The monoaminergic pathways are involved in the antidepressant-like effect of quercetin.

Quercetin, a plant-derived flavonoid, is an antioxidant and has demonstrated antidepressant and anti-inflammatory activities in several animal models. However, there is scanty information on the underlying mechanisms of its antidepressant property. This present study aimed at assessing the involvement of monoaminergic systems in the antidepressant-like activity of quercetin in experimental animals. Mice received varying doses of quercetin (25, 50 &100 mg/kg daily) and were then subjected to open field test (OPF), despair tests, the reserpine test, and the yohimbine lethality test (YLT). In addition, monoaminergic involvement was investigated by combining quercetin (100 mg/kg) with dopaminergic antagonists (haloperidol and sulpiride), adrenergic blockers (prazosin, propranolol and yohimbine), and serotonergic blockers/inhibitors (metergoline). The results showed that quercetin produced significant anti-immobility effects in the forced swim test (FST) and tail suspension test (TST), suggesting antidepressant activity. In addition, the potentiation of yohimbine lethality by quercetin further indicates its antidepressant-like property. This antidepressant action demonstrated was, however, blocked when quercetin was co-administered with dopaminergic, adrenergic and serotonergic antagonists, suggesting involvement of the monoaminergic system in the antidepressant action of quercetin. Nevertheless, quercetin did not significantly alter the locomotor activity of mice, which implies lack of stimulant effect. Taken together, these outcomes suggest that monoaminergic systems are likely involved in the anti-depressant effect of quercetin in mice.

Quercetin abrogates lipopolysaccharide-induced depressive-like symptoms by inhibiting neuroinflammation via microglial NLRP3/NFκB/iNOS signaling pathway.

BACKGROUND: Major depressive disorder is a serious psychiatric illness having serious damaging effect on the quality of life of suffers. Quercetin is a plant flavonoid, mostly used as a constituent in dietary products. This study evaluated antidepressant effect of quercetin on lipopolysaccharide (LPS)-induced depression in rats. MATERIALS AND METHODS: Twenty-one male rats were randomly assigned into three groups (n = 7): group 1 (vehicle only), group 2 (quercetin), group 3 (LPS). Rats were treated with vehicle (10 mL/kg, p.o.) or quercetin (50 mg/kg, p.o.) for seven days. Sixty minutes after treatment on day seven, all animals were injected with LPS (0.83 mg/kg, i.p.) except group 1 (vehicle only). Twenty-four hours after LPS injection, animals were assessed for depressive symptoms using forced swim, sucrose splash and open field tests. Animals were sacrificed; brain samples collected for bioassay of pro-inflammatory mediators, TNF-α, IL-6 and IL-17 were measured using enzyme-linked immunosorbent assay (ELISA) while expressions of NF-κB, inflammasomes, microglia and iNOS were quantified by immunohistochemistry. RESULTS: The LPS significantly (p < 0.05) decreased mobility of rats in FST and decreased sucrose preference, which is indicative of depressive-like behaviours. These behaviours were significantly (p < 0.05) attenuated by quercetin compared to control (vehicle only). Following LPS exposure, the expressions of inflammasomes, NF-κB, iNOS, proinflammatory cytokines and microglia positive cells in the hippocampus and prefrontal cortex were significantly (p < 0.05) elevated. All these were attenuated by pretreating animals with quercetin. CONCLUSION: Quercetin exhibit antidepressant-like property, which may be related to inhibition of neuroinflammatory signaling pathways.

Psychobiotic interventions attenuate chronic alcohol use-mediated exacerbation of posttraumatic stress disorder in rats: the role of gut-liver axis response.

OBJECTIVES: The incidence of co-occurring alcohol-use disorder (AUD) and post-traumatic stress disorder (PTSD) is high, and the presence of one disorder aggravates the severity of the other. Emerging evidence shows the neuroprotective and anti-inflammation functions of psychobiotics. Hence, the study explored the effects of probiotics and synbiotic inulin on the gut- and liver-oxidative and inflammatory biomarkers in chronic alcohol exacerbation of PTSD symptoms in rats. METHODS: Young adult rats were administered 10% ethanol in a two-bottle choice test for six weeks and were subjected to single prolonged stress. Probiotics and synbiotic intervention followed this. Markers of oxido-inflammatory stress, liver functions, intestinal (faecal) metabolites, occludin expression, and histopathology of the ileum and liver were evaluated. RESULTS: Chronic alcohol drinking and PTSD increased oxido-inflammatory stress, markers of hepatic damage, and reduced faecal metabolites, which were attenuated by probiotic and synbiotic interventions. Furthermore, reduced immunoexpression of gut and liver occludin, with loss of barrier integrity, viable hepatocytes, congestive portal area, and shortened villi and crypt depth, were observed. Probiotic and synbiotic interventions mitigated these effects. CONCLUSIONS: The study demonstrates that psychobiotics mitigate the detrimental effects of co-occurring chronic alcohol intake in the context of PTSD.

Ameliorating Effect of Morin Hydrate on Chronic Restraint Stress-induced Biochemical Disruption, Neuronal, and Behavioral Dysfunctions in BALB/c Mice.

Introduction: Morin hydrate (MH) is a bioflavonoid component of many fruits and vegetables. Our previous research demonstrated that MH provides neuroprotection in mouse models of acute restraint stress and sleep deprivation by attenuating hippocampal neuronal damage and enhancing memory. Based on these findings, our study investigated the role of MH in chronic stress-induced neuronal and biochemical perturbations in BALB/c mice. Methods: Male BALB/c mice were divided into 6 groups (n=6). Groups 1 and 2 received vehicle (10 mL/kg normal saline), groups 3-5 received MH (5, 10, 20 mg/kg IP), while group 6 received ginseng (25 mg/kg) daily and 30 minutes afterward were restrained in a plastic cylindrical restrainer for 14 days. Results: Immobility time in the forced swim test increased in the MH-treated group, indicating an antidepressant-like effect. Also, a reduction in frequency and duration of open arms exploration was observed in the elevated plus-maze (EPM) test in stressed mice, and administration of MH (5, 10, 20 mg/kg, IP) reversed these effects. An increase in blood levels of glucose, triglycerides, total cholesterol, and brain malondialdehyde and nitrite levels was observed in the stressed groups, which was reversed by MH. Furthermore, MH reversed the stress-induced reduction in HDL cholesterol and glutathione (GSH) levels and attenuated stress-induced alterations in the prefrontal cortex and hippocampus. Conclusion: Our findings suggest that MH attenuated chronic restraint stress-behavioral and biochemical perturbations, probably due to its capability to decrease oxidative stress and brain neuronal damage. Highlights: Chronic stress perturbs physiological and psychological homeostasis;Morin hydrate normalized chronic stress-induced biochemical disruptions;Morin hydrate attenuated structural changes in prefrontal cortex and hippocampus. Plain Language Summary: Stress is a state of being overwhelmed by demands exceeding the personal and social means of coping. Exposure to excessive stress has resulted in disruption of neurochemical and physiological processes, which sometimes manifest as behavioural abnormalities. Therefore to cope with the stressful life style, there is need to develop a therapeutic agent of plant origin. Morin hydrate is a flavonoid with known antioxidant and neuroprotective properties; however, its effect in a stressful condition has not been studies. The study thus evaluated ameliorating effect of Morin hydrate on chronic restraint stress-induced biochemical disruption, neuronal and behavioral dysfunctions in BALB/c mice. To achieve this, mice were exposed to chronic restraint stress protocol for fourteen days. Behavioural changes were examined using various techniques. The vital parameters like antioxidant, glucose and nitrite levels were also taken. Our findings show that Morin hydrate prevented behavioral abnormalities and damage to the brain cells. It also inhibited stress-induced biochemical disturbance.

Quercetin mitigates memory deficits in scopolamine mice model via protection against neuroinflammation and neurodegeneration.

AIMS: Neurodegenerative disorders like Alzheimer's disease (AD) are outcomes of neuroinflammatory processes that result in memory impairment. Quercetin (QT), a plant based flavonoid, has demonstrated notable effects against neurodegeneration and inflammation in models of dementia. However, the underlying mechanisms have not been well elucidated. This study evaluated the possible effects of QT against neuroinflammation and neurodegeneration in scopolamine (SC) induced memory impairment. MAIN METHODS: SC was used to induce memory loss in mice after which novel object recognition test (NORT) was used to assess memory function. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in the brain tissues of the animals. Brain histology was carried out on the hippocampus (cornus ammonis 1, cornus ammonis 3 and dentate gyrus), and the prefrontal cortex. The population of healthy neuronal cells was counted, using ImageJ software. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) was employed for the identification of cells undergoing apoptosis. KEY FINDINGS: QT reversed memory impairment in the NORT. Increases in TNF-α and IL-6 were attenuated by QT, and histology revealed that QT attenuated SC-induced cell degeneration and death in the hippocampal sub-regions and prefrontal cortex. QT diminished the population of dead cells in SC-treated mice, and also reversed the process of apoptosis induced by SC. SIGNIFICANCE: Findings from the study suggest that QT mitigates pro-inflammatory mediators and reverses neurodegeneration to restore memory function.

Quercetin mitigates scopolamine-induced memory dysfunction: impact on oxidative stress and cholinergic mechanisms.

Despite the promising neuroprotective activities of quercetin (QT), its' effect on cholinergic neurotransmission needs further elucidation. In this study, we explored the impact of QT on oxidative stress and cholinergic neurotransmission with emphasis on the possible involvement of choline acetyltransferase (ChAT) as a potential mechanism of QT on memory function at the hippocampal sub-regions and prefrontal cortex of mice brains. Mice were administered orally with QT (12.5 and 25 mg/kg) alone or in combination with SC (3 mg/kg, intraperitoneally) once daily for seven consecutive days. Thirty minutes after the last treatment, memory function was assessed using the Y-maze test. Levels of biomarkers of oxidative stress and acetylcholinesterase (AChE) activity were determined using a microplate reader. ChAT activity was determined by immunohistochemistry. QT pretreatment enhanced memory performance and reversed scopolamine (SC)-induced memory impairment in the Y-maze test. QT also reduced malondialdehyde and nitrite levels in mice brains. Glutathione levels were increased in mice brains as a result of QT administration. Levels of antioxidant enzymes (superoxide dismutase and catalase) were significantly increased in the mice brains, but AChE activity was reduced by QT. The activity of ChAT was significantly enhanced by QT in the hippocampal sub-regions and the prefrontal cortex of the mice brains. This study has shown that QT mitigated SC-induced memory dysfunction by inhibiting oxidative stress and AChE activity. Also, QT enhanced ChAT activity, particularly in the hippocampal sub-regions and the prefrontal cortex. These mechanisms, may be possible means through which QT improves memory performance.

Morin hydrate mitigates rapid eye movement sleep deprivation-induced neurobehavioural impairments and loss of viable neurons in the hippocampus of mice.

Rapid eye movement sleep deprivation distorts the body's homeostasis and results in oxidative breakdown which may be responsible for a variety of neurological disorders. Some naturally occurring compounds of plant origin with antioxidant and neuroprotective properties are known to attenuate the detrimental effects of REM sleep deprivation. Morin hydrate, a flavonoid from Mulberry has demonstrated antioxidant and neuroprotective activities but its effect in sleep disturbed mice is unknown. The study was designed to explore the neuroprotective effect of Morin hydrate on 48 h. REM sleep deprivation-induced behavioural impairments and neuronal damage in mice. Mice were allotted into six treatment groups (n = 6): groups 1 and 2 received vehicle (10 ml/kg normal saline), groups 3-5 received Morin hydrate (5, 10, 20 mg/kg i.p) while group 6 received ginseng (25 mg/kg) which served as the reference drug. Treatment was performed daily for 5 days and animals were sleep-deprived on the last 48 h. Various behavioural tests (Elevated plus maze, Y-maze, locomotor activity) followed by oxidative parameters (malondialdehyde, nitric oxide, reduced glutathione) and histolopathological changes in the Cornu ammonis 1 (CA1) region of the hippocampus were assessed. Data were analysed using ANOVA at α0.05. Morin hydrate (5, 10, 20 mg/kg) significantly enhanced memory performance, improves anxiolytic-like behaviour, reverses hyperlocomotion, restored depleted reduced glutathione, attenuated raised malondialdehyde and nitric oxide levels as compared to control animals and protects against loss of hippocampal neurons. Results of this present study suggest that Morin hydrate possess neuroprotective effects against sleep deprivation-induced behavioural impairments, oxidative stress and neuronal damage.

Flavonoid-Rich Fraction of Ocimum gratissimum Attenuates Lipopolysaccharide-Induced Sickness Behavior, Inflammatory and Oxidative Stress in Mice.

PURPOSE: Ocimum gratissimum L. leaves has been traditionally used for management of febrile illnesses and symptoms typified of sickness behavior. In this work we investigated the modulatory effect of flavonoid-rich fraction of O. gratissimum leaves (EAFOg) on sickness behavior, inflammatory and oxidative stress responses in LPS-challenged mice. METHOD: O. gratissimum leaf was first extracted with n-hexane, chloroform and methanol, and EAFOg was obtained by ethylacetate partitioning of a sequentially resultant methanol extract. The effect of EAFOg (25-100 mg/kg) on acute LPS-induced neurobehavioral impairment in an open field test (OFT) and depressive-like behavior in forced swimming test (FST) was investigated. Serum nitrite and TNF-α, as well as myeloperoxidase (MPO), malondialdehyde (MDA), and reduced glutathione (GSH) levels were determined in liver and brain tissues. RESULT: EAFOg prevented the reduction in locomotor and rearing activity in OFT and the increase in immobility time in FST. The fraction significantly attenuated the elevation of serum TNF- α and nitrite levels. EAFOg reversed LPS-induced increase in MDA, MPO, and nitrite levels and attenuated GSH depletion in liver and brain tissues of mice. CONCLUSION: Flavonoid-rich fraction of O. gratissimum leaf demonstrated significant modulation of LPS-induced sickness behavior, inflammatory and oxidative stress response in mice. This suggests an important therapeutic strategy in slowing down LPS-mediated hepatic and neuronal disease processes.

Protective Effects of Morin Hydrate on Acute Stress-Induced Behavioral and Biochemical Alterations in Mice.

INTRODUCTION: As stress affects the brain both physiologically and chemically, researchers try to find novel anti-stress compounds with beneficial therapeutic effects. In this regard, the effect of stress and its modulation by Morin hydrate was studied using different acute models in mice. METHODS: The models employed were anoxic tolerance, swimming endurance, and acute restraint test. Morin hydrate or the vehicle was administered 30 minutes prior to each stress exposure while in the acute restraint test; the animals were pretreated for 7 days with Morin hydrate, vehicle, imipramine, or diazepam before stress exposure. The measured parameters were the onset of convulsion and immobility time in the anoxic tolerance and swimming endurance test, respectively, while in the acute restraint test, the animals were assessed for stress-induced anxiety using the elevated plus maze and depression using the forced swim test. Thereafter blood was withdrawn from the retro-orbital plexus and plasma separated, the brain was also isolated, homogenized, centrifuged, and the supernatant was obtained for biochemical estimation. RESULTS: Morin hydrate (5, 10, 20 mg/kg) produced a significant reduction in immobility time in the swimming endurance test, while significantly increased the anoxic stress tolerance time. Acute restraint stress caused a significant decrease in reduced glutathione levels (which was reversed by Morin hydrate) and increased the level of malondialdehyde, a thiobarbituric acid reactive substance which is an index of oxidative stress and nitrite. These effects were attenuated by Morin hydrate. Also, pretreatment with Morin hydrate attenuates acute restraint stress-associated anxiety and depression, reversed the hyperglycemia evoked by the stressful exposure and normalized serum cholesterol levels. CONCLUSION: These findings suggest that Morin hydrate exhibits anti-stress effects and may be useful in the relief of stress.

Methyl jasmonate attenuated lipopolysaccharide-induced depressive-like behaviour in mice.

Depression is a recurrent neuropsychiatric disorder that affects millions of individuals worldwide and impact negatively on the patients' social functions and quality of life. Studies have shown that i.p injection of lipopolysaccharide (LPS) induces depressive-like behavior in rodents via induction of oxidative stress and neuroinflammation. Methyl jasmonate (MJ), an isolated compound from jasmine plant has gained reputation in aromatherapy for treatment of depression, nervousness and memory deficits. This study was designed to evaluate the effects of MJ on LPS-induced depressive-like behavior in mice. Mice were given MJ (5-20 mg/kg), imipramine (10 mg/kg) or vehicle (10 mL/kg) intraperitoneally for 7 consecutive days. On day 7, treatment was carried out 30 min prior to i.p injection of LPS (830 µg/kg). Twenty four hours after LPS administration, tail suspension, forced swim and sucrose preference tests were carried out. Thereafter, serum corticosterone levels were determined using ELISA. The levels of malondialdehyde (MDA), glutathione (GSH) and tumor necrosis factor-alpha (TNF-α) were determined in brain tissue homogenates. LPS significantly increased immobility time in the tail suspension and forced swim tests when compared with vehicle (p < 0.05), which indicates depressive-like syndromes. However, the increased immobility time was significantly reduced by MJ (5-20 mg/kg) when compared with LPS-treated group. LPS administration also altered the levels of MDA, GSH, corticosterone and TNF alpha in mice, which was significantly reversed by MJ. These findings suggest that attenuation of LPS-induced depressive-like behavior by MJ may be related to suppression of oxidative stress and release of TNF alpha.

Possible Mechanisms Involved in Attenuation of Lipopolysaccharide-Induced Memory Deficits by Methyl Jasmonate in Mice.

This present study was carried out to investigate the likely mechanisms by which methyl jasmonate (MJ), 'an agent widely used in aromatherapy for neurological disorders, attenuates lipopolysaccharide (LPS)-induced memory deficits in mice. Mice were given intraperitoneal administration of LPS (250 µg/kg) alone or in combination with MJ (10-40 mg/kg), donepezil, DP (1 mg/kg), or vehicle for 7 successive days. Thereafter, memory was assessed using object recognition test (ORT). Acetylcholinesterase and myeloperoxidase activities were estimated in brain tissue homogenates. Brain levels of nitric oxide and markers of oxidative stress as well as histopathologic changes of the prefrontal cortex and cornu ammonis 1 (CA1) of the hippocampal region were also assessed. MJ (10-40 mg/kg) attenuated LPS-induced memory impairment in ORT. Moreover, the increased brain activities of acetylcholinesterase and myeloperoxidase enzymes were suppressed by MJ when compared with control (p < 0.05). Increased brain oxidative stress and nitric oxide levels in LPS-treated mice were significantly decreased by MJ. It offers protection against LPS-induced neuronal degeneration of the prefrontal cortex and CA1 of the hippocampus, suggesting neuroprotective effect. Taken together, these findings showed that MJ offers protection against LPS-induced memory deficits via mechanisms related to inhibition of acetylcholinesterase, myeloperoxidase, oxidative stress and neuronal degeneration.

Antinociceptive property of Olax subscorpioidea Oliv (Olacaceae) extract in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Olax subscorpioidea is a shrub or tree found in Nigeria, and other parts of Africa. It is used in the management of inflammatory disorder, mental illness, convulsion, pain, and cancer. However, there is dearth of information on scientific basis for its folkloric use in the management of pain. Therefore, the study was designed to investigate the antinociceptive property of the extract of Olax subscorpioidea (EOS) leaves in mice. MATERIALS AND METHODS: Antinociceptive activity of EOS (12.5-50 mg/kg, i.p.) was investigated using acetic acid induced abdominal writhing, tail immersion, hot plate and formalin tests. RESULTS: Extract of Olax subscorpioidea produced significant dose dependent inhibition of writhing frequency [F(4,20)=155.9, p<0.0001] and significant dose dependent inhibition of neurogenic and inflammatory pains [F(4,20)=116.7, p<0.0001; F(4,20)=40.05, p<0.0001]. It also produced a significant dose dependent prolongation of the latent period and reaction times in tail immersion and hot plate tests in mice [F(4,20)=19.49, p<0.0001; F(4,20)=97.95, p<0.0001]. CONCLUSION: Olax subscorpioidea possessed potent analgesic action, mediated centrally and peripherally, thus justifying its use in the management of pain.

Pharmacological evaluation of the analgesic and anxiolytic activities of Jobelyn® in mice.

Abstract Background: This study presents the results of the pharmacological evaluation of the analgesic and anxiolytic potentials of Jobelyn®, a potent antioxidant African herbal formulation, in mice. The analgesic effect was assessed utilizing acetic acid-induced writhing, tail immersion and formalin-induced paw licking pain models. The anxiolytic activity was evaluated using elevated-plus maze (EPM) and light/dark box. Methods: Mice (5/group) were treated with JB (10-200 mg/kg, p.o.) 1 h before the tests were carried out. In the writhing test, the number of abdominal constrictions was recorded for a period of 30 min after induction of nociception with 0.6% acetic acid, i.p. In the tail immersion test, the latency to tail withdrawal responses to noxious heat was measured. The duration of paw licking (s) was measured as an index of nociception in the formalin test. In the anxiolytic test, the patterns of transition in the two arms of the EPM and in the light/dark box were assessed. Results: JB (10-200 mg/kg, p.o.) significantly inhibited the inflammatory pain produced by acetic acid as evidenced by decreased number of abdominal constrictions in comparison with the control. It also shows higher potency in suppressing the inflammatory pain associated with the second phase of the formalin test. However, JB did not exhibit anxiolytic properties nor modify the pain behavior in the tail immersion test. Conclusions: The results obtained from this study suggest that Jobelyn® might be efficacious against inflammatory pain and further support its recommendation for the management of pain with inflammation as the underlying factor.