PDE3 Inhibition by Cilostazol Ameliorated Behavioral and Biochemical Deficits in Prenatal Alcohol Induced Experimental ADHD

2021 ◽  
Vol 17 ◽  
Author(s):  
Niti Sharma ◽  
Bhupesh Sharma ◽  
Neerupma Dhiman ◽  
Lalit K. Golani
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Ethyl Alcohol ◽  
Neuronal Survival ◽  
Brain Inflammation ◽  
Protein Markers ◽  
Tnf Α ◽  
Brain Oxidative Stress ◽  
Prenatal Alcohol ◽  
Pde3 Inhibitor

Background: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with complex aetiology and phenotypes. Maternal consumption of alcohol is known to produce deleterious effects in the progeny, generating ADHD related phenotypes. Phosphodiesterase-3 (PDE3) has been shown to provide benefits in various brain conditions. Objective: To investigate the role of a selective PDE3 inhibitor, effects of cilostazol administration on core phenotypes of prenatal alcohol exposure (PAE) model of ADHD were assessed. Methods: PAE was established by exposing animals to 6/4 g.kg-1 (weekdays/weekends) ethyl alcohol from gestational day 8-20 and cilostazol (30/60 mg.kg-1 p.o.) was administered to the offspring (PND21-48) of females exposed to ethyl alcohol. To identify probable mechanisms involved, the effects on protein markers of neuronal function such as, neuronal survival-BDNF, neuronal transcription factor-pCREB, brain inflammation (IL-6, IL-10 and TNF-α) and brain oxidative stress (TBARS and GSH) were studied in frontal cortex, cerebellum, and striatum. Also, effects on behaviour such as hyperactivity, inattention and anxiety were assessed. Result: PAE induced hyper-locomotion, inattention, and anxiety in tested animals. Administration of cilostazol to PAE group of animals resulted in amelioration of behavioural deficits. Also, cilostazol resulted in a significant increase in the levels of BDNF, pCREB, IL-10 and GSH along with significant decrease in TNF-α, IL-6 and TBARS in different brain areas of PAE group. Conclusion: Cilostazol, a selective PDE3 inhibitor rectified behavioural phenotypes associated with ADHD, possibly by altering protein markers associated with neuronal survival, neuronal transcription factor, brain inflammation, and brain oxidative stress.

scholarly journals 4R-cembranoid confers neuroprotection against LPS-induced hippocampal inflammation in mice

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Luis A. Rojas-Colón ◽  
Pramod K. Dash ◽  
Fabiola A. Morales-Vías ◽  
Madeline Lebrón-Dávila ◽  
Pedro A. Ferchmin ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Nicotinic Receptor ◽  
Neuronal Survival ◽  
Hippocampal Slices ◽  
Brain Inflammation ◽  
Mrna Levels ◽  
Efferent Nerve ◽  
Tnf Α ◽  
Alpha 7 ◽  
Pro Inflammatory Cytokines

Abstract Background Chronic brain inflammation has been implicated in the pathogenesis of various neurodegenerative diseases and disorders. For example, overexpression of pro-inflammatory cytokines has been associated with impairments in hippocampal-dependent memory. Lipopolysaccharide (LPS) injection is a widely used model to explore the pathobiology of inflammation. LPS injection into mice causes systemic inflammation, neuronal damage, and poor memory outcomes if the inflammation is not controlled. Activation of the alpha-7 nicotinic receptor (α7) plays an anti-inflammatory role in the brain through vagal efferent nerve signaling. 4R-cembranoid (4R) is a natural compound that crosses the blood-brain barrier, induces neuronal survival, and has been shown to modulate the activity of nicotinic receptors. The purpose of this study is to determine whether 4R reduces the deleterious effects of LPS-induced neuroinflammation and whether the α7 receptor plays a role in mediating these beneficial effects. Methods Ex vivo population spike recordings were performed in C57BL/6J wild-type (WT) and alpha-7-knockout (α7KO) mouse hippocampal slices in the presence of 4R and nicotinic receptor inhibitors. For in vivo studies, WT and α7KO mice were injected with LPS for 2 h, followed by 4R or vehicle for 22 h. Analyses of IL-1β, TNF-α, STAT3, CREB, Akt1, and the long-term novel object recognition test (NORT) were performed for both genotypes. In addition, RNA sequencing and RT-qPCR analyses were carried out for 12 mRNAs related to neuroinflammation and their modification by 4R. Results 4R confers neuroprotection after NMDA-induced neurotoxicity in both WT and α7KO mice. Moreover, hippocampal TNF-α and IL-1β levels were decreased with 4R treatment following LPS exposure in both strains of mice. 4R restored LPS-induced cognitive decline in NORT. There was a significant increase in the phosphorylation of STAT3, CREB, and Akt1 with 4R treatment in the WT mouse hippocampus following LPS exposure. In α7KO mice, only pAkt levels were significantly elevated in the cortex. 4R significantly upregulated mRNA levels of ORM2, GDNF, and C3 following LPS exposure. These proteins are known to play a role in modulating microglial activation, neuronal survival, and memory. Conclusion Our results indicate that 4R decreases the levels of pro-inflammatory cytokines; improves memory function; activates STAT3, Akt1, and CREB phosphorylation; and upregulates the mRNA levels of ORM2, GDNF, and C3. These effects are independent of the α7 nicotinic receptor.

scholarly journals Effects of Chronic Lithium Chloride and L-Arginine Treatment on Prevention of Streptozotocin Induced Cognitive Deficits by Ellagic Acid

2018 ◽  
Vol 11 (1) ◽  
pp. 53-65
Author(s):  
Manish Kumar ◽  
Nitin Bansal
Keyword(s):  
Oxidative Stress ◽  
Cognitive Deficits ◽  
Ellagic Acid ◽  
Oral Route ◽  
Cognitive Improvement ◽  
Ldh Activity ◽  
Tnf Α ◽  
Brain Oxidative Stress ◽  
Memory Enhancing ◽  
Nitrite Content

Administration of streptozotocin (STZ) through intracerebroventricular (ICV) route manifests AD symptoms in rats. STZ deregulates the control over GSK-3 and eNOS activities through disruption of phosphoinositides mediated signaling. We attempted to elucidate the functions of GSK-3 and eNOS in memory enhancing activity of ellagic acid (EGA) in STZ (ICV) triggered AD type dementia. A 3 mg/kg dose of STZ was injected gently in lateral cerebral ventricles of rats on day 1 and 3. The rats were given EGA (35 mg/kg b.w.) through oral route for four weeks daily. LiCl (GSK-3 inhibitor) and L-Arginine (NO precursor) were administered for four weeks to explore the modulation of GSK-3 and eNOS respectively by EGA in STZ (ICV) injected rats. MWM and EPM paradigms were utilized for evaluation of memory of rats. The rats were sacrificed on day 28 to determine markers of oxidative stress (TBARS, GSH, SOD, CAT), nitrite, AChE, LDH, TNF-α and eNOS in brain. STZ (ICV) initiated cognitive deficits through enhancement of brain oxidative stress, nitrite, TNF-α, AChE, LDH activity and reduction in eNOS levels. EGA attenuated the rise in oxidative stress, inflammation and LDH activity in STZ (ICV) treated rats. Decrease in nitrite content, AChE activity and resurrection of eNOS activity by EGA averted STZ (ICV) induced memory dysfunction in rats. Chronic inhibition of GSK-3 by LiCl (100 mg/kg, i.p.) enhanced these effects of EGA in STZ (ICV) injected rats which thereby exhibited marked cognitive improvement. L-Arginine group manifested inflation in brain oxidative stress, TNF-α content, AChE and LDH activities. L-Arginine (200 mg/kg, i.p.) surged the nitrite content even though eNOS expression was diminished in brain of EGA and STZ (ICV) administered rats resulting in profound loss of memory. It can be concluded that GSK-3 and eNOS are involved in memory enhancing activity of EGA in STZ (ICV) injected rats.

Inhibition of microRNA-155 Alleviates Neurological Dysfunction Following Transient Global Ischemia and Contribution of Neuroinflammation and Oxidative Stress in the Hippocampus

2020 ◽  
Vol 25 (40) ◽  
pp. 4310-4317 ◽  
Author(s):  
Lichao Sun ◽  
Shouqin Ji ◽  
Jihong Xing
Keyword(s):  
Oxidative Stress ◽  
Brain Edema ◽  
Severity Score ◽  
Global Ischemia ◽  
Signal Pathways ◽  
Neurological Severity Score ◽  
Tnf Α ◽  
Transient Global Ischemia ◽  
And Oxidative Stress

Background/Aims: Central pro-inflammatory cytokine (PIC) signal is involved in neurological deficits after transient global ischemia induced by cardiac arrest (CA). The present study was to examine the role of microRNA- 155 (miR-155) in regulating IL-1β, IL-6 and TNF-α in the hippocampus of rats with induction of CA. We further examined the levels of products of oxidative stress 8-isoprostaglandin F2α (8-iso PGF2α, indication of oxidative stress); and 8-hydroxy-2’-deoxyguanosine (8-OHdG, indication of protein oxidation) after cerebral inhibition of miR-155. Methods: CA was induced by asphyxia and followed by cardiopulmonary resuscitation in rats. ELISA and western blot analysis were used to determine the levels of PICs and products of oxidative stress; and the protein expression of NADPH oxidase (NOXs) in the hippocampus. In addition, neurological severity score and brain edema were examined to assess neurological functions. Results: We observed amplification of IL-1β, IL-6 and TNF-α along with 8-iso PGF2α and 8-OHdG in the hippocampus of CA rats. Cerebral administration of miR-155 inhibitor diminished upregulation of PICs in the hippocampus. This also attenuated products of oxidative stress and upregulation of NOX4. Notably, inhibition of miR-155 improved neurological severity score and brain edema and this was linked to signal pathways of PIC and oxidative stress. Conclusion: We showed the significant role of blocking miR-155 signal in improving the neurological function in CA rats likely via inhibition of signal pathways of neuroinflammation and oxidative stress, suggesting that miR-155 may be a target in preventing and/or alleviating development of the impaired neurological functions during CA-evoked global cerebral ischemia.

TA-65, A Telomerase Activator improves Cardiovascular Markers in Patients with Metabolic Syndrome

2018 ◽  
Vol 24 (17) ◽  
pp. 1905-1911 ◽  
Author(s):  
Maria Luz Fernandez ◽  
Minu Sara Thomas ◽  
Bruno S. Lemos ◽  
Diana M. DiMarco ◽  
Amanda Missimer ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Plasma Lipids ◽  
Disease Risk ◽  
Glycosylated Hemoglobin ◽  
Cardiovascular Disease Risk ◽  
Hdl Cholesterol ◽  
Double Blind ◽  
Tnf Α ◽  
Luminex Technology

Background: Telomerase Activator 65 (TA-65), a compound extracted from Astragalus membranaceus has been used in Chinese traditional medicine for extending lifespan. Scarce information exists on the effects of TA-65 on parameters of metabolic syndrome (MetS). Methods: We recruited 40 patients with MetS to determine the effects of TA-65 on dyslipidemias, hypertension, and oxidative stress in this at-risk population. The study was a double-blind, randomized crossover design in which patients were allocated to consume either 16 mg daily of a TA-65 supplement or a placebo for 12 weeks. Following a 3-week washout, participants were allocated to the alternate treatment for an additional 12 weeks. Anthropometric and biological markers were measured at the end of each treatment. Plasma lipids, glucose, CReactive Protein (CRP), liver enzymes, and glycosylated hemoglobin were measured using a Cobas c-111. Inflammatory cytokines were measured by Luminex technology and markers of oxidative stress by the use of spectroscopy. Results: Compared to the placebo period, HDL cholesterol (HDL-C) was higher while body mass index, waist circumference, and the LDL/HDL ratio were lower (p < 0.05) during TA-65 treatment. In addition, plasma tumor necrosis factor-α (TNF-α) was lower during the TA-65 period (p< 0.05). Positive correlations were observed in changes between the placebo and the TA-65 periods in HDL-C and CRP (r = -0.511, p < 0.01), alanine aminotransferase (r = -0.61, p < 0.001) and TNF-α (r = -0.550, p < 0.001) suggesting that the favorable changes observed in HDL were associated with decreases in inflammation. Conclusion: TA-65 improved key markers of cardiovascular disease risk, which were also associated with reductions in inflammation.

scholarly journals Feasibility of 3-month melatonin supplementation for brain oxidative stress and sleep in mild cognitive impairment: protocol for a randomised, placebo-controlled study

BMJ Open ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. e041500
Author(s):  
Zoe Menczel Schrire ◽  
Craig L Phillips ◽  
Shantel L Duffy ◽  
Nathaniel S Marshall ◽  
Loren Mowszowski ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Randomised Controlled Trial ◽  
Controlled Trial ◽  
Feasibility Trial ◽  
Controlled Study ◽  
Brain Oxidative Stress ◽  
Randomised Controlled

IntroductionMelatonin has multiple proposed therapeutic benefits including antioxidant properties, synchronisation of the circadian system and lowering of blood pressure. In this protocol, we outline a randomised controlled trial to assess the feasibility, acceptability and tolerability of higher dose (25 mg) melatonin to target brain oxidative stress and sleep disturbance in older adults with mild cognitive impairment (MCI).Methods and analysisThe study design is a randomised double-blind, placebo-controlled, parallel group trial. Forty individuals with MCI will be recruited from the Healthy Brain Ageing Clinic, University of Sydney and from the community, and randomised to receive either 25 mg oral melatonin or placebo nightly for 12 weeks. The primary outcomes are feasibility of recruitment, acceptability of intervention and adherence to trial medication at 12 weeks. Secondary outcomes will include the effect of melatonin on brain oxidative stress as measured by magnetic resonance spectroscopy, blood pressure, blood biomarkers, mood, cognition and sleep. Outcomes will be collected at 6 and 12 weeks. The results of this feasibility trial will inform a future conclusive randomised controlled trial to specifically test the efficacy of melatonin on modifiable risk factors of dementia, as well as cognition and brain function. This will be the first trial to investigate the effect of melatonin in the population with MCI in this way, with the future aim of using this approach to reduce progression to dementia.Ethics and disseminationThis protocol has been approved by the Sydney Local Health District Ethics Committee (X18-0077). This randomised controlled trial will be conducted in compliance with the protocol published in the registry, the International Conference for Harmonisation on Good Clinical Practice and all other applicable regulatory requirements. The findings of the trial will be disseminated via conferences, publications and media, as applicable. Participants will be informed of results of the study at the conclusion of the trial. Eligible authors will include investigators who are involved in the conception and design of the study, the conduct of the trial, the analysis of the results, and reporting and presentation of study findings.Trial registration numberAustralian and New Zealand Clinical Trials Registry (ANZCTRN 12619000876190).Protocol versionV.8 15 October 2020.

scholarly journals Supplementation with ribonucleotide-based ingredient (Ribodiet®) lessens oxidative stress, brain inflammation, and amyloid pathology in a murine model of Alzheimer

2021 ◽  
Vol 139 ◽  
pp. 111579
Author(s):  
Anella Saviano ◽  
Gian Marco Casillo ◽  
Federica Raucci ◽  
Alessia Pernice ◽  
Cristina Santarcangelo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Murine Model ◽  
Brain Inflammation ◽  
Amyloid Pathology

scholarly journals Ozone effect on inflammatory and proteomic profile of human macrophages and airway epithelial cells

2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
L Falcone ◽  
E Aruffo ◽  
P Di Carlo ◽  
P Del Boccio ◽  
M C Cufaro ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Air Pollution ◽  
Epithelial Cells ◽  
Cell Lines ◽  
Urban Areas ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Proteomics Analysis ◽  
Human Macrophages ◽  
Tnf Α

Abstract Background Reactive oxygen species (ROS) and oxidative stress in the respiratory system are involved in lung inflammation and tumorigenesis. Ozone (O3) is one of the main components of air pollution in urban areas able to act as strong pro-oxidant agent, however its effects on human health is still poorly investigated. In this study the effect of O3 has been evaluated in THP-1 monocytes differentiated into macrophages with PMA and in HBEpC (primary human bronchial epithelial) cells, two model systems for in vitro studies and translational research. Methods Cell viability, ROS and pro-inflammatory cytokines like interleukin-8(IL-8) and tumor necrosis factor(TNF-α) have been tested in the above-mentioned cell lines not exposed to any kind of pollution (basal condition-b.c.) or exposed to O3 at a concentration of 120 ppb. In HBEpC a labelfree shotgun proteomics analysis has been also performed in the same conditions. Results Ozone significantly increased the production of IL-8 and TNF-α in THP-1 whereas no changes were shown in HBEpC. In both cell lines lipopolysaccharide(LPS) caused an increase of IL-8 and TNF-α production in b.c. and O3 treatment potentiated this effect. Ozone exposure increased ROS formation in a time dependent manner in both cell lines and in THP-1 cells a decrease in catalase activity was also shown. Finally, according to these data, functional proteomics analysis revealed that in HBEpC exposure to O3 many differential proteins are related to oxidative stress and inflammation. Conclusions Our results indicate that O3, at levels that can be reached in urban areas, causes an increase of pro-inflammatory agents either per se or potentiating the effect of immune response stimulators in cell models of human macrophages and human airway epithelial cells. Interestingly, the proteomic analysis showed that besides the dysregulated proteins, O3 induced the expression of AKR1D1 and AKR1B10, proteins recognized to play a significant role in cancer development. Key messages This study adds new pieces of information on the association between O3 exposure and detrimental effects on respiratory system. This study suggests the need for further research on the mechanisms involved and for a continued monitoring/re-evaluation of air pollution standards aimed at safeguarding human health.

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