Apigenin attenuates depressive-like behavior via modulating monoamine oxidase A enzyme activity in chronically stressed mice.

Chronic stress is a risk factor for depression and is characterized by elevated levels of brain monoamine oxidase A (MAOA). Mounting evidence has shown that MAOA is a biochemical link between stress and depression. Apigenin (API), a natural flavonoid, as demonstrated in vitro inhibitory effect on MAOA, is suggestive of antidepressant-like activity. However, the in vivo inhibitory effect of API on MAOA and how it affects depression still remain unclear. Here, we report the probable mechanisms of action of API in chronic unpredictable mild stress (CUMS)-induced depression in mice. Treatment with API reversed anhedonia, and reduced anxiety and immobility time in behavioral studies. API reduced brain corticosterone and malondialdehyde (MDA) levels but increased brain levels of glutathione and superoxide dismutase. Furthermore, interleukin-6 and tumor necrosis factor-α were attenuated by API. It also restored cell loss and inhibited the activity of MAOA in the hippocampal brain regions and prefrontal cortex. Comparative binding affinity of API for MAOA (-7.7 kcal/mol) through molecular docking studies was greater than that of reference compound, clorgyline (-6.8 kcal/mol). Favorable hydrophobic interactions important to API binding at MAOA binding cavity was revealed to include conventional hydrogen bond (Cys323 and Tyr444), π-Sulfur (Cys323), π-π Stacked (Tyr407), π-π T-shaped (Phe208), π-lone pair and π-alkyl (Ile335, Ile180) interactions. These results suggest that API is a potent, selective, reversible inhibitor of MAOA with capability of attenuating CUMS-induced depression via inhibiting MAOA enzyme activity and altering other pathomechanisms.

Co-administration of metformin and/or glibenclamide with losartan reverse NG-nitro-l-arginine-methyl ester-streptozotocin-induced hypertensive diabetes and haemodynamic sequelae in rats.

Over the years, there have been opinions on whether to reduced blood pressure (BP) to a different levels in patients with diabetes mellitus. Hence, this study investigated the efficacy of the co-administration of losartan (angiotensin receptor blocking antihypertensive agent) with metformin and/or glibenclamide (antidiabetic agents) on hypertensive-diabetic experimental rats induced by NG-nitro-l-arginine-methyl-ester hydrochloride (l-NAME), and streptozotocin (STZ). STZ (45 mg/kg, i.p.)-induced diabetic rats combined with l-NAME (40 mg/kg, p.o.)-induced hypertension were allotted into different groups. Group 1 received distilled water (10 mL/kg) and served as normal control, group 2 comprised hypertensive diabetic rats with distilled water, groups 3-5 were hypertensive-diabetic rats but received combination treatments of losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide daily for 8 weeks, respectively. Our finding revealed no changes in the body weights, but there was a significant increase in fasting blood sugar levels in l-NAME - STZ-induced hypertensive-diabetes, which were lowered by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide treatments. Moreover, the increased systolic-BP, mean arterial pressure but not diastolic-BP and heart rate by l-NAME + STZ were attenuated more significantly by losartan + metformin + glibenclamide between weeks 2-8 relative to hypertensive-diabetic control. l-NAME + STZ-induced elevated levels of lactate dehydrogenase and creatinine kinase, were differentially reversed by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide. However, l-NAME + STZ-induced decreased nitrite level was significantly restored by all treatments, suggesting increased nitrergic transmission. Additionally, l-NAME + STZ-induced degeneration of pancreatic islet and myocardial cells were dramatically alleviated by losartan + metformin + glibenclamide treatments. Our findings suggest hyperglycemia with raised systolic-BP should be managed with losartan combined with both metformin and glibenclamide than single combination of losartan with antidiabetics.

Taurine, an essential ß-amino acid insulates against ketamine-induced experimental psychosis by enhancement of cholinergic neurotransmission, inhibition of oxidative/nitrergic imbalances, and suppression of COX-2/iNOS immunoreactions in mice.

Cholinergic, oxidative, nitrergic alterations, and neuroinflammation are some key neuropathological features common in schizophrenia disease. They involve complex biological processes that alter normal behavior. The present treatments used in the management of the disorder remain ineffective together with some serious side effects as one of their setbacks. Taurine is a naturally occurring essential ß-amino acid reported to elicit antipsychotic property in first episode psychosis in clinical setting, thus require preclinical investigation. Hence, we set out to investigate the effects of taurine in the prevention and reversal of ketamine-induced psychotic-like behaviors and the associated putative neurobiological mechanisms underlying its effects. Adult male Swiss mice were sheared into three separate cohorts of experiments (n = 7): drug alone, preventive and reversal studies. Treatments consisted of saline (10 mL/kg/p.o./day), taurine (50 and 100 mg/kg/p.o./day) and risperidone (0.5 mg/kg/p.o./day) with concomitant ketamine (20 mg/kg/i.p./day) injections between days 8-14, or 14 days entirely. Behavioral hyperactivity, despair, cognitive impairment, and catalepsy were measured. Brain oxidative/nitrergic imbalance, immunoreactivity (COX-2 and iNOS), and cholinergic markers were determined in the striatum, prefrontal-cortex, and hippocampus. Taurine abates ketamine-mediated psychotic-like episodes without cataleptogenic potential. Taurine attenuated ketamine-induced decrease in glutathione, superoxide-dismutase and catalase levels in the striatum, prefrontal-cortex and hippocampus. Also, taurine prevented and reversed ketamine-mediated elevation of malondialdehyde, nitrite contents, acetylcholinesterase activity, and suppressed COX-2 and iNOS expressions in a brain-region dependent manner. Conclusively, taurine insulates against ketamine-mediated psychotic phenotype by normalizing brain central cholinergic neurotransmissions, oxidative, nitrergic and suppression of immunoreactive proteins in mice brains.

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.

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.

Probable mechanisms involved in the antipsychotic-like activity of methyl jasmonate in mice.

Psychosis is a chronic neuropsychiatric disorder that affects millions of individuals worldwide and impairs the quality of life and productivity of the patients. The clinical efficacy of antipsychotic drugs has been compromised by adverse effects, relapse, and therapeutic failures, thus necessitating search for alternative agents. Methyl jasmonate (MJ) is a bioactive compound reported to have beneficial effects in various neurological disorders. This study was undertaken to investigate the antipsychotic-like effects of MJ in mice. Male Swiss mice were pretreated intraperitoneally with MJ (25-100 mg/kg) or vehicle (10 mL/kg) 60 min prior to bromocriptine (5 mg/kg) or acute injection of ketamine (10 mg/kg). Thereafter, each mouse was observed for stereotype behaviors for 2 min at 10, 15, 20, 30, and 45 min post-bromocriptine injection. Another set of mice received MJ (25-100 mg/kg) or vehicle (10 mL/kg) 60 min after chronic ketamine injection (20 mg/kg, i.p) once daily for 14 consecutive days. Afterwards, locomotor activity and memory function in this sequence were evaluated using open field and Y-maze tests. The levels of malondialdehyde (MDA) and glutathione (GSH) and activity of catalase and superoxide dismutase (SOD) in the brain were determined. MJ significantly inhibited stereotypy behavior induced by bromocriptine or acute ketamine injection, which suggest antipsychotic-like activity. It also attenuated hyper-locomotion and memory deficits induced by chronic injection of ketamine in mice. The increased oxidative stress as shown by the altered brain levels of MDA, GSH, and activity of antioxidant enzymes induced by chronic injection of ketamine was reduced by MJ. Taken together, these findings suggest that MJ demonstrated antipsychotic-like property via mechanism related to its antioxidant property and interference with dopaminergic neurotransmission.

Evaluation of adaptogenic-like property of methyl jasmonate in mice exposed to unpredictable chronic mild stress.

This study was undertaken to evaluate the adaptogenic-like activity of methyl jasmonate (MJ) in mice exposed to unpredictable chronic mild stress (UCMS). Male Swiss mice were treated with MJ (25-100mg/kg, i.p.) 30 min before exposure to UCMS daily for 14 days prior to testing for memory and anxiety. Thereafter, the blood glucose and serum corticosterone levels were estimated using glucometer and ELISA. The brain concentrations of malondialdehyde (MDA) and glutathione (GSH) were estimated using spectrophotometer. Brain histology and the population of healthy neurons in the hippocampal regions were also assessed. MJ reversed anxiety and memory impairment produced by UCMS, which suggest adaptogenic-like property. The reduction in the weight of adrenal gland and liver in MJ-treated groups further indicates adaptogenic activity. It further decreases the blood glucose and serum corticosterone levels in UCMS-mice. Also, MJ decreases the concentrations of MDA and elevated the levels of GSH in the brain of mice exposed to UCMS. Brain histology revealed that MJ attenuated UCMS-induced degeneration and death of neuronal cells in the pyramidal layer of the cornu ammonis 3 (CA3) and the sub-granular zone of the dentate gyrus of the hippocampus. Moreover, MJ decreased the population of dead neuronal cells of the pyramidal layer of the CA3 and the sub-granular zone of the dentate gyrus of the UCMS-mice, which suggests neuroprotection. Taken together, these findings suggest that MJ demonstrated adaptogenic-like activity in mice; which might be related to modulation of serum corticosterone levels, inhibition of oxidative stress and neuroprotection.

Jobelyn® exhibited anti-inflammatory, antioxidant, and membrane-stabilizing activities in experimental models.

BACKGROUND: Jobelyn® (JB) is an African sorghum-based food supplement claimed to be efficacious for the treatment of rheumatoid arthritis (RA). Although in vitro studies confirmed its anti-inflammatory property, no study had shown the effect of JB using in vivo animal models of inflammation. Thus, its effects on acute and chronic inflammation in rats were evaluated in this study. Its effect on rat red blood cell (RBC) lysis was also assessed. METHODS: Acute inflammation was induced with intraplanter injection of carrageenan and increase in rat paw volume was measured using plethysmometer. The volume of fluid exudates, number of leukocytes, concentrations of malondialdehyde (MDA), and glutathione (GSH) in the fluid were measured on day 5 after induction of chronic inflammation with carrageenan in the granuloma air pouch model. RBC lysis induced by hypotonic medium as determined by release of hemoglobin was measured spectrophotometerically. RESULTS: JB (50-200 mg/kg) given orally produced a significant inhibition of acute inflammation induced by carrageenan in rats. It reduced the volume and number of leukocytes in inflammatory fluid in the granuloma air pouch model of chronic inflammation. It further decreased the levels of MDA in the fluid suggesting antioxidant property. JB elevated the concentrations of GSH in inflammatory exudates indicating free radical scavenging activity. It also significantly inhibited RBC lysis caused by hypotonic medium, suggesting membrane-stabilizing property. CONCLUSIONS: JB has in vivo anti-inflammatory activity, which may be related to its antioxidant and membrane-stabilizing properties, supporting its use for the treatment of arthritic disorder.

Methyl jasmonate enhances memory performance through inhibition of oxidative stress and acetylcholinesterase activity in mice.

AIMS: Current research effort focuses on the development of safer natural compounds with multipronged mechanisms of action that could be used to ameliorate memory deficits in patients with Alzheimer's disease, as cure for the disease still remains elusive. In this study, we evaluated the effect of methyl jasmonate (MJ), a naturally occurring bioactive compound on memory, acetylcholinesterase activity and biomarkers of oxidative stress in mice. MAIN METHODS: Male Swiss mice were treated with intraperitoneal injection of MJ (10-40 mg/kg) alone or in combination with scopolamine (3mg/kg) once daily for 7 days. Thirty minutes after the last treatment, memory functions were assessed using Y-maze and object recognition tests. Thereafter, acetylcholinesterase activity and levels of biomarkers of oxidative stress were assessed in mice brains using standard biochemical procedures. KEY FINDINGS: MJ significantly enhanced memory performance and reversed scopolamine-induced cognitive impairment in mice. MJ demonstrated significant inhibition of acetylcholinesterase activity suggesting increased cholinergic neurotransmission. It further decreased malondialdehyde concentrations in mouse brain indicating antioxidant activity. Moreover, MJ significantly increased glutathione levels and activity of antioxidant enzymes (catalase and superoxide dismutase) in mice brains. The increased oxidative stress; evidenced by elevated levels of malondialdehyde and decreased antioxidant defense systems in scopolamine-treated mice was attenuated by MJ. SIGNIFICANCE: The results of this study suggest that MJ may be useful in conditions associated with memory dysfunctions or age-related cognitive decline. The positive effect of MJ on memory may be related to inhibition of oxidative stress and enhancement of cholinergic neurotransmission through inhibition of acetylcholinesterase activity.

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.

Evaluation of the anticonvulsant and anxiolytic potentials of methyl jasmonate in mice.

Methyl jasmonate (MJ) is one of the most well-studied plant stress hormones belonging to the jasmonate family. Previous studies have shown that MJ potentiated pentobarbitone sleeping time and enhanced GABA-mediated inhibitory neurotransmission, suggesting potential benefits in disorders associated with hyperactivity of the brain. This study was carried out to evaluate whether MJ has anticonvulsant and anxiolytic properties in mice. The anticonvulsant effect was assessed based on the prevention of tonic-clonic seizures induced by chemoconvulsant agents in mice. The anxiolytic property was evaluated utilizing the elevated plus maze (EPM) and light/dark transition paradigms. The effect of MJ on spontaneous locomotor activity (SMA) was also assessed. Mice received intraperitoneal (i.p.) injections of MJ 30 min before the tests were carried out and diazepam (2 mg/kg, i.p.) was used as the reference drug. MJ (50-400 mg/kg) did not protect the mice against tonic-clonic convulsions induced by picrotoxin (10 mg/kg, i.p.) or strychnine (3 mg/kg, i.p.). However, MJ (100, 200, and 400 mg/kg) offered 20, 60, and 100% protection against pentylenetetrazole (100 mg/kg, i.p.)-induced convulsions. In a similar manner to diazepam (2 mg/kg), MJ (400 mg/kg) produced a marked sedative effect as shown by decreases in the number of lines crossed and the duration of ambulation in the open field test. In contrast to diazepam (2 mg/kg), MJ (5-50 mg/kg) did not show anxiolytic effects in the EPM and light/dark transition paradigms. These findings suggest that methyl jasmonate at high doses possessed anticonvulsant properties in the pentylenetetrazole animal model of epilepsy, but did not produce anxiolytic activity in mice.

Anti-aggressive activity of methyl jasmonate and the probable mechanism of its action in mice.

This study examines the anti-aggressive activity of methyl jasmonate (MJ) and its probable mechanism of action in mice. Male mice that showed aggression after housing individually with female counterparts for 3 weeks or kept in isolation for 4 weeks were treated with MJ, vehicle or haloperidol (HP) 60 min before the test for aggression. Effects of p-chlorophenylalanine (PCPA) or fluoxetine (FL) given alone or in combination with MJ were also investigated. In the interaction studies, PCPA or FL was given to the animals 30 min after MJ injection and aggression testing was carried out 30 min later. Parameters assessed in the study were latency to attack, frequency of attacks, aggressive postures, lateral threats, tail rattling and pursuit frequency. MJ (1, 5, 10 mg/kg) produced a significant dose-dependent decrease in offensive aggressive behaviors. MJ did not impair the defensive mechanisms of the animals and its anti-aggressive effect was not accompanied by sedation or catalepsy. PCPA (50 mg/kg), an inhibitor of 5-hydroxytryptamine (5-HT) biosynthesis, produced a significant increase in aggressive responses and reversed the anti-aggressive effect of MJ. Additionally, FL (10 mg/kg), a 5-HT reuptake inhibitor, produced a significant suppression of aggressive behaviors and also enhanced the antiaggressive effect of MJ. Taken together, these findings suggest that methyl jasmonate exhibits specific anti-offensive aggressive activity and may be relevant in the treatment of reactive aggression in humans. Although, it appears that MJ may be affecting 5-HT(1B) receptors, additional data are needed to clearly define the mechanism(s) by which MJ exhibit antiaggressive activity.