogram, plasmatic biochemical markers for tissue damage and inflammatory cytokine levels and profile. To assess the impact on the experimental T. cruzi infection, different schemes (prior and post infection) and periods of AWB administration (from one up to 10 days) were conducted, also employing heterologous whole blood (HWB) and evaluating plasma cytokine profile.ResultsNo major adverse events were observed in healthy AWB-treated mice, except gait impairment in animals that received three doses of 20 μL AWB in the same hind limb. AWB and SAL triggered an immediate polymorphonuclear response followed by mononuclear infiltrate. Although SAL triggered an inflammatory response, the kinetics and intensity of the histological profile and humoral mediator levels were different from AWB, the latter occurring earlier and more intensely with concomitant elevation of plasma IL-6. Inflammatory peak response of SAL, mainly composed of mononuclear cells with IL-10, was increased at 24 h. According to the mouse model of acute T. cruzi infection, only minor decreases (< 30%) in the parasitemia levels were produced by AWB and HWB given before and after infection, without protecting against mortality. Rises in IFN-gamma, TNF-alpha and IL-6 were detected at 9 dpi in all infected animals as compared to uninfected mice but only Bz displayed a statistically significant diminution (p = 0.02) in TNF-alpha levels than infected and untreated mice.ConclusionsThis study revealed that the use of autologous whole blood (AWB) in the acute model employed was unable to reduce the parasitic load of infected mice, providing only a minor decrease in parasitemia levels (up to 30%) but without protecting against animal mortality. Further in vivo studies will be necessary to elucidate the effective impact of this procedure.

TBX20 Regulates Angiogenesis Through the Prokineticin 2-Prokineticin Receptor 1 Pathway.

Angiogenesis is integral for embryogenesis, and targeting angiogenesis improves the outcome of many pathological conditions in patients. TBX20 is a crucial transcription factor for embryonic development, and its deficiency is associated with congenital heart disease. However, the role of TBX20 in angiogenesis has not been described. Loss- and gain-of-function approaches were used to explore the role of TBX20 in angiogenesis both in vitro and in vivo. Angiogenesis gene array was used to identify key downstream targets of TBX20. Unbiased gene array survey showed that TBX20 knockdown profoundly reduced angiogenesis-associated PROK2 (prokineticin 2) gene expression. Indeed, loss of TBX20 hindered endothelial cell migration and in vitro angiogenesis. In a murine angiogenesis model using subcutaneously implanted Matrigel plugs, we observed that TBX20 deficiency markedly reduced PROK2 expression and restricted intraplug angiogenesis. Furthermore, recombinant PROK2 administration enhanced angiogenesis and blood flow recovery in murine hind-limb ischemia. In zebrafish, transient knockdown of tbx20 by morpholino antisense oligos or genetic disruption of tbx20 by CRISPR/Cas9 impaired angiogenesis. Furthermore, loss of prok2 or its cognate receptor prokr1a also limited angiogenesis. In contrast, overexpression of prok2 or prokr1a rescued the impaired angiogenesis in tbx20-deficient animals. Our study identifies TBX20 as a novel transcription factor regulating angiogenesis through the PROK2-PROKR1 (prokineticin receptor 1) pathway in both development and disease and reveals a novel mode of angiogenic regulation whereby the TBX20-PROK2-PROKR1 signaling cascade may act as a "biological capacitor" to relay and sustain the proangiogenic effect of vascular endothelial growth factor. This pathway may be a therapeutic target in the treatment of diseases with dysregulated angiogenesis.

Assessing the welfare level of intensive fattening pig farms in Germany with the Welfare Quality® protocol: does farm size matter?

AbstractThe housing condition of pig (Sus scrofa) fattening farms are increasingly receiving criticism, because they are associated with impaired animal welfare. Consumers view the increase in farm sizes critically, even though scientifically based knowledge on the relationship between farm size and welfare is still limited. Therefore, the aim of this study was to assess the welfare level of conventional fattening pig farms in Germany and to evaluate the relationship between farm size and animal welfare level. In total, the Welfare Quality® protocol (WQ) for pigs was applied on 60 farms. Farms were classified according to their size into small (&lt; 1,500 pigs per farm), medium (1,500-3,000 pigs per farm) and large (&gt; 3,000 pigs per farm). Independent of the farm size, the overall WQ classifications ‘excellent’ and ‘not classified’ were not recorded in any of the farms, while ‘enhanced’ and ‘acceptable’ was achieved by 80 and 20% of the farms, respectively. Farm sizes had no effect on any of the four principles ‘good feeding’, ‘good housing’, ‘good health’ or ‘appropriate behaviour’. Overall, moderate bursitis (35%) was found to be the most prevalent indicator of welfare-related problems. However, it did not differ between farm sizes. Another highly prevalent indicator, moderately soiled body, increased from 11.1% in small-to 20.8% in large-sized farms. In conclusion, our findings show that none of the farm sizes were superior in terms of animal welfare. Overall, acceptable or enhanced scores were achieved for many of the criteria, however the need for improvement in other criteria such as ‘expression of other behaviour’ and ‘positive emotional state’, was clear.

Behavioral Assessment of Vision in Pigs.

Swine (Sus scrofa) are often the 'gold standard' laboratory animal for ophthalmology research due to the anatomic and physiologic similarities between the porcine and human eye and retina. Despite the importance of this model, few tools for behavioral vision assessment in pigs are available. The aim of this study was to identify and validate a feasible and reproducible behavioral test to assess vision in a pig model of photoreceptor degeneration. In addition, a robust behavioral test will reduce stress and enhance enrichment by allowing animals opportunities for environmental exploration and by reducing the number of invasive experimental procedures. Two distinct behavioral approaches were tested: the obstacle-course test and temperament test. In the obstacle-course test, pigs were challenged (after an initial training period) to navigate a 10-object obstacle course; time and the number of collisions with the objects were recorded. In the temperament test, the time needed for pigs to complete 3 different tasks (human-approach, novel-object, and open-door tests) was recorded. The obstacle-course test revealed significant differences in time and number of collisions between swine with vision impairment and control animals, and the training period proved to be pivotal to avoid bias due to individual animal characteristics. In contrast, the temperament test was not altered by vision impairment but was validated to measure stress and behavioral alterations in laboratory pigs undergoing experimental procedures, thus achieving marked refinement of the study.

Long-term neurocognitive outcomes following surgery and anaesthesia in early life

Repeated controversial and alarming statements of the potential dangers of anaesthetic agents on neurological outcomes in children continue to be issued based primarily on preclinical studies. This review assesses the current evidence of laboratory and clinical data and identifies areas of concerns. Published animal and laboratory data consistently indicate that prolonged and excessive use of anaesthetic agents can lead to morphological changes and neurocognitive impairment in animals without a clear cut-off age or a superiority of one technique over another. Retrospective human studies and prospective clinical trials indicate that short exposures to anaesthesia and surgery are safe and have no effect on long-term neurological outcomes. Small and consistent continuing improvements in the perioperative period (aggregation of marginal gains) will impact on long-term neurological morbidity in humans. It is biologically plausible that anaesthetic agents may induce structural changes during mammalian brain development and beyond. However, in the absence of alternatives the impact of the choice of anaesthetic drugs on long-term neurocognitive outcomes is almost certainly to be of limited relevance in humans. The underlying disease processes, surgical intervention, and trauma as well as other known perioperative factors more significantly affect these outcomes.

The novel histone de acetylase 6 inhibitor, MPT0G211, ameliorates tau phosphorylation and cognitive deficits in an Alzheimer\u2019s disease model

Alzheimer’s disease (AD) is a dreadful neurodegenerative disease that leads to severe impairment of cognitive function, leading to a drastic decline in the quality of life. The primary pathological features of AD include senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs), comprising aggregated amyloid β (Aβ) and hyperphosphorylated tau protein, respectively, in the hippocampus of AD patients. Histone deacetylase 6 (HDAC6) is a key enzyme in this neurodegenerative disease, in particular, as it relates to tau hyperphosphorylation. This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment. In AD in vivo models, MPT0G211 appeared to ameliorate learning and memory impairment in animals. Furthermore, MPT0G211 treatment reduced the amount of phosphorylated tau in the hippocampal CA1 region. In summary, MPT0G211 treatment appears to be a promising strategy for improving the AD phenotypes, including tau hyperphosphorylation and aggregation, neurodegeneration, and learning and memory impairment, making it a valuable agent for further investigation.

Long-Term, Fructose-Induced Metabolic Syndrome-Like Condition Is Associated with Higher Metabolism, Reduced Synaptic Plasticity and Cognitive Impairment in Octodon degus.

There has been a progressive increase in the incidence of fructose-induced metabolic disorders, such as metabolic syndrome (MetS). Moreover, novel evidence reported negative effects of high-fructose diets in brain function. This study was designed to evaluate for the first time the effects of long-term fructose consumption (LT-FC) on the normal ageing process in a long-lived animal model rodent, Octodon degus or degu. Moreover, we could replicate human sugar consumption behaviour over time, leading us to understand then the possible mechanisms by which this MetS-like condition could affect cognitive abilities. Our results support that 28months (from pup to adulthood) of a 15% solution of fructose induced clinical conditions similar to MetS which includes an insulin-resistance scenario together with elevated basal metabolic rate and non-alcoholic fatty liver disease. Additionally, we extended our analysis to evaluate the impact of this MetS-like condition on the functional and cognitive brain processes. Behavioural test suggests that fructose-induced MetS-like condition impair hippocampal-dependent and independent memory performance. Moreover, we also reported several neuropathological events as impaired hippocampal redox balance, together with synaptic protein loss. These changes might be responsible for the alterations in synaptic plasticity and transmitter release observed in these cognitively impaired animals. Our results indicate that LT-FC induced several facets of MetS that eventually could trigger brain disorders, in particular, synaptic dysfunction and reduced cognition.

MicroRNA-188-3p is involved in sevoflurane anesthesia-induced neuroapoptosis by targeting MDM2.

Sevoflurane is a commonly used inhalation anesthetic. Sevoflurane-induced neuroapoptosis and cognitive impairments in animals are widely reported, however, the underlying molecular mechanisms remain largely unknown. The results of the present study demonstrated that sevoflurane anesthesia induced spatial memory impairments in rats, as determined by the Morris water maze test. Mechanistically, the current study demonstrated that sevoflurane administration significantly enhanced the expression of microRNA (miR)-188-3p. Furthermore, inhibition of miR-188-3p using lentiviral miR-188-3p inhibitors attenuated sevoflurane-induced cognitive impairments in rats. The present study also demonstrated that miR-188-3p targeted MDM2 proto-oncogene (MDM2) and negatively regulated the expression of MDM2, as determined by luciferase assays, reverse transcription-quantitative polymerase chain reaction and western blot analysis. Furthermore, decreased abundance of MDM2 following transfection with miR-188-3p mimics was associated with increased stability of p53 protein. Suppression of p53 activity using the specific p53 inhibitor pifithrin-α alleviated sevoflurane-induced neuroapoptosis. These results indicate that the miR-188-3p-MDM2-p53 axis may have a critical role in sevoflurane-induced cognitive dysfunction. Therefore, miR-188-3p may be a potential target for the treatment of sevoflurane-induced cognitive impairment.

Antinociceptive, anti-inflammatory and toxicological evaluation of semi-synthetic molecules obtained from a benzyl-isothiocyanate isolated from Moringa oleifera Lam. in a temporomandibular joint inflammatory hypernociception model in rats

Inflammation is a key component of many clinical conditions that affect the temporomandibular joint (TMJ) and Moringa oleifera Lam. has been used to treat inflammatory diseases. Here, we evaluated the toxicological effects on mice of a naturally-occurring isothiocyanate from M. oleifera and its seven analogue molecules. Further, the anti-nociceptive and anti-inflammatory effects on a rat model of TMJ inflammatory hypernociception were assessed. The systemic toxicological profile was determined in mice over a 14-day period: MC-1 1 μg/kg; MC-D1 1 μg/kg, MC-D3 100 μg/kg, MC-D6 1 μg/kg, MC-D7 1 μg/kg, MC-D8 1 μg/kg, MC-D9 10 μg/kg, and MC-H 1 μg/kg. The safest molecules were assayed for anti-nociceptive efficacy in the formalin (1.5%, 50 μL) and serotonin (255 mg) induced TMJ inflammatory hypernociception tests. The anti-inflammatory effect was evaluated through the vascular permeability assay using Evans blue. Further, the rota-rod test evaluated any motor impairment. Among the tested molecules, MC-D7, MC-D9, and MC-H were not toxic at the survival rate test, biochemical, and hystological analysis. They reduced the formalin-induced TMJ inflammatory hypernociception, but only MC-H decreased the serotonin-induced TMJ inflammation, suggesting an adrenergic receptor-dependent effect. They diminished the plasmatic extravasation, showing anti-inflammatory activity. At the rota-rod test, no difference was observed in comparison with control groups, reinforcing the hypothesis of anti-nociceptive effetc without motor impairment in animals. The analogues MC-D7, MC-D9, and MC-H were safe at the tested doses and efficient in reducing the formalin-induced TMJ hypernociception in rats. Our next steps include determining their mechanisms of anti-nociceptive action.

Nitric oxide mediates apoptosis and mitochondrial dysfunction and plays a role in growth hormone deficiency by nivalenol in GH3 cells

Nivalenol (NIV), a type B trichothecenes commonly found in cereal crops, can cause growth impairment in animals. However, limited information about its mechanisms is available. Trichothecenes have been characterized as an inhibitor of protein synthesis and induce apoptosis in cells. Oxidative stress is considered an underlying mechanism. However, whether NIV can induce oxidative stress and apoptosis in rat pituitary cells line GH3 is unclear. The present study showed that NIV significantly reduced the viability of cells and caused oxidative stress in GH3 cells. Further experiments showed that nitric oxide (NO), but not ROS, mediated NIV-induced oxidative stress. Additionally, NIV induced caspase-dependent apoptosis, decrease in mitochondrial membrane potential and mitochondrial ultrastructural changes. However, NIV-induced caspase activation, mitochondrial damage and apoptosis were partially alleviated by Z-VAD-FMK or NO scavenger hemoglobin. Finally, NIV changed the expression of growth-associated genes and pro-inflammatory cytokines. NIV also reduced the GH secretion in GH3 cells, which was reversed by hemoglobin. Taken together, these results suggested that NIV induced apoptosis in caspase-dependent mitochondrial pathway in GH3 cells, which might be an underlying mechanism of NIV-induced GH deficiency. Importantly, NO played a critical role in the induction of oxidative stress, apoptosis and GH deficiency in NIV-treated GH3 cells.

Sevoflurane Induces Exaggerated and Persistent Cognitive Decline in a Type II Diabetic Rat Model by Aggregating Hippocampal Inflammation.

Recent studies show that a moderate duration of sevoflurane, one of the most commonly used volatile anesthetics in clinical practice, does not induce cognitive impairment in animals under physiological conditions. However, the influence of sevoflurane on cognitive function under diabetic conditions remains unclear. The aim of this study was to determine whether sevoflurane causes cognitive decline in a rat model of type 2 diabetes mellitus (DM) and if so, to explore a possible underlying mechanism. Diabetic Goto–Kakizaki (GK) rats and non-diabetic Wistar rats underwent 2.6% sevoflurane for 4 h or sham (control) exposure. Cognitive function and hippocampal inflammation were assessed 1 week and 5 months after sevoflurane or sham exposure. Compared with Wistar control rats, GK control rats exhibited shorter freezing times in Trace fear conditioning task 1 week after exposure, took longer to locate the submerged platform and had shorter dwell-time in the target quadrant in Morris Water Maze task 5 months after exposure. GK rats that received sevoflurane not only exhibited less freezing times 1 week after exposure, but also spent more time to locate the submerged platform and had less dwell-time in the target quadrant, compared with GK control rats. Molecular studies revealed that the levels of pro-inflammatory cytokines and activated microglia in the hippocampus were higher in GK control rats than those in Wistar control rats at both time points and were further increased in GK rats receiving sevoflurane. Wistar rats that received sevoflurane and Wistar control rats did not differ in any cognitive performance and molecular assessment. The results suggest that diabetic GK rats exhibit cognitive dysfunction probably due to increased hippocampal inflammation, and that sevoflurane induces exaggerated and persistent cognitive decline in GK rat by aggregating hippocampal inflammation.

Effects of Choline Alfoscerate and Memantine on Memory Improvement of Scopolamine-induced Memory Impairment animal Model of Alzheimer’s Disease

Effects of Choline Alfoscerate and Memantine on Memory Improvement of Scopolamine-induced Memory Impairment animal Model of Alzheimer’s Disease