Brain Tissue Concentrations Research Articles

Inhibition of the NLRP3 inflammasome reduces brain edema and regulates the distribution of aquaporin-4 after cerebral ischaemia-reperfusion

AimsBrain edema is a common threat to life in ischaemic brain injury. The NLRP3 inflammasome promotes the inflammatory injury after ischaemic stroke. Previous studies have shown that aquaporin-4 (AQP4) modulates brain water transport and endothelin-1 (ET-1) induces cerebral edema. However, the contribution of the NLRP3 inflammasome to regulation of brain edema and blood-brain barrier (BBB) disruption in cerebral ischaemia-reperfusion is elusive. The aim of this study is to investigate the effect of inhibition of the NLRP3 inflammasome by MCC950 on regulation of cerebral edema, BBB disruption and the expression of AQP4 and ET-1 in cerebral ischaemia-reperfusion. Main methodsThe male C57BL/6 mice were used to establish the experimental transient middle cerebral artery occlusion (tMCAO) model. The mice were intraperitoneally injected with MCC950. Changes in NLRP3, IL-1β, IL-18, the pyroptosis protein gasdermin D (GSDMD), brain water content, AQP4 and ET-1 in brain tissue were detected. Key findingsMCC950 inhibited NLRP3 and GSDMD after tMCAO. MCC950 improved cerebral edema and alleviated the damage of BBB after tMCAO. The levels of AQP4 and ET-1 were decreased by MCC950. In addition, MCC950 regulated the distribution of AQP4 after tMCAO in mice. SignificanceThe NLRP3 inflammasome facilitated brain edema and BBB disruption after cerebral ischaemia-reperfusion in mice, and NLRP3 inflammasome inhibition with MCC950 regulated the expression and distribution of AQP4 in the infarct area. Hence, the NLRP3 inflammasome is considered to be an important target for the treatment of brain edema in cerebral ischaemia-reperfusion, and MCC950 has potential value for ischaemic stroke treatment.

Progressive impairment of learning and memory in adult zebrafish treated by Al2O3 nanoparticles when in embryos

Al2O3 Nanoparticles (Al2O3-NPs) have been widely used because of their unique physical and chemical properties, and Al2O3-NPs can be released into the environment directly or indirectly. Our previous research found that 13 nm Al2O3-NPs can induce neural cell death and autophagy in primarily cultured neural cells in vitro. The aim of this study was to determine where Al2O3-NPs at 13 nm particle size can cause neural cells in vivo and assess related behavioural changes and involved potential mechanisms. Zebrafish from embryo to adult were selected as animal models. Learning and memory as functional indicators of neural cells in zebrafish were measured during the development from embryo to adult. Our results indicate that Al2O3-NPs treatment in zebrafish embryos stages can cause the accumulation of aluminium content in zebrafish brain tissue, leading to progressive impaired neurodevelopmental behaviours and latent learning and memory performance. Additionally, oxidative stress and disruption of dopaminergic transmission in zebrafish brain tissues are correlated with the dose-dependent and age-dependent accumulation of aluminium content. Moreover, the number of neural cells in the telencephalon tissue treated with Al2O3-NPs significantly declined, and the ultramicroscopic morphology indicated profound autophagy alternations. The results suggest that Al2O3-NPs has dose-dependent and time-dependent progressive damage on learning and memory performance in adult zebrafish when treated in embryos. This is the first study of the effects of Al2O3-NPs on learning and memory during the development of zebrafish from embryo to adult.

Comprehensive Parent-Metabolite PBPK/PD Modeling Insights into Nicotine Replacement Therapy Strategies.

BackgroundNicotine, the pharmacologically active substance in both tobacco and many electronic cigarette (e-cigarette) liquids, is responsible for the addiction that sustains cigarette smoking. With 8 million deaths worldwide annually, smoking remains one of the major causes of disability and premature death. However, nicotine also plays an important role in smoking cessation strategies.ObjectivesThe aim of this study was to develop a comprehensive, whole-body, physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of nicotine and its major metabolite cotinine, covering various routes of nicotine administration, and to simulate nicotine brain tissue concentrations after the use of combustible cigarettes, e-cigarettes, nicotine gums, and nicotine patches.MethodsA parent–metabolite, PBPK/PD model of nicotine for a non-smoking and a smoking population was developed using 91 plasma and brain tissue concentration–time profiles and 11 heart rate profiles. Among others, cytochrome P450 (CYP) 2A6 and 2B6 enzymes were implemented, including kinetics for CYP2A6 poor metabolizers.ResultsThe model is able to precisely describe and predict both nicotine plasma and brain tissue concentrations, cotinine plasma concentrations, and heart rate profiles. 100% of the predicted area under the concentration–time curve (AUC) and maximum concentration (Cmax) values meet the twofold acceptance criterion with overall geometric mean fold errors of 1.12 and 1.15, respectively. The administration of combustible cigarettes, e-cigarettes, nicotine patches, and nicotine gums was successfully implemented in the model and used to identify differences in steady-state nicotine brain tissue concentration patterns.ConclusionsOur PBPK/PD model may be helpful in further investigations of nicotine dependence and smoking cessation strategies. As the model represents the first nicotine PBPK/PD model predicting nicotine concentration and heart rate profiles after the use of e-cigarettes, it could also contribute to a better understanding of the recent increase in youth e-cigarette use.Electronic supplementary materialThe online version of this article (10.1007/s40262-020-00880-4) contains supplementary material, which is available to authorized users.

Exhaled Propofol Concentrations Correlate With Plasma and Brain Tissue Concentrations in Rats.

Propofol can be measured in exhaled gas. Exhaled and plasma propofol concentrations correlate well, but the relationship with tissue concentrations remains unknown. We thus evaluated the relationship between exhaled, plasma, and various tissue propofol concentrations. Because the drug acts in the brain, we focused on the relationship between exhaled and brain tissue propofol concentrations. Thirty-six male Sprague-Dawley rats were anesthetized with propofol, ketamine, and rocuronium for 6 hours. Animals were randomly assigned to propofol infusions at 20, 40, or 60 mg·kg·h (n = 12 per group). Exhaled propofol concentrations were measured at 15-minute intervals by multicapillary column-ion mobility spectrometry. Arterial blood samples, 110 µL each, were collected 15, 30, and 45 minutes, and 1, 2, 4, and 6 hours after the propofol infusion started. Propofol concentrations were measured in brain, lung, liver, kidney, muscle, and fat tissue after 6 hours. The last exhaled and plasma concentrations were used for linear regression analyses with tissue concentrations. The correlation of exhaled versus plasma concentrations (R = 0.71) was comparable to the correlation of exhaled versus brain tissue concentrations (R = 0.75) at the end of the study. In contrast, correlations between plasma and lung and between lung and exhaled propofol concentrations were poor. Less than a part-per-thousand of propofol was exhaled over 6 hours. Exhaled propofol concentrations correlate reasonably well with brain tissue and plasma concentrations in rats, and may thus be useful to estimate anesthetic drug effect. The equilibration between plasma propofol and exhaled gas is apparently independent of lung tissue concentration. Only a tiny fraction of administered propofol is eliminated via the lungs, and exhaled quantities thus have negligible influence on plasma concentrations.

Aluminium in Brain Tissue in Non-neurodegenerative/Non-neurodevelopmental Disease: A Comparison with Multiple Sclerosis

Human exposure to aluminium is a burgeoning issue. The brain is a sink for systemically available aluminium and a putative target of neurotoxicity. An increasing number of studies continue to confirm the presence of aluminium in human brain tissue though primarily in relation to donors who have died of a neurodegenerative or neurodevelopmental disorder. Herein, we have measured aluminium in brain tissue in donors who died of a specific disease or condition though without showing any neurodegeneration. The donors were diagnosed as not suffering from multiple sclerosis. Herein, these novel data are compared with recent data on aluminium in brain tissue in multiple sclerosis. Brain tissues from all four lobes were obtained from the Multiple Sclerosis Society Tissue Bank. Tissues were digested using microwave-assisted acid digestion and their aluminium content was measured by transversely heated graphite furnace atomic absorption spectrometry. Both are established methods in our laboratory. Detailed statistical analyses were used to compare new data with recent data for multiple sclerosis. Aluminium was found in brain tissue in each donor with a high proportion of measurements (189/291) being below 1.00 μg/g dry weight. The data for all cases (median and IQR) were 0.74 (0.48–1.28), 1.23 (0.62–1.63), 0.84 (0.45–1.14) and 1.01 (0.62–1.65) μg/g dry weight for occipital, parietal, temporal and frontal lobes, respectively. There was a statistically significant positive correlation between aluminium content of brain tissue and the age of donor. Comparison of data for this non-multiple sclerosis group with brain aluminium data for donors dying with a diagnosis of multiple sclerosis showed that the latter had a statistically significant higher content of brain aluminium. The data reinforce a previous conclusion that the aluminium content of brain tissue in multiple sclerosis is elevated and support the suggestion that human exposure to aluminium may have a role to play in the aetiology of multiple sclerosis.

Minocycline attenuates neurological impairment and regulates iron metabolism in a rat model of traumatic brain injury

There is currently no effective treatment for neurological impairment caused by traumatic brain injury (TBI). It has been reported that excessive iron production in the brain may be a key factor in neurological impairment. In the present study, we investigated the effects of minocycline, a semi-synthetic tetracycline antibiotic, against TBI-induced neurological impairment and explored its underlying mechanism. Neurological impairment was assessed by foot-fault test, cylinder test, wire hang test, and Morris water maze. Nissl staining was performed to evaluate cell viability in the brain. The iron concentrations in cerebrospinal fluid (CSF), serum, and brain tissues were examined. The Fe2+- and Fe3+- chelating activity of minocycline was measured. Finally, the expression levels of important iron metabolism proteins ferritin, transferrin receptor 1 (TfR1), divalent metal transporter 1 (DMT1), ferroportin 1 (FPN1), and hepcidin in the hippocampus and cortex were measured by Western blot analysis. The results indicate that minocycline significantly attenuated the neurological impairment caused by TBI and increased neuronal viability. Minocycline showed a Fe2+- and Fe3+- chelating activity in vitro and reduced the iron concentration in CSF and brain tissues (cortex and hippocampus). Minocycline also inhibited the overexpression of ferritin and TfR1, but did not affect the expression of DMT1. Minocycline restored the expression of FPN1 by decreasing the expression of hepcidin. In conclusion, minocycline may attenuate neurological impairment caused by TBI and regulate iron metabolism.

Regulation of CSF and Brain Tissue Sodium Levels by the Blood-CSF and Blood-Brain Barriers During Migraine

Cerebrospinal fluid (CSF) and brain tissue sodium levels increase during migraine. However, little is known regarding the underlying mechanisms of sodium homeostasis disturbance in the brain during the onset and propagation of migraine. Exploring the cause of sodium dysregulation in the brain is important, since correction of the altered sodium homeostasis could potentially treat migraine. Under the hypothesis that disturbances in sodium transport mechanisms at the blood-CSF barrier (BCSFB) and/or the blood-brain barrier (BBB) are the underlying cause of the elevated CSF and brain tissue sodium levels during migraines, we developed a mechanistic, differential equation model of a rat's brain to compare the significance of the BCSFB and the BBB in controlling CSF and brain tissue sodium levels. The model includes the ventricular system, subarachnoid space, brain tissue and blood. Sodium transport from blood to CSF across the BCSFB, and from blood to brain tissue across the BBB were modeled by influx permeability coefficients PBCSFB and PBBB, respectively, while sodium movement from CSF into blood across the BCSFB, and from brain tissue to blood across the BBB were modeled by efflux permeability coefficients and , respectively. We then performed a global sensitivity analysis to investigate the sensitivity of the ventricular CSF, subarachnoid CSF and brain tissue sodium concentrations to pathophysiological variations in PBCSFB, PBBB, and . Our results show that the ventricular CSF sodium concentration is highly influenced by perturbations of PBCSFB, and to a much lesser extent by perturbations of . Brain tissue and subarachnoid CSF sodium concentrations are more sensitive to pathophysiological variations of PBBB and than variations of PBCSFB and within 30 min of the onset of the perturbations. However, PBCSFB is the most sensitive model parameter, followed by PBBB and , in controlling brain tissue and subarachnoid CSF sodium levels within 3 h of the perturbation onset.

Rhynchophylline Loaded-mPEG-PLGA Nanoparticles Coated with Tween-80 for Preliminary Study in Alzheimer's Disease.

PurposeAlzheimer’s disease (AD) is a growing concern in the modern society. The current drugs approved by FDA are not very promising. Rhynchophylline (RIN) is a major active tetracyclic oxindole alkaloid stem from traditional Chinese medicine uncaria species, which has potential activities beneficial for the treatment of AD. However, the application of rhynchophylline for AD treatment is restricted by the low water solubility, low concentration in brain tissue and low bioavailability. And there is no study of brain-targeting therapy with RIN. In this work, we prepared rhynchophylline loaded methoxy poly (ethylene glycol)–poly (dl-lactide-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPS-RIN), which coupled with Tween 80 (T80) further for brain targeting delivery (T80-NPS-RIN).MethodsPreparation and characterization of T80-NPS-RIN were followed by the detection of transportation across the blood–brain barrier (BBB) model in vitro, biodistribution and neuroprotective effects of nanoparticles.ResultsThe results indicated T80-NPS-RIN could usefully assist RIN to pass through the BBB to the brain. T80-NPS-RIN treatment regulated the activity of neurons in vitro.ConclusionThe presented data confirmed that rhynchophylline encapsulated mPEG-PLGA nanoparticles coated with Tween 80 could across through the BBB and exhibited efficient neuroprotective effects. The T80-NPS-RIN nanoparticles have a chance to be an alternative drug to the therapy of AD.

Abstract WP144: Cerebral Amyloid Angiopathy Pathology Worsens Stroke Outcome and Has a Detrimental Effect on the Gut Microbiome in Mice

Background: Cerebral amyloid angiopathy (CAA) is associated with both ischemic and hemorrhagic stroke, is a known cause of vascular cognitive impairment (VCI), and predicts worsened outcome after stroke. A growing body of literature has highlighted the importance of the gut microbiome in stroke outcome and neurodegenerative diseases such as Alzheimerz’s. However, little is known about how changes in the microbiome can affect CAA progression. The gut-brain axis is highly involved in the systemic inflammatory response following stroke. Furthermore, the gut is a primary source of bacterial translocation resulting in cerebral inflammation which further may contribute to vascular pathology. Therefore, the cross talk between CAA, stroke, and gut function could be key in our understanding and treatment of stroke in patients with CAA. Methods: Symptomatic male Tg-SwDI (4 mths old) and C57BL/6 wild type (WT) mice underwent a 60 minute transient MCAO. Stroke was confirmed with cresyl violet staining and presence of amyloid β (Aβ) plaques were demonstrated with thioflavin. Post-stroke motor function was assessed at day 4 with open field-testing and results were compared to pre-stroke baseline and WT values and cognitive assessment was performed with the Y-maze test. Furthermore, PCR was used to identify the presence of Firmicutes and Bacteroidetes ratio (F:B) in both brain tissue and gut content. Results: We demonstrate a significant decrease in the total distance traveled in both open field and cognitive Y-maze (p<0.05 and p<0.01 respectively) at baseline of Tg-SwDI mice. This was associated with the presence of Aβ plaque in the brain. PCR did not reveal any conclusive evidence for bacterial translocation in the brain at day 4. However, there was a pathogenic shift in the gut F:B ratio following stroke in Tg-SwDI mice compared to sham Tg-SwDI or sham WT controls and this will be confirmed by 16S rRNA gene sequencing. Conclusion: Symptomatic CAA mice exhibit decreased motor and cognitive function compared to WT controls. Furthermore, 16S sequencing was performed to look at the bacterial translocation in detail from the gut to the brain. This is the first study to link CAA, stroke, and the gut brain axis, that may be crucial in understanding the complexity of stroke pathology.

Study on Effects and Mechanism of Lead and High-Fat Diet on Cognitive Function and Central Nervous System in Mice

We sought to investigate the effects and mechanism of lead and a high-fat diet on cognitive function and the central nervous system in mice. Eighty-four healthy male mice were randomly divided into a control group (n= 21) (fed with common diet and free drinking), a lead exposure group (n= 21) (fed with common diet and 300 mg/L lead acetate solution), a high-fat group (n= 21) (fed with high-fat diet and free drinking), and a lead+ high-fat group (n= 21) (fed with high-fat diet and 300 mg/L lead acetate solution). In 10 weeks after lead exposure, the mice of all groups were tested for the cognition, learning and memory abilities, body weight, serum triglyceride (TG), low-density lipoprotein, and high-density lipoprotein, as well as for the contents of lead, interleukin 6 (IL-6), interleukin 17 (IL-17), interferon γ, advanced glycation end products (AGEs), glutathione S-transferase (GSH-ST), and hydrogen peroxide in the brain tissues. Compared with the control group and the lead-exposed group, the body weights of mice in the high-fat group and the lead+ high-fat group increased significantly from the sixth week of the experiment, of which the difference was statistically significant (P < 0.05). Compared with the control group and the high-fat group, the lead content in brain tissue of the lead exposure group and the lead+ high-fat group increased significantly, of which the difference was statistically significant (P < 0.05). Compared with the control group, the escape latent period, triglyceride, low-density lipoprotein, IL-6, IL-17, interferon γ, and AGEs of the remaining 3 groups increased significantly, but the recognition index, passing platform times, high-density lipoprotein, and GSH-ST significantly decreased (P < 0.05); the second and third escape latent periods, IL-6, IL-17, and AGEs of lead+ high-fat group, were obviously higher than the remaining 3 groups, but the passing platform times were obviously lower than the remaining 3 groups, of which the difference was statistically significant. The content of hydrogen peroxide in brain tissues had no difference among groups (P > 0.05). The lead and high-fat diet resulted in lipid metabolism disorders and impaired the cognitive function and central nervous system by promoting the secretion of inflammatory factors in glial cells, inducing the inflammatory reaction of brain tissue, inhibiting GSH-ST expression, and increasing AGEs content.

Влияние различных режимов ритмических экстремальных холодовых воздействий на интенсивность процессов перекисного окисления липидов в тканях головного мозга и содержание гормонов в сыворотке крови старых крыс

Влияние различных режимов ритмических экстремальных холодовых воздействий на интенсивность процессов перекисного окисления липидов в тканях головного мозга и содержание гормонов в сыворотке крови старых крыс

Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study.

BackgroundThere is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways.Methods and findingsWe first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione [GSH]: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators.ConclusionsIn this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD.

Effect of Escitalopram on Serum GDNF and BDNF Levels and 5-HT Level of Brain Tissue of Obsessive-Compulsive Disorder Rats.

The present study aims to discuss the effect of escitalopram in glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) levels, and 5-Hydroxytryptamine (5-HT) in obsessive-compulsive disorder rats. A total of 42 rats were divided into three groups randomly: control group (n = 14), model group (n = 14) (obsessive-compulsive disorder group), and escitalopram group (n = 14) (model + obsessive-compulsive disorder group + escitalopram treatment). The open-field method was used to test the rat behavior, enzyme-linked immunosorbent assay (ELISA) was used to determine the serum GDNF and BDNF levels. In addition, Western blot was used to determine the brain tissue protein levels of GDNF and BDNF and high-performance liquid chromatography + electrochemistry method to determine the 5-HT level of brain tissue. Visiting place was changed, rotational frequency and fixed duration enhanced in escitalopram group compared to model group (P < 0.05). Besides, GDNF and BDNF levels of serum and brain tissue were decreased in model group and escitalopram group compared to control group (P < 0.05), while GDNF and BDNF levels of serum and brain tissue were increased in escitalopram group compared to model group (P < 0.05). Moreover, the 5-HT level of brain tissue in escitalopram group was higher than that in model group (P < 0.05). Escitalopram could increase GDNF and BDNF levels and 5-HT content in serum and brain tissue in obsessive-compulsive disorder rats, which contributes to a function on the treatment of obsessive-compulsive disorder.

Magnesium acetyl taurate prevents tissue damage and deterioration of prosocial behavior related with vasopressin levels in traumatic brain injured rats

To investigate the effects of different magnesium forms on tissue damage, cognitive and emotional behavioural impairment after mild traumatic brain injury (TBI). Rats were divided into 5 groups (control, trauma, magnesium sulphate, magnesium citrate, magnesium acetyl taurate) and following head trauma, empathy-like behaviour, anxiety-like behaviour (elevated plus maze and open field tests), and depression (forced swim test) were measured. The rats were then sacrificed 12 days later. Oxytocin, vasopressin and receptors levels in the amygdala and prefrontal cortex regions were measured. Histopathological damage (with haematoxylin-eosin staining) and apoptosis (with caspase-3 immunohistochemistry) was evaluated. Following head trauma, anxiety-like behaviour and depression tests did not change; empathy-like behaviour deteriorated on the 3rd day and improved gradually on the 6th and 12th days. Oxytocin, vasopressin and vasopressin v1b receptor levels decreased in the amygdala; morphological damage and apoptosis were significant. Magnesium acetyl taurate effectively ameliorated histopathological deteriorations and improved vasopressin and v1b receptor levels in the amygdala. Transient deterioration of empathy-like behaviour was impeded only in magnesium taurate treatment. Magnesium acetyl taurate can be a promising candidate agent to prevent structural and functional damage in traumatic brain injury.

Analyzing the co-localization of substantia nigra hyper-echogenicities and iron accumulation in Parkinson's disease: A multi-modal atlas study with transcranial ultrasound and MRI.

Transcranial B-mode sonography (TCS) can detect hyperechogenic speckles in the area of the substantia nigra (SN) in Parkinson's disease (PD). These speckles correlate with iron accumulation in the SN tissue, but an exact volumetric localization in and around the SN is still unknown. Areas of increased iron content in brain tissue can be detected in vivo with magnetic resonance imaging, using quantitative susceptibility mapping (QSM). In this work, we i) acquire, co-register and transform TCS and QSM imaging from a cohort of 23 PD patients and 27 healthy control subjects into a normalized atlas template space and ii) analyze and compare the 3D spatial distributions of iron accumulation in the midbrain, as detected by a signal increase (TCS+ and QSM+) in both modalities. We achieved sufficiently accurate intra-modal target registration errors (TRE<1 mm) for all MRI volumes and multi-modal TCS-MRI co-localization (TRE<4 mm) for 66.7% of TCS scans. In the caudal part of the midbrain, enlarged TCS+ and QSM+ areas were located within the SN pars compacta in PD patients in comparison to healthy controls. More cranially, overlapping TCS+ and QSM+ areas in PD subjects were found in the area of the ventral tegmental area (VTA). Our findings are concordant with several QSM-based studies on iron-related alterations in the area SN pars compacta. They substantiate that TCS+ is an indicator of iron accumulation in Parkinson's disease within and in the vicinity of the SN. Furthermore, they are in favor of an involvement of the VTA and thereby the mesolimbic system in Parkinson's disease.

Protease-activated receptor 1 inhibitor improves brain edema in rats with intracerebral hemorrhage.

To investigate the changes of water content in brain tissue, the expression of AQP4mRNA after cerebral hemorrhage in rats, and the intervention effect of Protease activated receptor 1 inhibitor (PAR1 inhibitor) on both. Establish sham operation group (Sham group), ICH group, ICH+PAR1 inhibitor high-dose group (PI(H)group), ICH+PAR1 inhibitor low-dose group (PI(L)group), 25 in each group. Neural dysfunction scores were performed at 1d, 3d, 7d, 14d, and 21d after surgery, and brain water content and AQP4mRNA content were measured. Results: The neurological dysfunction and cerebral edema of rats with cerebral hemorrhage reached the peak at 3 days after operation. With the increase of time, the water content and AQP4mRNA content in the PL(H)group were higher than those in the PI(L)group. The differences were statistically significant. Appropriate inhibition of PAR1 can alleviate cerebral edema around the hematoma and play a role in improving the function of nerve defects. The mechanism may be realized by down-regulating the expression of AQP4mRNA in brain tissue (Tab. 3, Fig. 3, Ref. 25).

Neuroprotective Effects of D-(-)-Quinic Acid on Aluminum Chloride-Induced Dementia in Rats.

Objective The present study was designed to evaluate the neuroprotective effects of D-(-)-quinic acid on aluminum chloride- (AlCl3-) induced neurobehavioral and biochemical changes in rats. This study showed the behavioral and biochemical effects of D-(-)-quinic acid on rats with particular emphasis on the hippocampus and frontal cortex which are associated with memory. Materials and Methods Chronic administration of aluminum chloride at a dose of 175 mg/kg, p.o. for a period of 25 days markedly increased the level of acetylcholinesterase (AChE) activity and reduced the levels of antioxidant enzymes in the brain. Two doses of D-(-)-quinic acid (200 mg/kg and 400 mg/kg) were selected based on previous safety/toxicity studies and administered orally from the 26th day to the 36th day of the trial. Behavioral parameters were assessed using the Morris water maze test and an actophotometer in rats. Biochemical parameter content and histology of brain tissue were assessed on the final day of the experiment. Results D-(-)-Quinic acid (200 mg/kg and 400 mg/kg) orally administered alongside AlCl3 rescued AChE activity and the behavioral impairments caused by aluminum. There was significant inhibition of MAO-B in D-(-)-quinic acid-treated rats. Histopathological studies in the hippocampus and cortex of the rat brain also supported that D-(-)-quinic acid markedly reduced the toxicity of AlCl3 and preserved the normal histoarchitecture pattern of the hippocampus and cortex. These results indicate that D-(-)-quinic acid can reverse memory loss caused by aluminum intoxication by attenuating AChE activity and rescuing the deleterious effect of AlCl3.

Epalrestat improves motor symptoms by reducing oxidative stress and inflammation in the reserpine induced mouse model of Parkinson's disease.

BackgroundParkinson's disease (PD) is a progressive neurodegenerative disorder affecting a large number of elderly people worldwide. The current therapies for PD are symptom‐based; they do not provide a cure but improve the quality of life. Muscular dysfunction is the hallmark clinical feature of PD and oxidative stress and inflammation play a critical role in its pathogenesis. Epalrestat is used for the treatment of diabetic neuropathy and is known to improve antioxidative defense mechanisms in the CNS. Therefore, in this study, we investigated the role of Epalrestat in the reserpine induced mouse model of PD.MethodWe used Swiss Albino mice for the PD model and tested for akinesia/bradykinesia, muscular rigidity, palpebral ptosis, and tremor, as well as conducting swim and open field tests. Brain samples were used to determine oxidative stress parameters and infiltration of immune cells.ResultsEpalrestat treatment significantly improved akinesia and bradykinesia, muscular dysfunctions, tremor level, and gait functions compared to the reserpine group. It also improved the latency in the swim test. Eplarestat significantly reduced lipid peroxidation and NO concentration in different brain tissues and increased the activity of antioxidative enzymes, glutathione, catalase, and superoxide dismutase. Furthermore, Epalrestat reduced neuroinflammation by reducing the number of infiltrating immune cells.ConclusionEplarestat improves muscular dysfunction in PD by reducing oxidative stress and inflammation.

Beneficial Effects of Some Nutraceuticals Containing Glucosamine and Antioxidant against CCL4 Induced Brain Injury in Rats

The present study is performed to investigate the effect of two different glucosamine containing drugs: Drug 1 and Drug 2 (D1 and D2) against CCl4 induced brain damage in male albino rats. Liverin (AM) was employed in the current study as an antioxidant reference drug. CCl4 administration caused a significant elevation in the levels of MDA and NO of brain tissue, in association with a significant decrease in the antioxidant defense system (GSH, SOD and GPX) that indicated the induction of oxidative stress in brain tissue. CCl4 administration induced brain injury as manifested by the obtained changes in neurotransmitter parameter (norepinephrine (NE), Dopamine (DA), Serotonin (5-HT), and Acetylcholinesterase AChE). The tested nutraceuticals and the antioxidant drug displayed a significant improvement against the undue effect of CCl4 via decreasing the brain tissue content of MDA, NO with the elevation of GSH content. Also, the significant increase in SOD and GPX enzymatic activity was obtained when compared to CCL4 group. In addition AM, D1, and D2 have an ameliorative effect on neurotransmitter parameter NE, DA, 5HT, and AChE. Results of this study suggest that both antioxidant drugs and tested nutraceuticals palliate the brain injuries through anti-oxidative effect, with the elimination of the deleterious effect of toxic metabolites of CCl4 on brain tissue.

Increased inflammation in BA21 brain tissue from African Americans with Alzheimer's disease.

Chronic neuroinflammation is strongly associated with AD and altered peripheral and central levels of chemokines and cytokines have been frequently described in those with AD. Given the increasing evidence of ethnicity-related differences in AD, it was of interest to determine if those altered chemokine and cytokine levels are ethnicity-related. Because African Americans exhibit a higher incidence of AD and increased symptom severity, we explored chemokine and cytokine concentrations in post-mortem brain tissue from the BA21 region of African Americans and Caucasians with AD using multiplex assays. IL-1β, MIG, TRAIL, and FADD levels were significantly increased in African Americans while levels of IL-3 and IL-8 were significantly decreased. Those effects did not interact with gender; however, overall levels of CCL25, CCL26 and CX3CL1 were significantly decreased in women. The NLRP3 inflammasome is thought to be critically involved in AD. Increased activation of this inflammasome in African Americans is consistent with the current results.