Exogenous monosodium glutamate exacerbates lipopolysaccharide-induced neurobehavioral deficits, oxidative damage, neuroinflammation, and cholinergic dysfunction in rat brain.

Extensive experimental evidence points to neuroinflammation and oxidative stress as major pathogenic events that initiate and drive the neurodegenerative process. Monosodium glutamate (MSG) is a widely used food additive in processed foods known for its umami taste-enhancing properties. However, concerns about its potential adverse effects on the brain have been raised. Thus, the present study investigated the impact of MSG on lipopolysaccharide (LPS)-induced neurotoxicity in rat brains. Wistar rats weighing between 180 g and 200 g were randomly allocated into four groups: control (received distilled water), MSG (received 1.5 g/kg/day), LPS (received 250 µg/kg/day), and LPS + MSG (received LPS, 250 µg/kg, and MSG, 1.5 g/kg). LPS was administered intraperitoneally for 7 days while MSG was administered orally for 14 days. Our results showed that MSG exacerbated LPS-induced impairment in locomotor and exploratory activities in rats. Similarly, MSG exacerbated LPS-induced oxidative stress as evidenced by increased levels of malondialdehyde (MDA) with a concomitant decrease in levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione-s-transferase (GST) in the brain tissue. In addition, MSG potentiated LPS-induced neuroinflammation, as indicated by increased levels of pro-inflammatory cytokines such as interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) as well as myeloperoxidase (MPO) and nitric oxide (NO) in the brain. Moreover, MSG aggravated LPS-induced cholinergic dysfunction, as demonstrated by increased activity of acetylcholinesterase (AChE) in the brain. Further, we found a large number of degenerative neurons widespread in hippocampal CA1, CA3 regions, cerebellum, and cortex according to H&E staining. Taken together, our findings suggest that MSG aggravates LPS-induced neurobehavioral deficits, oxidative stress, neuroinflammation, cholinergic dysfunction, and neurodegeneration in rat brains.

Antioxidant and anti-arthritic activity of Bombax buonopozense P. Beauv. leaves.

BACKGROUND AND AIM: Bombax buonopozense (Bombacaceae) leaves have been used traditionally for arthritis in south-western Nigeria. Therefore, the aim of the study was to investigate the antioxidant and anti-arthritic activity of B. buonopozense in Complete Freund adjuvant-induce arthritic wistar rats. EXPERIMENTAL PROCEDURE: The plant leaves methanol extract and fractions were screened for preliminary phytochemicals and brine shrimp lethality was determined. Total phenolic content (TPC), Total flavonoid content (TFC) as well as anti-oxidant activity of the extract and fractions were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH). Cyclophosphamide, gallic acid, and ascorbic acid were used as standards respectively. Anti-arthritic activity of crude methanol extract (BBME) at 100, 200 and 400mg/kg was evaluated in complete Freund's adjuvant (CFA) induced arthritis model in rats. Data were analysed using Graph pad prism version 5, two-way and one-way ANOVA, and Bonferroni post hoc test. RESULTS AND CONCLUSION: Phytochemical screening revealed the presence of flavonoids, alkaloids, and phenolics. The brine shrimp lethality assay of the crude extract and fractions gave LC50 value≥1000µg/mL, compared to Cyclophosphamide (LC50=224.7±0.35µg/mL). The BBME had TPC value of 19.8±0.56mg GAE/g, while the TFC of ethyl acetate fraction was the highest (173.5±0.05mg QE/g). The ethyl acetate fraction has the highest antioxidant activity (IC50=20.96±0.23µg/mL) as compared to ascorbic acid (2.8±0.01) and rutin (20.6±9.26µg/mL). BBME significantly reduced the paw circumference. BBME (400mg/kg) prevented biochemical changes to a greater extent than Celecoxib (20mg/kg). Bombax buonopozense leaves could be an effective antiarthritic and holds prospect in the treatment of rheumatoid arthritis.

Diosgenin alleviates alcohol-mediated escalation of social defeat stress and the neurobiological sequalae.

RATIONALE: Emerging evidence indicates that persistent alcohol consumption escalates psychosocial trauma achieved by social defeat stress (SDS)-induced neurobiological changes and behavioral outcomes. Treatment with compounds with neuroprotective functions is believed to reverse ethanol (EtOH)-aggravated SDS-induced behavioral impairments. OBJECTIVES: We investigated the outcomes of diosgenin treatment, a phytosteroidal sapogenin in mice co-exposed to repeated SDS and EtOH administration. METHODS: During a period of 14 days, SDS male mice were repeatedly administered EtOH (20%, 10 mL/kg) orally from days 8-14 (n = 9). Within days 1-14, SDS mice fed with EtOH were simultaneously treated with diosgenin (25 and 50 mg/kg) or fluoxetine (10 mg/kg) by oral gavage. Locomotor, cognitive-, depressive-, and anxiety-like behaviors were assessed. Adrenal weight, serum glucose, and corticosterone levels were assayed. Brain markers of oxido-inflammatory, neurochemical levels, monoamine oxidase-B, and acetylcholinesterase activities were measured in the striatum, prefrontal cortex, and hippocampus. RESULTS: The anxiety-like behavior, depression, low stress resilience, social, and spatial/non-spatial memory decline exhibited by SDS mice exposed to repeated EtOH administration were alleviated by diosgenin (25 and 50 mg/kg) and fluoxetine, illustrated by increased dopamine and serotonin concentrations and reduced monoamine oxidase-B and acetylcholinesterase activities in the prefrontal cortex, hippocampus, and striatum. Diosgenin attenuated SDS + EtOH interaction induced corticosterone release and adrenal hypertrophy, accompanied by reduced TNF-α, IL-6, malondialdehyde, and nitrite levels in the striatum, prefrontal cortex, and hippocampus. Diosgenin increased glutathione, superoxide dismutase, and catalase levels in SDS + EtOH-exposed mice. CONCLUSIONS: Our data suggest that diosgenin reverses SDS + EtOH interaction-induced behavioral changes via normalization of hypothalamic-pituitary-adrenal axis, neurochemical neurotransmissions, and inhibition of oxidative and inflammatory mediators in mice brains.

Anti-apoptotic and antioxidant mechanisms may underlie the abrogative potential of Ocimum gratissimum Linn. Leaf extract and fractions against trastuzumab-induced cardiotoxicity in Wistar rats.

Clinical use of trastuzumab (TZM), has been widely associated with increased incidence of cardiotoxicity. Ocimum gratissimum Linn. is a household medicinal plant popularly used for treating inflammatory conditions. In this study, we investigated the abrogative potential of 100 mg/kg/day of the ethanol leaf extract of Ocimum gratissimum Linn. (OG) and its petroleum ether (PEOG), ethyl acetate (EAOG) and ethanol (EOG) fractions in TZM intoxicated Wistar rats for 7 days using anthropometric, biochemical, histopathological and immunohistochemical endpoints. In addition, secondary metabolite constituents in OG and its fractions were determined through Gas Chromatography-Mass Spectrometry (GC-MS). The study results showed that oral pretreatments with OG and OG fractions as well as the fixed dose valsartan-lisinopril (VAL-LSP) combination effectively ameliorated and restore nearly normal levels the TZM-altered plasma cardiac troponin I and antioxidant profile which were corroborated by histopathological and immunohistochemical findings as indicated by the inhibition of TZM-induced activation of caspases-3 and - 9 and profound upregulation of BCL-2 expression. Phytoscan of OG and its fractions showed the presence of thymol and in high amount. Overall, our findings revealed the cardioprotective potentials of OG, OG fractions and fixed dose VAL-LSP combination against TZM-induced cardiotoxicity which probably was mediated via abrogation of cardiomyocyte apoptosis and antioxidant mechanisms.

Oxidized dietary lipids induce vascular inflammation and atherogenesis in post-menopausal rats: estradiol and selected antihyperlipidemic drugs restore vascular health in vivo.

BACKGROUND: Thermoxidation of edible oil through deep fat frying results in the generation of several oxidized products that promote lipid peroxidation and ROS production when eaten. Consumption of thermoxidized oil in post-menopausal conditions where the estrogen level is low contributes to cardiovascular disease. This study evaluates the role of estradiol and antihyperlipidemic agents (AHD) in restoring the vascular health of ovariectomized (OVX) rats fed with thermoxidized palm oil (TPO) and thermoxidized soya oil (TSO) diets. METHOD: A total of 10 groups of rats (n = 6) were set up for the experiment. Group I (normal control) rats were sham handled while other groups were OVX to bring about estrogen deficient post-menopausal state. Group II (OVX only) was not treated and received normal rat chow. Groups III-X were fed with either TPO or TSO diet for 12 weeks and treated with estradiol (ETD) 0.2 mg/kg/day, atorvastatin (ATV) 10 mg/kg/day, and a fixed-dose combination of ezetimibe and ATV (EZE 3 mg/kg/day + ATV 10 mg/kg/day). RESULTS: Pro-atherogenic lipids levels were significantly elevated in untreated TSO and TPO groups compared to OVX and sham, resulting in increased atherogenic and Coronary-risk indices. Treatment with Estradiol and AHDs significantly reduced the total cholesterol, triglycerides, low-density lipoprotein cholesterol as well as AI and CRI compared to untreated TSO and TPO groups, whereas TSO and TPO groups showed significant elevation in these parameters compared to Group I values. Moreover, aortic TNF-α levels were extremely elevated in the untreated TSO and TPO compared to Group I. TNF-α levels were significantly reduced in rats treated with AHDs and ETD. Localized oxidative stress was indicated in the aortic tissues of TSO and TPO-fed OVX rats by increased malondialdehyde and decreased glutathione, catalase, and superoxide dismutase levels. This contributed to a depletion in aortic nitric oxide. AHDs and ETD replenished the nitric oxide levels significantly. Histological evaluation of the aorta of TSO and TPO rats revealed increased peri-adventitia fat, aortic medial hypertrophy, and aortic recanalization. These pathologic changes were less seen in AHDs and ETD rats. CONCLUSION: This study suggests that ETD and AHDs profoundly attenuate oxidized lipid-induced vascular inflammation and atherogenesis through oxidative-stress reduction and inhibition of TNF-α signaling.

Jobelyn® improves motor dysfunctions induced by haloperidol in mice via neuroprotective mechanisms relating to modulation of cAMP response-element binding protein and mitogen-activated protein kinase.

The clinical efficacy of haloperidol in the treatment of psychosis has been limited by its tendency to cause parkinsonian-like motor disturbances such as bradykinesia, muscle rigidity and postural instability. Oxidative stress-evoked neuroinflammation has been implicated as the key neuropathological mechanism by which haloperidol induces loss of dopaminergic neurons and motor dysfunctions. This study was therefore designed to evaluate the effect of Jobelyn® (JB), an antioxidant supplement, on haloperidol-induced motor dysfunctions and underlying molecular mechanisms in male Swiss mice. The animals were distributed into 5 groups (n = 8), and treated orally with distilled water (control), haloperidol (1 mg/kg) alone or in combination with each dose of JB (10, 20 and 40 mg/kg), daily for 14 days. Thereafter, changes in motor functions were evaluated on day 14. Brain biomarkers of oxidative stress, proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6), cAMP response-element binding protein (CREB), mitogen-activated protein kinase (MAPK) and histomorphological changes were also investigated. Haloperidol induces postural instability, catalepsy and impaired locomotor activity, which were ameliorated by JB. Jobelyn® attenuated haloperidol-induced elevated brain levels of MDA, nitrite, proinflammatory cytokines and also boosted neuronal antioxidant profiles (GSH and catalase) of mice. It also restored the deregulated brain activities of CREB and MAPK, and reduced the histomorphological distortions as well as loss of viable neuronal cells in the striatum and prefrontal cortex of haloperidol-treated mice. These findings suggest possible benefits of JB as adjunctive remedy in mitigating parkinsonian-like adverse effects of haloperidol through modulation of CREB/MAPK activities and oxidative/inflammatory pathways.

Involvement of oxidative stress and pro-inflammatory cytokines in copper sulfate-induced depression-like disorders and abnormal neuronal morphology in mice.

Epidemiological studies have implicated copper as one of the key environmental risk factors for the pathogenesis of depression. However, the precise mechanism by which copper contribute to the genesis of depression particularly the involvement of oxidative stress-driven neuroinflammation is yet to be fully investigated. Thus, this study was designed to evaluate the effects of copper sulfate (CuSO4) on depression-like behaviors and the role of oxidative stress and pro-inflammatory cytokines in mice. Forty male Swiss mice were distributed into control and three test groups (n = 10), and were treated orally with distilled water (10 mL/kg) or CuSO4 (25, 50 and 100 mg/kg) daily for 28 days. Afterwards, the tail suspension, forced swim, and sucrose splash tests were used for the detection of depression-like effects. The animals were then euthanized and the brains were processed for the estimation of biomarkers of oxidative stress and pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6). The histomorphological features and neuronal viability of the prefrontal cortex, hippocampus and striatum were also determined. Mice exposed to CuSO4 displayed depression-like features when compared with controls. The brain concentrations of malondialdehyde, nitrite and pro-inflammatory cytokines were elevated in CuSO4-treated mice. Mice exposed to CuSO4 also had reduced brain antioxidant status (glutathione, glutathione-s-transferase, total thiols, superoxide-dismutase and catalase), as well as altered histomorphological features, and decreased population of viable neuronal cells. These findings suggest that CuSO4 increases oxidative stress and pro-inflammatory cytokines to elicit depression-like effects in mice.

Lipopolysaccharide Exacerbates Ketamine-Induced Psychotic-Like Behavior, Oxidative Stress, and Neuroinflammation in Mice: Ameliorative Effect of Diosmin.

Schizophrenia, a neuropsychiatric disorder has been associated with aberrant neurotransmission affecting behaviors, social preference, and cognition. Limitations in understanding its pathogenesis via the dopamine hypothesis have engendered other hypotheses such as the glutamate hypothesis. That antagonism of the N-methyl-D-aspartate receptor (NMDAR) elicits schizophrenia-like behaviors indistinguishable from the disorder in animal and human models. There are growing concerns that redox imbalance and neuro-immuno dysfunction may play role in aggravating the symptomologies of this disorder. This 14-day treatment study was designed to investigate the effect of diosmin on lipopolysaccharide (LPS) plus ketamine (NMDAR antagonist). Mice were divided into 4 groups (n = 6). Group 1 was administered 5% DMSO (10 mL/kg, i.p) while group 2-4 received LPS (0.1 mg/kg, i.p) daily for 14 days. Diosmin (50 mg/kg, i.p) and risperidone (0.5 mg/kg, i.p) were given to groups 3 and 4 respectively. Groups 2-4 were given KET (20 mg/kg, i.p.) daily from days 8-14. Behavioral tests were done 30 min after the last dose, and oxidative stress and neuroinflammatory maker were assayed. LPS plus ketamine-induced hyperlocomotion, stereotypy, decreased social preference, and memory impairment. Furthermore, LPS plus-ketamine-induced oxidative stress (reduced GSH, CAT, SOD, and increased MDA and nitrite levels) and marked pro-inflammatory cytokines TNF-α and IL-6 suggesting neuroinflammation. However, diosmin attenuated behavioral deficits and improved memory. Additionally, diosmin potentiated antioxidant level via increased GSH, CAT, and SOD while reducing MDA and nitrite levels. Finally, diosmin reduced TNF-α and IL-6 suggesting anti-neuro-immuno activity. Conclusively, diosmin attenuated LPS plus ketamine-induced behavioral deficits, oxidative stress, neuroinflammation, and improved memory.

Neuropharmacological effects of honey in lipopolysaccharide-induced neuroinflammation, cognitive impairment, anxiety and motor impairment.

Objectives: Honey contains phenolic acids and flavonoids, which are significant in developing drugs against neuroinflammation. The study was designed to evaluate the ameliorative potential of honey in lipopolysaccharides-induced neuroinflammation.Methods: Thirty male Wistar rats were divided into six groups, namely: the control group (10 mL/kg vehicle), the LPS only group (250 µg/kg), the honey (0.26, 0.31 and 0.36 g/kg) and the ibuprofen (100 mg/kg). LPS (250 µg/kg i.p) was administered for 7days followed by the treatment with honey and Ibuprofen for another 7days. Animals were assessed for memory impairment and anxiety levels using a Novel object recognition test (NORT), elevated plus maze (EPM), and open field test (OFT). Brain levels of pro-inflammatory cytokine level, acetylcholinesterase activity, and oxidative stress were determined. The neuronal alteration was assessed histologically using cresyl fast violet staining of the hippocampus, prefrontal cortex, and striatum.Results: Honey (0.31 and 0.36 g/kg) significantly ameliorated LPS-induced memory impairment on NORT and increased time spent in the open arm and increased the locomotor activity in the OFT. Honey significantly (p < 0.05) reduced LPS-induced elevation of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6). It significantly reduced malondialdehyde and nitrite levels in mice brains and reversed depletion of reduced glutathione levels. Honey attenuated LPS-induced elevation of acetylcholinesterase activity in rat brains. Cresyl violet staining showed the restoration of neuronal organization and Nissl body distribution in the hippocampus, prefrontal cortex and striatum compared to the LPS only group.Discussion: Honey effectively ameliorated LPS-induced poor cognitive performance, anxiety, motor coordination responses to neuroinflammation, and oxidative stress.

Up-regulation of B-cell lymphoma factor-2 expression, inhibition of oxidative stress and down-regulation of pro-inflammatory cytokines are involved in the protective effect of cabbage (Brassica oleracea) juice in lead-induced endothelial dysfunction in rats.

BACKGROUND: Oxido-inflammatory stress and dysregulation of nitric oxide (NO) system has been implicated in lead toxicity. Cabbage is an antioxidant-rich household vegetable with plethora of therapeutic potentials. The present study investigated the anti-oxido-inflammatory activity of cabbage in lead-induced endothelial dysfunction. METHODS: Twenty (20) male Wistar rats were selected into four groups (n = 5) and treated with distilled water (1 mL/100 g b.wt), lead acetate (25 mg/kg b.wt), cabbage juice (1 mL/100 g b.wt) and lead acetate (25 mg/kg b.wt) plus cabbage juice (1 mL/100 g b.wt) respectively. Treatment was done orally for 28 days, thereafter, oxidative stress (SOD, CAT, GSH, and MDA), inflammatory (TNF-α and IL-6) and apoptotic (Bcl-2) markers were assayed using standard biochemical assays as well as histoarchitectural study of the endothelium. RESULTS: The results showed that they were significant increase in MDA, ET-1, TNF-α and IL-6 while SOD, GSH, CAT, NO and Bcl-2 protein expression were decreased in Lead exposed animals. Endothelial histoarchitecture was also altered. Following Cabbage juice treatment, MDA, ET-I, TNF-α and IL-6 were down-regulated while SOD, GSH, CAT, NO and Bcl-2 protein expression were up-regulated. Histoarchitecture was significantly recovered. CONCLUSION: The study suggests that cabbage juice could mitigates Lead-induced endothelial dysfunction by modulating oxido-inflammatory and anti-apoptotic mediators. DATA AVAILABILITY: All data are available upon request.

D-ribose-L-cysteine reduces oxidative stress and inflammatory cytokines to mitigate liver damage, and memory decline induced by copper sulfate in mice.

BACKGROUND: Current evidences have implicated copper in amyloid aggregation that trigger the downstream oxidative stress-mediated neuroinflammation that characterized memory deterioration in patients with Alzheimer's disease (AD). Thus, this study was designed to evaluate the effect of D-Ribose-L-Cysteine (DRLC), a potent antioxidant agent, on copper sulfate (CuSO4)-induced memory deterioration and the biochemical mechanisms underpinning its action in mice. METHODS: Male Swiss mice were randomly distributed into 5 groups (n = 10/group). Mice in group 1 were given distilled water (control), group 2 CuSO4 (100 mg/kg) while groups 3-5 were pretreated with CuSO4 (100 mg/kg) 30 min before administration of DRLC (10, 25 and 50 mg/kg). Treatments were given through oral gavage, daily for 28 days. Memory function was evaluated on day 28 using Y-maze test. The isolated liver and brain tissues were then processed for oxidative stress biomarkers, and proinflammatory cytokines [tumor necrosis factor- α (TNF-α) and interleukin-6)] assays. Brian acetylcholinesterase (AChE) and liver enzymes [aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were also determined. RESULTS: DRLC reversed memory impairment and dysregulated levels of malondialdehyde, glutathione, nitrite and glutathione S-transferase in the liver and brain tissues of mice pretreated with CuSO4. The increased proinflammatory cytokines concentrations in the liver and brain tissues of mice pretreated with CuSO4 were reduced by DRLC. The elevated brain AChE and liver enzymes activities induced by CuSO4 were also reduced by DRLC. CONCLUSION: Taken together, these findings suggest that DRLC attenuates CuSO4-induced memory dysfunctions in mice through enhancement of antioxidative pathway, inhibition of pro-inflammatory cytokines and augmentation of liver function.

Jobelyn® extends the life span and improves motor function in Drosophila melanogaster exposed to lipopolysaccharide via augmentation of antioxidant status.

Jobelyn® (JB), a dietary supplement, derived from polyphenol-rich leaf sheath of Sorghum bicolor, has been reported to attenuate sensorimotor deficits and oxidative stress evoked by complete Freund-adjuvant in mice. This present study evaluated its effects on the life span, motor function and changes in oxidative stress parameters as well as acetylcholinesterase activity in Drosophila melanogaster exposed to lipopolysaccharide (LPS). The flies (50 per vial), in 5 replicates were fed with LPS (250 µg/kg diet) alone or in combination with JB (0.25-1.0 mg/kg diet) daily for 7 days. The mortality rate and motor function were evaluated on day 7. The flies were afterwards processed for determination of oxidative stress parameters and acetylcholinesterase activity. The effects of JB (0.25-1.0 mg/g diet) on the longevity of Drosophila was also investigated wherein the flies were monitored daily for mortality throughout their lifespan. The flies exposed to LPS (250 µg/kg diet) had reduced life span and elevated oxidative stress when compared with control. However, JB (0.25 and 1.0 mg/kg diet) improved the motor function and also reduced the mortality rate of the flies exposed to LPS. It also restored the cellular antioxidant status and reduced acetylcholinesterase activity, accumulation of hydrogen peroxide as well as nitric oxide in Drosophila fed with LPS. JB also extended the longevity of the flies relative to control. The findings that JB improves motor function and extended the lifespan of Drosophila flies by boosting the antioxidant status and cholinergic function, suggest it might be helpful in delaying the onset of neuropsychiatric illnesses associated with the aging processes.

The antioxidant and neuroprotective effects of the Psychotria camptopus Verd. Hook. (Rubiaceae) stem bark methanol extract contributes to its antiepileptogenic activity against pentylenetetrazol kindling in male Wistar rats.

A substantial number of epileptic patients are resistant to the current medication thus necessitating the search for alternative therapies for intractable forms of the disease. Previous studies demonstrated the acute anticonvulsant properties of the methanol extract of the stem bark of Psychotria camptopus (MEPC) in rats. This study investigated the effects of MEPC on pentylenetetrazole-kindled Wistar rats. Kindling was induced by intraperitoneal injection of pentylenetetrazole (37.5 mg/kg) on every alternate day, 1 h after each daily oral pretreatment of rats (8 ≤ n ≤ 10) with MEPC (40, 80 and 120 mg/kg), vehicle or diazepam (3 mg/kg) for 43 days. The kindling development was monitored based on seizure episodes and severity. Rats' brains were collected on day 43 for the determination of oxidative stress parameters. The histomorphological features and neuronal cell viability of the prefrontal cortex (PFC) and hippocampus were also assessed using H&E and Cresyl violet stains. Chronic administration of pentylenetetrazole time-dependently decreased the latency to myoclonic and generalized seizures, and increased seizure scores and the number of kindled rats. MEPC and diazepam significantly increased the latencies to myoclonic jerks and generalized tonic-clonic seizures. These substances also reduced seizure score and the number of rats with PTZ-kindling. MEPC improved glutathione status and decreased lipid peroxidation in the brains of kindled rats. MEPC also exhibited neuroprotection against pentylenetetrazole-induced hippocampal and PFC neuronal damages. These results suggest that P. camptopus has antiepileptogenic activity, which might be related to the augmentation of antioxidant and neuroprotective defense mechanisms, and further confirm its usefulness in the management of epilepsy.

Monosodium glutamate induces memory and hepatic dysfunctions in mice: ameliorative role of Jobelyn® through the augmentation of cellular antioxidant defense machineries.

This study investigated the effect of high doses of monosodium glutamate (MSG), a known food additive on hepatic, memory and locomotor functions in mice, and the ameliorative potentials of Jobelyn® (JB), a unique dietary supplement. Twenty four  male Swiss mice  divided into 4 groups (n = 6) were given MSG (2, 4 and 8 g/kg) or normal saline (10 mL/kg) orally for 14 days. In the intervention study, another set of 30 male Swiss mice distributed into 5 groups (n = 6) received normal saline, MSG (8 g/kg) alone or in combination with JB (5, 10 and 20 mg/kg) orally, for 14 days. Memory and locomotor functions as well as brain oxido-nitrergic stress biomarkers were then assessed in both studies. The hepatic oxido-nitrergic stress biomarkers, liver enzymes functions and histomorphology of the liver were also assessed. MSG (2, 4 and 8 g/kg) produced memory dysfunction, hyperlocomotion, increased malondialdehyde and nitrite levels accompanied by decreased antioxidant status in the brain and hepatic tissues. MSG-treated mice had increased hepatic enzyme activities (alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase) and distorted cyto-architectural integrity of the liver. These findings further suggest that MSG compromised hepatic functioning, which might also contribute to its neurotoxicity. However, JB (5, 10 and 20 mg/kg, p.o) attenuated the memory deficit, hyperlocomotion, increased oxido-nitrergic stress responses in the brain and hepatic tissues induced by MSG (8 g/kg, p.o). JB also normalized hepatic enzymes activities and histomorphological changes in MSG-treated mice. Taken together, JB mitigated MSG-induced toxicity through mechanisms relating to enhancement of cellular antioxidant-machineries and normalization of hepatic enzymatic functions.

Molecular mechanisms involved in the prevention and reversal of ketamine-induced schizophrenia-like behavior by rutin: the role of glutamic acid decarboxylase isoform-67, cholinergic, Nox-2-oxidative stress pathways in mice.

Mounting evidences have shown that nicotinamide adenine dinucleotide phosphate oxidase-2 (Nox-2) pathway modifies glutamic-acid decarboxylase-67 (GAD67) (GABAergic enzyme) and cholinergic systems via oxidative-nitrergic mechanisms in schizophrenia pathology. Rutin, a neuroactive antioxidant compound, with proven neuroprotective property has been shown to reduce schizophrenic-like behavior in mice. This study sought to investigate the mechanisms of action of the psychopharmacological activity of rutin in the preventive and reversal effects of ketamine-induced schizophrenic-like behavior, oxidative-nitrergic stress, cholinergic and GABAergic derangements in mice. In the preventive treatment, male mice were given rutin (0.1, 0.2 and 0.4 mg/kg) or risperidone (0.5 mg/kg) orally for 14 days prior to ketamine (20 mg/kg, i.p.) treatment from the 8 to 14th day. However, in the reversal treatment, ketamine was given for 14 days prior to rutin and risperidone. Behavioral (open-field, social-interaction and Y-maze tests), biochemical (oxidative/nitrergic stress markers, acetylcholinesterase activity), immunohistochemical (GAD67, Nox-2) and neuronal cell deaths in the striatum, prefrontal cortex, and hippocampus were evaluated. Ketamine-induced behavioral impairments were prevented and reversed by rutin. Exposure of mice to ketamine increased malondialdehyde, nitrite contents, acetylcholinesterase activity, neuronal cell death and Nox-2 expressions in the striatum, prefrontal cortex and hippocampus. Conversely, these derangements were prevented and reversed by rutin. The decreased glutathione levels due to ketamine were marked increased by rutin. Rutin only prevented ketamine-induced decrease in GAD67 expression in the striatal-hippocampal region. Altogether, the study showed that the prevention and reversal treatments of mice with rutin attenuated ketamine-induced schizophrenic-like behaviors via reduction of Nox-2 expression, oxidative/nitrergic stresses, acetylcholinesterase activity, and increased GAD67 enzyme.

Naringin Confers Protection against Psychosocial Defeat Stress-Induced Neurobehavioral Deficits in Mice: Involvement of Glutamic Acid Decarboxylase Isoform-67, Oxido-Nitrergic Stress, and Neuroinflammatory Mechanisms.

Psychosocial stress has been widely reported to contribute to psychiatric disturbances. Perturbations in the enzymes of GABAergic and cholinergic systems have been implicated as precursors in different stress-related neuropsychiatric diseases. Targeting glutamic acid decarboxylase-67 kDa (GAD67) and acetylcholinesterase (AChE) via oxidative, nitrergic, and neuroinflammatory mechanisms have been recognized as prospective strategies for the prevention of psychosocial stress-induced behavioral impairments. Naringin, a neuro-active flavonoid compound isolated from citrus fruits, has been shown to produce memory-enhancing, antiepileptic, antidepressant, and anti-inflammatory activities similarly to ginseng, a very potent adaptogen. In this communication, we assessed the effect of naringin on social-defeat stress (SDS)-induced behavioral, GABAergic, cholinergic, oxidative, nitrergic, and neuroinflammatory changes in mice using the resident-intruder paradigm. The intruder male mice were culled into six groups. Groups 1 and 2 (normal- and SDS-controls) received sterile saline, groups 3-5 were given naringin (25-100 mg/kg, i.p.) whereas group 6 had ginseng (50 mg/kg, i.p.) daily for 14 days, but followed by 10 min SDS (physical and psychological) exposure to groups 2-6 with aggressor-resident mice. Behavioral effects using Y-maze, elevated-plus maze, sociability, and tail-suspension tests were assessed on day 14. GAD67, AChE enzymes, and biomarkers of oxidative, nitrergic, and neuroinflammatory changes were assayed in the striatum, prefrontal cortex, and hippocampus. Naringin and ginseng reversed all SDS-induced behavioral impairments. Naringin increased the levels of GAD67 and decreased AChE activities in the striatum, prefrontal cortex, and hippocampus. Furthermore, naringin reduced pro-inflammatory cytokines (TNF-α, IL-6), malondialdehyde, nitrite concentrations, and increased glutathione levels in a region-dependent manner. Our study suggests that naringin attenuated SDS-induced behavioral endophenotypes of neuropsychiatric disease through increased GAD67 synthesis, inhibition of AChE activity, oxidative, nitrergic stress, and neuroinflammatory processes in stress-sensitive brain regions.

Repeated psychosocial stress causes glutamic acid decarboxylase isoform-67, oxidative-Nox-2 changes and neuroinflammation in mice: Prevention by treatment with a neuroactive flavonoid, morin.

Psychosocial stress and biological predispositions are linked to mood and personality disorders related to psychiatric behaviors. Targeting neuroinflammation and oxidative stress has been recognized as a potential strategy for the prevention of psychosocial stress-induced psychiatric disorders. Morin, a bioactive compound isolated from mulberry leaf has been shown to produce antiamnesic, antipsychotic and anti-inflammatory effects relative to ginseng, a well-known adaptogen. Hence, the present study investigated the effect of morin on social-defeat stress (SDS)-induced behavioral, neurochemical, neuroimmune and neurooxidative changes in mice using intruder-resident paradigm. The intruder male mice were distributed into 6 groups (n = 10). Groups 1 (normal-control) and 2 (SDS-control) received normal saline, groups 3-5 had morin (25-100 mg/kg) while group 6 received ginseng (50 mg/kg) intraperitoneally daily for 14 days. Thirty minutes after treatment from days 7-14 onwards, mice in groups 2-6 were exposed to SDS for 10 min physical and psychological confrontations respectively with aggressive-resident mice. Neurobehavioral effects (locomotor activity, cognitive performance, anxiety- and depressive-like behavior) were assessed on day 14. Biomarkers of oxidative/nitrergic stress and neuroinflammation; acetylcholinesterase (AChE) and glutamic-acid decarboxylase-67 (GAD67) were measured in the striatum, prefrontal-cortex and hippocampus. Behavioral deficits induced by SDS were attenuated by morin and ginseng. Both morin and ginseng decreasedmalondialdehyde, nitrite levels and increased glutathione concentrations in the brain regions. They also reduced inflammatory mediators (TNF-α, IL-6, COX-2 and NF-κB), AChE activity and Nox-2 expression in the specific brain regions. However, morin increased the levels of GAD67 in the striatum, prefrontal-cortex and hippocampus in contrast to ginseng. Our results suggest that morin mitigates SDS-induced neurobehavioral deficits through enhancement of GAD67, inhibition of AChE activity, oxidative stress, Nox-2 and neuroinflammatory pathways.

Therapeutic Potentials of Selected Antihypertensive Agents and Their Fixed-Dose Combinations Against Trastuzumab-Mediated Cardiotoxicity.

Trastuzumab (TZM) is useful in the clinical management of HER2-positive metastatic breast, gastric, and colorectal carcinoma but has been limited by its off-target cardiotoxicity. This study investigates the therapeutic potentials of 0.25 mg/kg/day amlodipine, 0.035 mg/kg/day lisinopril, 5 mg/kg/day valsartan, and their fixed-dose combinations in TZM-intoxicated Wistar rats that were randomly allotted into 10 groups of 6 rats for each group. Group I rats were treated with 10 ml/kg/day sterile water orally and 1 ml/kg/day sterile water intraperitoneally; Groups II, III, and IV rats were orally gavaged with 5 mg/kg/day valsartan and 1 ml/kg/day sterile water intraperitoneally, 0.25 mg/kg/day amlodipine and 1 ml/kg/day sterile water via the intraperitoneal route, 0.035 mg/kg/day lisinopril and 1 ml/kg/day sterile water administered intraperitoneally, respectively. Group V rats were orally treated with 10 ml/kg/day of sterile water prior to intraperitoneal administration of 2.25 mg/kg/day of TZM. Groups VI-VIII rats were equally pretreated with 5 mg/kg/day valsartan, 0.25 mg/kg/day amlodipine, and 0.035 mg/kg/day lisinopril before intraperitoneal 2.25 mg/kg/day TZM treatment, respectively; Groups IX and X rats were orally pretreated with the fixed-dose combinations of 0.25 mg/kg/day amlodipine +0.035 mg/kg/day lisinopril and 5 mg/kg/day valsartan +0.035 mg/kg/day lisinopril, respectively, before TZM treatment. Cardiac injury and tissue oxidative stress markers, complete lipids profile, histopathological, and immunohistochemical assays were the evaluating endpoints. Results showed that repeated TZM treatments caused profound increases in the serum TG and VLDL-c levels, serum cTnI and LDH levels, and cardiac tissue caspase-3 and -9 levels but decreased BCL-2 expression. TZM also profoundly attenuated CAT, SOD, GST and GPx activities, and increased MDA levels in the treated tissues. In addition, TZM cardiotoxicity was characterized by marked vascular and cardiomyocyte congestion and coronary artery microthrombi formation. However, the altered biochemical, histopathological, and immunohistochemical changes were reversed with amlodipine, lisinopril, valsartan, and fixed-dose combinations, although fixed-dose valsartan/lisinopril combination was further associated with hyperlipidemia and increased AI and CRI values and coronary artery cartilaginous metaplasia. Thus, the promising therapeutic potentials of amlodipine, lisinopril, valsartan and their fixed-dose combinations in the management of TZM cardiotoxicity, majorly mediated via antiapoptotic and oxidative stress inhibition mechanisms were unveiled through this study.

Chrysophyllum albidum (African star apple) fruit-supplemented diet enhances cognitive functions and attenuates lipopolysaccharide-induced memory impairment, oxidative stress, and release of proinflammatory cytokines.

Purpose: Fruit-based supplement has an important role in protecting the brain against oxido-inflammatory stress. Chrysophyllum albidum fruit contained several phytonutrients that possess antioxidants and anti-inflammatory properties. Hence, this study investigated the effect of C. albidum fruit supplemented diet (CAFD) on cognitive functions and lipopolysaccharide (LPS)-induced memory impairment and oxido-inflammatory response in mice. Methods: Mice were randomized into two experiments. Experiment 1 with naïve mice contained four groups (n = 6) while experiment 2 with LPS contains five groups (n = 6). Mice in experiments 1 and 2 were fed on CAFD (5%, 10%, and 20%) in naïve (6 weeks) and LPS (250 µg/kg, i.p.) in the 7th week, respectively. Cognitive performance was tested using Y-maze test (YMT) and novel object recognition test (NORT) in the naïve and LPS mice. Brain samples were obtained for determination of oxido-inflammatory parameters and acetylcholinesterase activity. Results: The CAFD significantly enhanced cognitive performance in the YMT and NORT in naïve and LPS mice, as evidenced by increased % alternation and discrimination index, respectively. CAFD supplementation significantly reduced acetylcholinesterase enzyme activity while it attenuated depletion of reduced glutathione and catalase activities in brains of naive and LPS-treated animals. The CAFD significantly reduced LPS-induced increased malondialdehyde levels in mice brains. CAFD supplementation significantly attenuated LPS-induced pro-inflammatory cytokines (IL-6, TNF-α) in mice brains. Conclusion: Chrysophyllum albidum fruit supplementation in diet enhances memory function and prevents cognitive deficits induced by LPS via mechanisms associated with inhibition of oxidative stress-related processes, acetylcholinesterase activity, and pro-inflammatory mediators.