Reduced Brain Oxidative Stress Research Articles

Ameliorative effects of aqueous extract of Colocasia esculenta leaf against lipopolysaccharide-induced prefrontal cortex damage in mice

IntroductionThe prefrontal cortex (PFC), crucial for cognition and memory, occupies a third of the cerebral cortex. This study investigated the protective effects of aqueous extract of Colocasia esculenta leaf (AECEL) against lipopolysaccharide (LPS)-induced PFC damage in mice.Methods42 male Swiss albino mice (18–22 g) were divided into six groups. Group A: healthy controls. Groups B-F received daily intraperitoneal LPS injections (0.5 mg/kg) for seven days. Group B: received distilled water, (2 ml) subsequently. Groups C-E: AECEL at 400, 600, and 800 mg/kg, respectively. Group F: donepezil (DPZ, 2.5 mg/kg) by oral gavage. All treatments continued for 28 days.ResultsLPS exposure significantly increased brain oxidative stress markers and reduced antioxidant enzymes compared to controls (p < 0.05). AECEL and DPZ administration significantly reduced brain oxidative stress markers and reduced antioxidant enzymes, as well as tumor necrosis factor-α and interleukin-6 levels (p < 0.05) compared to LPS ONLY group. Y-maze testing revealed decreased alternation (%) in the LPS group compared to controls (p < 0.05). Based on Y-maze performance, AECEL at 400 mg/kg emerged as the most effective dose, significantly improving alternation (%) compared to both LPS and LPS + DPZ groups (p < 0.05). Bielschowsky staining showed senile plaques and neurofibrillary tangles in the LPS group.ConclusionLPS induced PFC damage. Among the tested doses, AECEL at 600 mg/kg demonstrated the most effective improvement in cognitive function, memory, and anxiety-like behaviors as measured by the Y-maze test.

A novel nitric oxide-driven nanomotor for synergistic treatment of ischaemic stroke: Enhanced deep brain penetration and therapeutic efficacy

Ischaemic stroke is a medical condition characterised by neuroinflammation and oxidative damage. Its treatment faces challenges related to drug delivery, particularly in overcoming the blood–brain barrier (BBB) and effectively targeting the stroke’s core. To overcome this challenge, we developed a novel nitric oxide (NO)-driven chemotactic nanomotor to increase the efficacy of ischaemic stroke treatment. The mesoporous nanomotor is loaded with tanshinone IIA, which actively inhibits pyroptosis and regulates the inflammatory response. Additionally, we conjugated a chemotactic nanomotor with a stroke-afflicted region-homing peptide, precisely guiding them to target damaged neurons within the ischaemic region. Notably, the chemotactic nanomotor reacts with ROS in the ischaemic microenvironment to produce NO, thereby not only reducing brain oxidative stress but also providing the driving force for deep brain penetration. The multifunctional nanomotor efficiently decreases reactive oxygen species (ROS) production and significantly mitigates inflammation-related pathology, thus imparting dual anti-oxidative and anti-inflammatory effects to remodel the ischaemic core microenvironment. In vitro and in vivo studies confirmed the synergistic role of antioxidant and anti-inflammatory effects in improving the ischaemic microenvironment. These findings suggest that an NO-driven nanomotor with synergistic therapeutic functions is highly effective to enhance therapeutic performance and clinical outcomes in ischaemic stroke.

The Use of Ascorbic Acid in Adjunctive Treatment for Schizophrenia-Current State of Knowledge.

Schizophrenia is a mental illness characterized by disturbances in the perception of reality, thinking, emotions, and social functioning. This significantly impacts the quality of life of patients and leads to long-term disability. Despite advances in understanding its pathogenesis and treatment, schizophrenia remains a clinical challenge, especially due to the diversity of its symptoms and the complexity of its mechanisms. Schizophrenia is associated with abnormal functioning of the dopaminergic system, disturbances in glutamatergic neurotransmission, and oxidative stress in the brain. In recent years, there has been increasing interest in optimizing the treatment of mental disorders. The potential use of ascorbic acid, or vitamin C, in the therapy of schizophrenia could bring substantial benefits to patients. Ascorbic acid exhibits antioxidant and neuroprotective properties, suggesting its potential efficacy in reducing brain oxidative stress and improving neurotransmission. Additionally, there have been reports of its positive effects on psychotic symptoms and its potential in reducing the side effects of antipsychotic drugs. In this review article, we present the current state of knowledge on the potential use of ascorbic acid in the treatment of schizophrenia as an adjunct to standard pharmacological therapy. We analyze existing clinical studies and the mechanisms of action of vitamin C, suggesting its promising role as an adjunctive therapy in the treatment of schizophrenia. These insights, though not yet widely disseminated, may be significant for the further development of therapeutic strategies for this mental illness.

Daidzein ameliorates nonmotor symptoms of manganese-induced Parkinsonism in zebrafish model: Behavioural and biochemical approach.

Parkinson's disease (PD) is a prevalent neurodegenerative movement disorder characterized by motor dysfunction. Environmental factors, especially manganese (Mn), contribute significantly to PD. Existing therapies are focused on motor coordination, whereas nonmotor features such as neuropsychiatric symptoms are often neglected. Daidzein (DZ), a phytoestrogen, has piqued interest due to its antioxidant, anti-inflammatory, and anxiolytic properties. Therefore, we anticipate that DZ might be an effective drug to alleviate the nonmotor symptoms of Mn-induced Parkinsonism. Naïve zebrafish were exposed to 2mM of Mn for 21 days and intervened with DZ. Nonmotor symptoms such as anxiety, social behaviour, and olfactory function were assessed. Acetylcholinesterase (AChE) activity and antioxidant enzyme status were measured from brain tissue through biochemical assays. Dopamine levels and histology were performed to elucidate neuroprotective mechanism of DZ. DZ exhibited anxiolytic effects in a novel environment and also improved intra and inter fish social behaviour. DZ improved the olfactory function and response to amino acid stimuli in Mn-induced Parkinsonism. DZ reduced brain oxidative stress and AChE activity and prevented neuronal damage. DZ increased DA level in the brain, collectively contributing to neuroprotection. DZ demonstrated a promising effect on alleviating nonmotor symptoms such as anxiety and olfactory dysfunction, through the mitigation of cellular damage. These findings underscore the therapeutic potential of DZ in addressing nonmotor neurotoxicity induced by heavy metals, particularly in the context of Mn-induced Parkinsonism.

Corinthian Currants Promote the Expression of Paraoxonase-1 and Enhance the Antioxidant Status in Serum and Brain of 5xFAD Mouse Model of Alzheimer's Disease.

Paraoxonase-1 (PON1), a serum antioxidant enzyme, has been implicated in Alzheimer's disease (AD) pathogenesis that involves early oxidative damage. Corinthian currants and their components have been shown to display antioxidant and other neuroprotective effects in AD. We evaluated the effect of a Corinthian currant paste-supplemented diet (CurD), provided to 1-month-old 5xFAD mice for 1, 3, and 6 months, on PON1 activity and levels of oxidation markers in serum and the brain of mice as compared to a control diet (ConD) or glucose/fructose-matched diet (GFD). Administration of CurD for 1 month increased PON1 activity and decreased oxidized lipid levels in serum compared to ConD and GFD. Longer-term administration of CurD did not, however, affect serum PON1 activity and oxidized lipid levels. Furthermore, CurD administered for 1 and 3 months, but not for 6 months, increased PON1 activity and decreased free radical levels in the cortex of mice compared to ConD and GFD. To probe the mechanism for the increased PON1 activity in mice, we studied the effect of Corinthian currant polar phenolic extract on PON1 activity secreted by Huh-7 hepatocytes or HEK293 cells transfected with a PON1-expressing plasmid. Incubation of cells with the extract led to a dose-dependent increase of secreted PON1 activity, which was attributed to increased cellular PON1 expression. Collectively, our findings suggest that phenolics in Corinthian currants can increase the hepatic expression and activity of antioxidant enzyme PON1 and that a Corinthian currant-supplemented diet during the early stages of AD in mice reduces brain oxidative stress.

Dihydroxytrimethoxyflavone possess memory improvement effects against scopolamine in mice via modulating multiple pathways: In‐silico and in‐vivo evidences

AbstractBackgroundDementia is a deliberating neurodegenerative disorder which causes impairment of intellectual functions. The USFDA approved drugs has limited efficacy and numerous side effects. Thus, finding newer drugs to manage dementia and cognitive disorders is certainly required. The present study explores the potential of a natural flavone, 5,7‐dihydroxy‐3',4',5'‐trimethoxyflavone (DHF), as memory enhancer drug against scopolamine‐induced cognitive deficit in mice.MethodsAnimals were treated with DHF (5‐10 mg/kg, p.o.) for 7 days after inducing cognitive impairment by scopolamine (1mg/kg,i.p.). Memory functions (passive shock avoidance task and Morris Water Maze), brain acetylcholinesterase (AChE) activity, inflammatory markers, oxidative stress, apoptotic biomarkers and histopathological studies (H&amp;E and congo red staining for beta amyloid) were determined to measure memory improvement effects of DHF. In‐silico (molecular docking) studies were performed to understand the interactions of DHF with key pathological enzymes related to dementia.ResultsTreatment of scopolamine administered mice with DHF improved scopolamine‐induced cognitive impairment and restore brain biochemical parameters (inhibited acetylcholinesterase activity, enhanced glutathione levels, and reduced TBARS, TNF‐α, IL‐6, IL‐1β and caspase‐3 levels). Moreover, histopathological studies showed that DHF treatment reduced the neuronal cell death and amyloid depositions in mice brain. Further, molecular docking studies revealed string interactions of DHF with crucial amino acids of AChE and caspase‐3.ConclusionThese results suggest that DHF was effective in treating scopolamine induced cognitive deficit by improving cerebral cholinergic dysfunction and reducing brain oxidative stress, inflammation, apoptosis and beta‐amyloid depositions in mice. Thus, DHF could be developed as a potential alternative drug to treat memory disorders.

Tocotrienol-Rich Fraction Ameliorates the Aluminium Chloride-Induced Neurovascular Dysfunction-Associated Vascular Dementia in Rats.

Neurovascular dysfunction leads to the second most common type of dementia, i.e., vascular dementia (VaD). Toxic metals, such as aluminium, increase the risk of neurovascular dysfunction-associated VaD. Hence, we hypothesized that a natural antioxidant derived from palm oil, i.e., tocotrienol-rich fraction (TRF), can attenuate the aluminium chloride (AlCl3)-induced VaD in rats. Rats were induced with AlCl3 (150 mg/kg) intraperitoneally for seven days followed by TRF treatment for twenty-one days. The elevated plus maze test was performed for memory assessment. Serum nitrite and plasma myeloperoxidase (MPO) levels were measured as biomarkers for endothelial dysfunction and small vessel disease determination. Thiobarbituric acid reactive substance (TBARS) was determined as brain oxidative stress marker. Platelet-derived growth factor-C (PDGF-C) expression in the hippocampus was identified using immunohistochemistry for detecting the neovascularisation process. AlCl3 showed a significant decrease in memory and serum nitrite levels, while MPO and TBARS levels were increased; moreover, PDGF-C was not expressed in the hippocampus. However, TRF treatment significantly improved memory, increased serum nitrite, decreased MPO and TBARS, and expressed PDGF-C in hippocampus. Thus, the results imply that TRF reduces brain oxidative stress, improves endothelial function, facilitates hippocampus PDGF-C expression for neovascularisation process, protects neurons, and improves memory in neurovascular dysfunction-associated VaD rats.

Vinpocetine, a PDE1 modulator, regulates markers of cerebral health, inflammation, and oxidative stress in a rat model of prenatal alcohol-induced experimental attention deficit hyperactivity disorder.

Prenatal alcohol exposure (PAE) has been shown to induce symptomatology associated with attention deficit hyperactivity disorder (ADHD) by altering neurodevelopmental trajectories. Phosphodiesterase-1 (PDE1) is expressed centrally and has been used in various experimental brain conditions. We investigated the role of vinpocetine, a PDE1 inhibitor, on behavioral phenotypes and important biochemical deficits associated with a PAE rat model of ADHD. Protein markers of cerebral health (synapsin-IIa, BDNF, and pCREB), inflammation (IL-6, IL-10, and TNF-α), and oxidative stress (TBARS, GSH, and SOD) were analyzed in three brain regions (frontal cortex, striatum, and cerebellum). Hyperactivity, inattention, and anxiety introduced in the offspring due to PAE were assayed using open-field, Y-maze, and elevated plus maze, respectively. Administration of vinpocetine (10 & 20mg/kg, p.o. [by mouth]) to PAE rat offspring for 4 weeks resulted in improvement of the behavioral profile of the animals. Additionally, levels of protein markers such as synapsin-IIa, BDNF, pCREB, IL-10, SOD, and GSH were found to be significantly increased, with a significant reduction in markers such as TNF-α, IL-6, and TBARS in selected brain regions of vinpocetine-treated animals. Vinpocetine, a selective PDE1 inhibitor, rectified behavioral phenotypes associated with ADHD, possibly by improving cerebral function, reducing brain inflammation, and reducing brain oxidative stress. This study provides preliminary analysis and suggests that the PDE1 enzyme may be an important pharmacological tool to study ADHD as a result of PAE.

The Protein-Rich Fraction from Spirulina platensis Exerts Neuroprotection in Hemiparkinsonian Rats by Decreasing Brain Inflammatory-Related Enzymes and Glial Fibrillary Acidic Protein Expressions.

Spirulina platensis is a cyanobacterium with high protein content and presenting neuroprotective effects. Now, we studied a protein-enriched fraction (SPF), on behavior, neurochemical and immunohistochemical (IHC) assays in hemiparkinsonian rats, distributed into the groups: SO (sham-operated), 6-hydroxydopamine (6-OHDA), and 6-OHDA (treated with SPF, 5 and 10 mg/kg, p.o., 15 days). Afterward, animals were subjected to behavioral tests and euthanized, and brain areas used for neurochemical and IHC assays. SPF partly reversed the changes in the apomorphine-induced rotations, open field and forced swim tests, and also the decrease in striatal dopamine and 3,4-dihydroxyphenylacetic acid contents seen in hemiparkinsonian rats. Furthermore, SPF reduced brain oxidative stress and increased striatal expressions of tyrosine hydroxylase and dopamine transporter and significantly reduced hippocampal inducible nitric oxide synthase, cyclooxygenase-2 and glial fibrillary acidic protein expressions. The data suggest that the protein fraction from S. platensis, through its brain anti-inflammatory and antioxidative actions, exerts neuroprotective effects that could benefit patients affected by neurodegenerative diseases, like Parkinson's disease.

Baicalein 5,6-Dimethyl Ether Prevents Memory Deficits in the Scopolamine Zebrafish Model by Regulating Cholinergic and Antioxidant Systems.

Baicalein 5,6-dimethyl ether, a bioactive flavonoid isolated for the first time from Alnus rugosa, was explored for its capability to relieve memory deficits and decrease oxidative stress. We examined the neuropharmacological effects of baicalein 5,6-dimethyl ether on scopolamine (Sco)-induced zebrafish (Danio rerio) anxiety, amnesia, and brain oxidative stress and attempted to elucidate the underlying mechanisms. Anxiety-like behavior, exploratory behavior, and memory performance were measured using novel tank-diving test (NTT), Y-maze, and novel object recognition (NOR) tests. For 10 days, baicalein 5,6-dimethyl ether (1, 3, and 5 µg/L) was administered through immersion, whereas Sco (100 μM) was delivered 30 min before behavioral tests. Treatment with baicalein 5,6-dimethyl ether reduced anxiety and memory impairment, and increased exploratory behavior in specific tests, along with significant protection from neuronal oxidative stress in the brain tissue of Sco-treated zebrafish. Antioxidant and anti-acetylcholinesterase (AChE) activities of baicalein 5,6-dimethyl ether in the Sco-induced zebrafish were further confirmed using in vivo assays. In Sco-treated zebrafish, baicalein 5,6-dimethyl ether regulated cholinergic function by inhibiting AChE activity. Baicalein 5,6-dimethyl ether may be a promising candidate compound for treating anxiety and amnesia by restoring cholinergic activity and reducing brain oxidative stress, according to our findings.

Swimming exercise attenuates anxiety-like behavior by reducing brain oxidative stress in type 2 diabetic mice

Anxiety-related behaviors are among the most prevalent psychiatric disorders in patients with type 2 diabetes (T2D). The protective effect of exercise on neuropsychiatric disorders has been documented. However, there are no studies that examined whether swimming exercise can decrease anxiety-like symptoms in type 2 diabetes. We investigated the effects of swimming exercise on body weight, anxiety-like behavior, glucose and insulin levels, and brain oxidative stress in male C57BL/6 mice. T2D-induced mice were subjected to swimming exercise, then anxiety-like behaviors were measured by the open field, light-dark box, and elevated plus-maze tests. Glucose and insulin levels were measure in serum, and antioxidant/oxidative markers including glutathione (GSH), malondialdehyde (MDA), and glutathione disulfide (GSSG) were measured in the brain. Our findings showed that T2D increased body weight, anxiety-like symptoms, glucose and insulin resistance, and oxidative stress by increasing MDA and GSSG levels in the brain of mice. Interestingly, swimming exercise reversed these parameters in diabetic mice. Our findings clearly indicate that there is a protective impact of swimming exercise on anxiety-like behavior by reducing insulin resistance and brain oxidative stress in mice with type 2 diabetes. Further studies are needed to validate these findings in humans.

A Grape Juice Supplemented with Natural Grape Extracts Is Well Accepted by Consumers and Reduces Brain Oxidative Stress.

Neurodegenerative diseases pose a major health problem for developed countries. Stress, which induces oxidation in the brain, has been identified as the main risk factor for these disorders. We have developed an antioxidant-enriched drink and have examined its protective properties against acute oxidative stress. We found that addition of red grape polyphenols and MecobalActive® to grape juice did not provoke changes in juice organoleptic characteristics, and that the pasteurization process did not greatly affect the levels of flavonoids and vitamin B12. Out of all combinations, grape juice with red grape polyphenols was selected by expert judges (28.6% selected it as their first choice). In vivo, oral administration of grape juice supplemented with red grape polyphenols exerted an antioxidant effect in the brain of stressed mice reducing two-fold the expression of genes involved in inflammation and oxidation mechanisms and increasing three-fold the expression of genes related to protection against oxidative stress. In addition, we found that this drink augmented antioxidant enzyme activity (17.8 vs. 8.2 nmol/mg), and prevented lipid peroxidation in the brain (49.7 vs. 96.5 nmol/mg). Therefore, we propose supporting the use of this drink by the general population as a new and global strategy for the prevention of neurodegeneration.

Dimethyl Fumarate, an Approved Multiple Sclerosis Treatment, Reduces Brain Oxidative Stress in SIV-Infected Rhesus Macaques: Potential Therapeutic Repurposing for HIV Neuroprotection.

Dimethyl fumarate (DMF), an antioxidant/anti-inflammatory drug approved for the treatment of multiple sclerosis, induces antioxidant enzymes, in part through transcriptional upregulation. We hypothesized that DMF administration to simian immunodeficiency virus (SIV)-infected rhesus macaques would induce antioxidant enzyme expression and reduce oxidative injury and inflammation throughout the brain. Nine SIV-infected, CD8+-T-lymphocyte-depleted rhesus macaques were studied. Five received oral DMF prior to the SIV infection and through to the necropsy day. Protein expression was analyzed in 11 brain regions, as well as the thymus, liver, and spleen, using Western blot and immunohistochemistry for antioxidant, inflammatory, and neuronal proteins. Additionally, oxidative stress was determined in brain sections using immunohistochemistry (8-OHdG, 3NT) and optical redox imaging of oxidized flavoproteins containing flavin adenine dinucleotide (Fp) and reduced nicotinamide adenine dinucleotide (NADH). The DMF treatment was associated with no changes in virus replication; higher expressions of the antioxidant enzymes NQO1, GPX1, and HO-1 in the brain and PRDX1 and HO-2 in the spleen; lower levels of 8-OHdG and 3NT; a lower optical redox ratio. The DMF treatment was also associated with increased expressions of cell-adhesion molecules (VCAM-1, ICAM-1) and no changes in HLA-DR, CD68, GFAP, NFL, or synaptic proteins. The concordantly increased brain antioxidant enzyme expressions and reduced oxidative stress in DMF-treated SIV-infected macaques suggest that DMF could limit oxidative stress throughout the brain through effective induction of the endogenous antioxidant response. We propose that DMF could potentially induce neuroprotective brain responses in persons living with HIV.

Isolation and characterization of components responsible for neuroprotective effects of Allium cepa outer scale extract against ischemia reperfusion induced cerebral injury in mice.

The antioxidant-mediated neuroprotective effect of Allium cepa outer scale extract (ACE) in mice with cerebral ischemia-reperfusion (I-R) injury was demonstrated in our earlier work. The current investigation aimed at establishing the bioactive component(s) responsible for this activity. Thus ACE was fractionated into ethyl acetate (EF) and aqueous (AF) fractions. These fractions were evaluated against cerebral I-R injury in mice. I-R injury in mice was induced by bilateral common carotid artery occlusion followed by 24 hr reperfusion. Memory, sensorimotor functions, cerebral infarct size, and oxidative stress were measured to address the neuroprotective mechanism of test substances. EF showed marked improvement of memory and sensorimotor functions by reducing brain oxidative stress and infarct size in mice after I-R injury. The bioactive EF was subjected to chromatographic (HPLC-PDA, HPLC-MS, preparative HPLC) and spectroscopic studies to isolate and identify the neuroprotective compounds. This lead to separation of three components, namely quercetin, quercetin 4'-O-glucoside, and the remaining fraction, from EF. The separated components were biologically evaluated. These components showed improvement in mice with I-R injury. But, EF displayed more marked neuroprotective effects as compared to the isolated components. The distinct neuroprotective outcome of EF may be credited to the synergistic action of compounds present in EF. Further studies such as evaluation of neurotoxic effects and other possible neuroprotective mechanisms are required to develop EF as a neuroprotective drug.

In vivo and in silico characterization of apocynin in reducing organ oxidative stress: A pharmacokinetic and pharmacodynamic study.

Apocynin has been widely used in vivo as a Nox2‐contaninig nicotinamide adenine dinucleotide phosphate oxidase inhibitor. However, its time‐dependent tissue distribution and inhibition on organ reactive oxygen species (ROS) production remained unclear. In this study, we examined apocynin pharmacokinetics and pharmacodynamics (PKPD) after intravenous (iv) injection (bolus, 5 mg/kg) of mice (CD1, 12‐week). Apocynin was detected using a HPLC coupled to a linear ion‐trap tandem mass spectrometer. Apocynin peak concentrations were detected in plasma at 1 minute (5494 ± 400 ng/mL) (t 1/2 = 0.05 hours, clearance = 7.76 L/h/kg), in urine at 15 minutes (14 942 ± 5977 ng/mL), in liver at 5 minutes (2853 ± 35 ng/g), in heart at 5 minutes (3161 ± 309 ng/g) and in brain at 1 minute (4603 ± 208 ng/g) after iv injection. These were accompanied with reduction of ROS production in the liver, heart and brain homogenates. Diapocynin was not detected in these samples. Therapeutic effect of apocynin was examined using a mouse model (C57BL/6J) of high‐fat diet (HFD, 16 weeks)‐induced obesity and accelerated aging. Apocynin (5 mmol/L) was supplied in drinking water during the HFD period and was detected at the end of treatment in the brain (5369 ± 1612 ng/g), liver (4818 ± 1340 ng/g) and heart (1795 ± 1487 ng/g) along with significant reductions of ROS production in these organs. In conclusion, apocynin PKPD is characterized by a short half‐life, rapid clearance, good distribution and inhibition of ROS production in major organs. Diapocynin is not a metabolite of apocynin in vivo. Apocynin crosses easily the blood‐brain barrier and reduces brain oxidative stress associated with metabolic disorders and aging.

Self- assembled lactoferrin-conjugated linoleic acid micelles as an orally active targeted nanoplatform for Alzheimer's disease

Alzheimer's disease (AD) is neurological disorder characterized by dementia which causes severe problems with behavior, thinking and memory. Systemic administration of therapeutics to the central nervous system (CNS) is usually associated with very low efficiency due to presence of blood brain barrier (BBB), which only allows permeation of few types of molecules from the circulation to the CNS. As an alternative, naturally amphiphilic micelles can be utilized to enhance targeted drug delivery to the brain. In this sense, lactoferrin (LF) was covalently attached to conjugated linoleic acid (CLA) via carbodiimide coupling reaction to form a new micellar nanoplatform with particle size of about 53 nm. Afterwards, fabricated micelles were further loaded once again with CLA to enhance its delivery to the CNS. In vitro drug release study revealed that CLA exhibited sustained release at pH 6.8, associated with good hemocompatibility without any remarkable in vivo toxicity in terms of liver and kidney functions. Moreover, in vivo studies showed that the fabricated micelles manifested enhanced in vivo biodistrbution in brain tissue due to the active targeting potential of LF. Additionally, drug-loaded LF-CLA micelles exhibited enhanced cognitive capabilities, reduced brain oxidative stress, inflammation, apoptosis and acetylcholine esterase activity, besides a decline in the deposition of amyloid β peptide1–42 in aluminum chloride Alzheimer's-induced animal model. CLA-based micelles could be a promising CNS actively targeted delivery system with a sophisticated potential to reduce AD symptoms.

Neuroprotective Effects of Apple-Derived Drinks in a Mice Model of Inflammation.

Fruit-derived drinks consumption is considered beneficial due to the antioxidant and neuroprotective effects of polyphenols separately, but studies including their total constituents are scarce. In this work, the antioxidant and anti-inflammatory neuroprotective effects of apple-derived beverages are determined in a mouse model of lipopolysaccharide (LPS)-induced inflammation. Preliminary antioxidant and neuroinflammatory experiments are carried out with 15 drink polyphenolic extracts in SH-SY5Y and BV2 cells, using H2 O2 as pro-oxidant and LPS as pro-inflammatory stimulus, respectively. Extracts improve antioxidant systems functioning and present neuroprotective mitochondrial-related effects. In microglia, extracts reduce reactive oxygen species and modulate cytokine release. To better mimic human consumption, four concentrated dealcoholized apple-derived drinks (three ciders and apple juice) are supplied to mice for 7 days in substitution of drinking water. Mice treated with beverages present reduced brain oxidative stress and inflammatory markers after LPS injection. Interestingly, genetic expression of antioxidant enzymes and glutathione levels are also greatly augmented after drink intake. The results confirm the antioxidant and anti-inflammatory-mediated neuroprotective properties of apple-derived drinks, suggesting that their consumption could be a good approach for prevention of neurodegenerative disorders. To the authors' knowledge, this is the first description of cider neuroprotective effects.

The mitochondria-targeted antioxidant MitoQ inhibits memory loss, neuropathology, and extends lifespan in aged 3xTg-AD mice

Oxidative stress, likely stemming from dysfunctional mitochondria, occurs before major cognitive deficits and neuropathologies become apparent in Alzheimer's disease (AD) patients and in mouse models of the disease. We previously reported that treating 2- to 7-month-old 3xTg-AD mice with the mitochondria-targeted antioxidant MitoQ (mitoquinone mesylate: [10-(4,5-Dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl](triphenyl)phosphonium methanesulfonate), a period when AD-like pathologies first manifest in them, prevents AD-like symptoms from developing. To elucidate further a role for mitochondria-derived oxidative stress in AD progression, we examined the ability of MitoQ to inhibit AD-like pathologies in these mice at an age in which cognitive and neuropathological symptoms have fully developed. 3xTg-AD female mice received MitoQ in their drinking water for five months beginning at twelve months after birth. Untreated 18-month-old 3xTg-AD mice exhibited significant learning deficits and extensive AD-like neuropathologies. MitoQ-treated mice showed improved memory retention compared to untreated 3xTg-AD mice as well as reduced brain oxidative stress, synapse loss, astrogliosis, microglial cell proliferation, Aβ accumulation, caspase activation, and tau hyperphosphorylation. Additionally, MitoQ treatment significantly increased the abbreviated lifespan of the 3xTg-AD mice. These findings support a role for the involvement of mitochondria-derived oxidative stress in the etiology of AD and suggest that mitochondria-targeted antioxidants may lessen symptoms in AD patients.

MAS AGONISTS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASE

Alzheimer's disease (AD) is associated with loss of memory and executive function. Several studies have shown a direct correlation between hypertension and an increased incidence of AD like symptoms, including cognitive deficits and increased Aβ deposition. Most interestingly, individuals who are on anti-hypertensive medications (angiotensin receptor blockers and angiotensin converting enzyme inhibitors) targeting the Renin-Angiotensin System (RAS), have a reduced risk of developing AD. Recently, the protective arm of RAS, angiotensin (1-7)[A(1-7)]/Mas receptor/angiotensin converting enzyme 2, is reduced in AD patients. Mas activation increases cognition and is cardioprotective. Thus, we hypothesized that Mas agonists could help ameliorate AD-like pathology. Mice underwent transaortic constriction (TAC), a mouse model of heart failure and hypertension. One week after induction of TAC, mice started treatment with saline or one of three Mas agonists. Seven weeks after surgery, the cardiac function was assessed by echocardiography followed by assessment of their cognitive abilities (8 weeks) using novel object recognition. Upon necropsy, brain, heart, bone marrow and blood were collected. TAC surgery decreased cognition and increased mitochondrial oxidative stress (OS) in neurons and microglia. Treatment with Mas agonists increased cognition and reduced brain OS. Further, treatment with Mas agonists reduced inflammatory cytokines in the hippocampus. These data support the development of Mas agonist for the treatment of neurodegenerative diseases.

Astrocyte-produced carbon monoxide and the carbon monoxide donor CORM-A1 protect against cerebrovascular dysfunction caused by prolonged neonatal asphyxia.

Neonatal asphyxia leads to cerebrovascular disease and neurological complications via a mechanism that may involve oxidative stress. Carbon monoxide (CO) is an antioxidant messenger produced via a heme oxygenase (HO)-catalyzed reaction. Cortical astrocytes are the major cells in the brain that express constitutive HO-2 isoform. We tested the hypothesis that CO, produced by astrocytes, has cerebroprotective properties during neonatal asphyxia. We developed a survival model of prolonged asphyxia in newborn pigs that combines insults of severe hypoxia, hypercapnia, and acidosis while avoiding extreme hypotension and cerebral blood flow reduction. During the 60-min asphyxia, CO production by brain and astrocytes was continuously elevated. Excessive formation of reactive oxygen species during asphyxia/reventilation was potentiated by the HO inhibitor tin protoporphyrin, suggesting that endogenous CO has antioxidant effects. Cerebral vascular outcomes tested 24 and 48 h after asphyxia demonstrated the sustained impairment of cerebral vascular responses to astrocyte- and endothelium-specific vasodilators. Postasphyxia cerebral vascular dysfunction was aggravated in newborn pigs pretreated with tin protoporphyrin to inhibit brain HO/CO. The CO donor CO-releasing molecule-A1 (CORM-A1) reduced brain oxidative stress during asphyxia/reventilation and prevented postasphyxia cerebrovascular dysfunction. The antioxidant and antiapoptotic effects of HO/CO and CORM-A1 were confirmed in primary cultures of astrocytes from the neonatal pig brain exposed to glutamate excitotoxicity. Overall, prolonged neonatal asphyxia leads to neurovascular injury via an oxidative stress-mediated mechanism that is counteracted by an astrocyte-based constitutive antioxidant HO/CO system. We propose that gaseous CO or CO donors can be used as novel approaches for prevention of neonatal brain injury caused by prolonged asphyxia. NEW & NOTEWORTHY Asphyxia in newborn infants may lead to lifelong neurological disabilities. Using the model of prolonged asphyxia in newborn piglets, we propose novel antioxidant therapy based on systemic administration of low doses of a carbon monoxide donor that prevent loss of cerebral blood flow regulation and may improve the neurological outcome of asphyxia.