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.

Methanol leaf extract of Paullinia pinnata exerts sleep-enhancing and anticonvulsant effects via a mechanism involving the GABAergic pathway.

PURPOSE: Leaf extracts of Paullinia pinnata L. (Sapindaceae) are used in ethnomedicine for the treatment of central nervous system-related diseases such as insomnia and epilepsy. We determined the bioactive constituents, sleep-enhancing and anti-convulsant potentials, and possible mechanisms of action of P. pinnata methanol leaf extract (PPME). METHODS: Gas Chromatography-Mass spectrometry (GC-MS) was used to identify the bioactive compounds in PPME. Adult Swiss albino mice were used. Oral LD50 was estimated before administering PPME at oral doses of 100, 200, and 400 mg/kg to test for sleep-enhancing and anticonvulsant properties. To evaluate the possible mechanisms involved, mice were pretreated for five days with isoniazid (NIH) a GABA synthesis inhibitor before re-evaluation of sleep-enhancing property. The activities of glutamic acid decarboxylase (GAD), superoxide dismutase (SOD), catalase (CAT), and the level of malondialdehyde (MAD) in the brain of mice were also evaluated after a 7-day treatment with the extract. RESULTS: Twenty-five phytochemical compounds were identified from GC-MS analysis with fatty acid esters of lauric and fumaric acids being the most abundant. The oral LD50 of PPME was estimated to be greater than 5000 mg/kg. Doses of PPME significantly (p < 0.001) reduced sleep latency and increased the duration of sleep of phenobarbital-treated mice. Except for 100 mg/kg, the doses also significantly protected mice against maximum electroshock (p < 0.001) and pentylenetetrazole (p < 0.05) but not strychnine-induced convulsions. Pretreatment with isoniazid (INH) almost completely reversed the sleep-enhancing effects of PPME. The activities of GAD, SOD, and CAT, and level of MDA in brains of the mice were significantly (p < 0.001) increased by doses of PPME administered for five days. CONCLUSION: The extract possesses sleep-enhancing and anticonvulsant properties which depend on increased level of GABA in the brain. Its antioxidant action may be neuroprotective against free radicals-induced damage.

Creatine attenuates seizure severity, anxiety and depressive-like behaviors in pentylenetetrazole kindled mice.

Epilepsy has been associated with several behavioral changes such as depression and anxiety while some antiepileptic drugs can precipitate psychiatric conditions in patients. This study evaluated the ameliorative effect of creatine on seizure severity and behavioral changes in pentylenetetrazole (PTZ) kindled mice. Mice were kindled by administering sub-convulsive doses of PTZ (35 mg/kg i.p.) at interval of 48 h. The naïve group (n = 7) constituted group 1, while successfully kindled mice were randomly assigned to five groups (n = 7). Group II served as vehicle treated group; groups III-V were treated with creatine 75, 150, and 300 mg/kg/day, p.o; Group V was given 25 mg/kg/day of phenytoin p.o. The treatment was for 15 consecutive days. The intensity of convulsion was scored according to a seven-point scale ranging from stage 0-7. Tail suspension test (TST) and Elevated plus maze (EPM) were utilized to assess depression and anxiety-like behavior respectively. After behavioral evaluation on day 15th, their brain was isolated and assayed for catalase, superoxide dismutase, reduced glutathione, and malondialdehyde. There was a significant (p < 0.05) reduction in the seizure scores, anxiety and depression-like behaviors in mice from the 5th day of treatment. The antioxidant assays revealed significant (p < 0.05) increase in catalase and reduced glutathione, and significant (p < 0.05) reduction in lipid peroxidation in treated mice. This study provides evidence for the seizure reducing property of creatine and its ameliorating potential on anxiety and depressive-like behaviors that follows seizure episodes.

Evaluation of some neuropharmacological effects of Caladium bicolor aiton (araceae) leaf extracts in mice.

Caladium bicolor Aiton (Araceae) is used in ethnomedicine for the treatment of boils, wound ulcers and convulsion. This study investigated the effects of the leaf extracts on some neuropharmacological parameters. The leaves were collected, dried, powdered and then extracted by maceration in methanol to yield the whole extract (WE). Extraction was also done using n-hexane, ethyl acetate and methanol in a Soxhlet apparatus to obtain n-hexane (HE), ethyl acetate (EA) and methanol (ME) extracts. Preliminary phytochemical screening was done using the whole extract. Some neuropharmacological evaluations were carried out using standard methods. Phytochemical screening revealed the presence of carbohydrates, proteins, alkaloids and flavonoids. WE showed varying levels of protection against strychnine-induced convulsion. Each of HE, EA and ME increased latency (P < 0.01) to pentylenetetrazole-induced convulsion and offered varying levels of protection against maximal electroshock-induced seizure. Each of WE, HE and ME significantly increased the duration of stay on the open arm of the elevated plus maze. Both EA and ME at doses of 100 and 200 mg/kg, and HE at a dose of 400 mg/kg significantly reduced the duration of immobility in forced swim test. It is concluded that the leaf extracts possess anticonvulsant, anxiolytic and antidepressant properties.

Effects of Concurrently Administered Aqueous Extract of Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), and Lead Acetate in Rats.

Ganoderma lucidum is a hard, bitter mushroom with many ethnomedicinal uses, including conditions similar to lead (Pb) toxicity. The aim of this study was to evaluate the protective effects of a G. lucidum aqueous extract (GL) when concurrently administered with Pb. Adult Wistar rats were administered oral doses of Pb (100 mg/kg) daily for 25 consecutive days. Of the Pb-treated rats, 3 groups received 100, 200, or 400 mg/kg/day GL, respectively; one group was given only 50 mg/kg/day 2,3-dimercaptosuccinic acid (DMSA); and another group was given 400 mg/kg/day GL and 50 mg/kg/day DMSA. Body weight, Pb levels in organs, enzyme and lipid levels in serum, and antioxidant capability were evaluated. Body weights were not significantly altered by GL. All doses of GL significantly reduced the amount of Pb in the liver (P < 0.01) and kidneys (P < 0.05), but not in the spleen. Doses of GL significantly reduced (P < 0.05) amounts of low-density lipoprotein, but not high-density lipoprotein or triglycerides, in serum. Pb-induced increases in amounts of serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were significantly (P < 0.01) attenuated by GL. Also, a Pb-induced reduction in the amount of superoxide dismutase was significantly (P < 0.05) reversed, but the nitric oxide level was not significantly elevated. An increased malondialdehyde level, which had been induced by Pb, was significantly (P < 0.01) reversed. In conclusion, GL protects against some of the deleterious effects of Pb ingestion, possibly through antioxidant and other mechanisms. DMSA did not enhance the beneficial effects of GL.

Evaluation of the anti-asthmatic and antitussive potentials of methanol leaf extract of Napoleona vogelii in rodents.

Napoleona vogelii is used in ethnomedicine for the treatment of asthma and cough. This study evaluated antiasthmatic and antitussive properties of its methanol leaf extract (NVE) in rodents. Phytochemical screening was conducted using established methods. Acute oral toxicity test was done in mice and guinea pigs. Ovalbumin (OA)-sensitized guinea pigs were orally pretreated with 100, 200 or 400 mg/kg/day of NVE or 0.5 mg/kg/day of salbutamol for 14 days before exposure to 0.2% histamine aerosol. Latency to preconvulsive dyspnea (PCD), tracheal fluid volume (TFV), flow rate (FR), and tracheal morphometry (TM) were evaluated. Tracheal rings from sensitized guinea pigs were tested in organ baths for antispasmodic and spasmolytic effects. Citric acid and ammonium hydroxide cough models were used to evaluate antitussive effects in guinea pigs and mice respectively. Tannins, alkaloids, flavonoids, and phenolic substances were found in NVE. LD50 values in mice and guinea pigs were greater than 5000 mg/kg. NVE caused a significant (P < 0.05) increase in the latency to PCD and a decrease in TFV in the group treated with 200 mg/kg. TM indicated a reduction in airway narrowing in NVE-treated groups. The presence of NVE significantly attenuated responses of tracheal rings to carbachol. Its addition to carbachol precontracted rings resulted in significant relaxation. Emax for calcium concentration-response was significantly (P < 0.01) decreased in the presence of NVE. Cough bouts dose-dependently decreased significantly (P < 0.05) in guinea pigs and mice. We conclude that NVE seems safe and possesses anti-asthmatic effect that involves inhibition of calcium influx. It also has antitussive properties that may be peripherally mediated.

Studies on the anti-asthmatic and antitussive properties of aqueous leaf extract of Bryophyllum pinnatum in rodent species.

OBJECTIVE: To evaluate the antiasthmatic and antitussive properties of the aqueous leaf extract of Bryophyllum pinnatum (B. pinnatum) (BP) Lam. METHODS: Ovalbumin-sensitized guinea pigs which were treated with BP for 21 consecutive days were exposed to 0.2% histamine aerosol in a glass chamber. Mucus viscosity, white blood cell and lymphocyte counts and tracheal wall morphometry were measured. Bouts of cough were counted pre and post acute exposure of extract-treated (× 7 d) guinea pigs to 7.5% citric acid aerosol in a chamber. Phenol red expectoration was estimated in mice after 7 d of daily administration of BP. RESULTS: Doses of 200 and 400 mg/kg/day (×21 d) BP significantly increased the time for guinea pigs to experience preconvulsive dyspnoea. BP and salbutamol (0.5 mg/kg/day ×21 d) reduced mucus viscosity in the sensitized group to values comparable with controls. White blood cell, lymphocyte counts and tracheal morphometry were not significantly altered. Both doses of BP also significantly reduced the bouts of cough but only 400 mg/kg/day significantly inhibited the amount of phenol red secreted. CONCLUSIONS: BP has demonstrated antiasthmatic and antitussive properties in these rodent models. These properties may underscore its use in Nigerian ethnomedicine.

Contractile effect of aqueous Pleurotus tuberregium extract on the isolated bovine iris.

BACKGROUND: Aqueous extract of Pleurotus tuberregium (PT) has been shown to reduce intraocular pressure (IOP) but the underlying mechanism has not been explained. PURPOSE: To investigate the effect of PT on the bovine iris in vitro in comparison with acetylcholine (ACh). METHOD: Strips of the iris were mounted in 10 ml organ baths and exposed to increasing concentrations of PT, ACh and a combination of both agents. The effect of atropine on the responses to the agents was also investigated. RESULTS: PT and ACh separately caused contractile responses on the iris, but their effect reduced with higher concentrations. Combination of PT and ACh did not significantly alter the reduced responses seen with high concentrations of either agent. Atropine completely abolished the contractile responses of the agents. CONCLUSION: The contractile effect of PT on muscarinic receptor-containing iris muscle may explain its IOP reducing property.

Evaluation of the protective and ameliorative properties of Garcinia kola on histamine-induced bronchoconstriction in guinea pigs.

BACKGROUND: Garcinia kola is popularly used in African traditional medicine for the relief of acute bronchoconstrictive episodes. OBJECTIVE: In this study, we examined the anti-asthmatic and morphological effects of the ethanol extract of G. kola in animal model. MATERIALS AND METHODS: Guinea pigs were sensitized with ovalbumin and then given doses of 200 or 400 mg/kg/day for 21 consecutive days. Theophylline (10 mg/kg/day) was used as a standard. At the end of the exposure, the animals were exposed to 0.2% histamine aerosol in a chamber. Lymphocyte count, bronchial histology and morphometry were done. RESULTS: Compared with non-sensitized controls, 200 mg/kg/day dose of the extract significantly (P < 0.05) increased the time taken for onset of preconvulsive dyspnea while the dose of 400 mg/kg/day significantly (P < 0.01) reduced bronchial wall thickness. Lymphocytes counts were not significantly affected but the bronchi of extract-treated animals were histologically clearer of lesions visible in the sensitized. CONCLUSION: These protective and ameliorative properties lend credence to the use of G. kola in ethnomedicine.

Possible mechanisms of action of the hypotensive effect of Annona muricata (soursop) in normotensive Sprague-Dawley rats.

CONTEXT: Annona muricata Linn (Annonaceae) (soursop) is a food plant reported to have antihypertensive properties. OBJECTIVE: We investigated the blood pressure reducing effect of its aqueous leaf extract and the possible mechanisms that may be responsible. METHODS: Intravenous administration of an aqueous leaf extract (9.17-48.5 mg/kg) of A. muricata on the mean arterial pressure and heart rate were recorded invasively on anaesthetized, normotensive Sprague-Dawley rats. Contractile responses of rat aortic rings to the extract (0.5-4.0 mg/mL) were studied using standard organ bath techniques. RESULTS: A. muricata (9.17-48.5 mg/kg) caused significant (p < 0.05) dose-dependent reduction in blood pressure without affecting the heart rates. The hypotensive effects were unaffected by atropine (2 mg/kg), mepyramine (5 mg/kg), propranolol (1 mg/kg) and L-NAME (5 mg/kg). A. muricata leaf aqueous extract significantly (p < 0.05) relaxed phenylephrine (10(-9)-10(-4) M) and 80 mM KCl induced contractions in endothelium intact and denuded aortic rings; and caused a significant (p < 0.05) rightward shift of the Ca(2+) dose response curves in Ca(2+)-free Kreb's solution containing 0.1 mM EGTA. CONCLUSIONS: The hypotensive effects of A. muricata are not mediated through muscarinic, histaminergic, adrenergic and nitric oxide pathways, but through peripheral mechanisms involving antagonism of Ca(2+).

Some characteristic relaxant effects of aqueous leaf extract of Andrographis paniculata and andrographolide on guinea pig tracheal rings.

The ethnomedicinal uses of the aqueous leaf extract of Andrographis paniculata Nees (AP) include treatment of pain and inflammation, malaria, asthma and common cold. We designed this study to characterize some effects of AP and those of its andrographolide constituent. Guinea pig tracheal rings suspended in organ baths containing PSS were precontracted with histamine or carbachol and then exposed to cumulative concentrations of AP, andographolide or theophylline. The effect of AP was tested in Ca2+-depleted tracheal rings stimulated with the EC50 of histamine in Ca2+-free PSS. IC50 and Emax values were calculated for each relaxant. Results showed that both AP and andrographolide possessed relaxant effects on the tracheal smooth muscle. While AP was more effective on histamine-induced contraction, andrographolide and theophylline were more effective on carbachol-induced contraction. The IC50 values of andrographolide were significantly higher than those of theophylline in the two contractile agents. The presence of AP significantly attenuated the contractile force produced by 6.4 x 10(-3) M Ca2+ in Ca2+-depleted rings. It is concluded that andographolide contributes at least in part to the relaxant action of AP on tracheal smooth muscles. The mechanism of action is related to inhibition of Ca2+ influx into tracheal smooth muscle cells.

Effects of aqueous leaf extract of Bryophyllum pinnatum on guinea pig tracheal ring contractility.

Aqueous leaf extract of Bryophyllum pinnatum Lam (Crassulaceae) is used as a cough remedy and for the prophylaxis of asthma. Since drugs used for the prophylaxis of asthma may be acting on airway smooth muscles, we investigated the effects of aqueous leaf extract of the plant on the contractile responses of isolated tracheal rings. Guinea pigs were grouped into non-sensitized, ovalbumin (OA)-sensitized, OA-sensitized but 200 mg/kg/day x 21 extract-treated, and OA-sensitized but 400 mg/kg/day x 21 extract-treated. The extract was administered orally. Tracheal rings obtained from the four groups were mounted in organ baths and used to test spasmolytic and antispasmodic effects of the extract on histamine or carbachol-induced contractions. Concentrations of 0.125-1.0 mg/ml of the extract did not relax histamine or carbachol-induced precontractions. The presence of 0.25-1.0 mg/ml of the extract in organ baths significantly reduced the maximal contractile responses (Emax) to cumulative concentrations of histamine or carbachol irrespective of the experimental group. pD2 values were significantly reduced for histamine and carbachol in rings obtained from 400 mg/kg/day x 21 extract-treated group. It is concluded that aqueous leaf extract of B. pinnatum possesses antispasmodic effects on the guinea pig tracheal rings. The results lend credence to the use of the extract for the prophylaxis of asthma in ethnomedicine.

Analgesic activity of aqueous extract of Stereospermum kunthianum (Cham, Sandrine Petit) stem bark.

The analgesic activity of the aqueous extract of Stereospermum kunthianum stem bark was studied using the acetic acid-induced writhing, the hot plate test, tail flick test, and formalin pain test in mice or rats. The aqueous extract (100, 200 or 400 mg/kg) produced a significant (p<0.001) dose-dependent inhibition of abdominal writhes in mice. The results of the hot plate test showed a dose-related and time-dependent significant (P<0.001) increase in pain threshold in mice 60 minutes after treatment at all the doses used in the study. The extract (100, 200 or 400 mg/kg) showed significant (p <0.05) dose-dependent increase in tail flick latency in rats and also inhibited both phases of the formalin pain test in mice with a more intense effect on the first phase than the second phase. The results indicate that the aqueous extract of Stereospermum kunthianum stem bark possesses analgesic activity which is mediated through both central and peripheral mechanisms. This is a possible rationale for its use in traditional human medicine for pain relief.

Acute and sub-acute toxicological assessment of the aqueous seed extract of Persea americana mill (Lauraceae) in rats.

The aqueous seed extract of Persea americana Mill (Lauraceae) is used by herbalists in Nigeria for the management of hypertension. As part of our on-going scientific evaluation of the extract, we designed the present study to assess its acute and sub-acute toxicity profiles in rats. Experiments were conducted to determine the oral median lethal dose (LD(50)) and other gross toxicological manifestations on acute basis. In the sub-acute experiments, the animals were administered 2.5 g/kg (p.o) per day of the extract for 28 consecutive days. Animal weight and fluid intake were recorded during the 28 days period. Terminally, kidneys, hearts, blood/sera were obtained for weight, haematological and biochemical markers of toxicity. Results show that the LD(50) could not be determined after a maximum dose of 10 g/kg. Sub-acute treatment with the extract neither affected whole body weight nor organ-to-body weight ratios but significantly increased the fluid intake (P < 0.0001). Haematological parameters and the levels of ALT, AST, albumin and creatinine were not significantly altered. However, the concentration of total proteins was significantly increased in the treated group. In conclusion, the aqueous seed extract of P. americana is safe on sub-acute basis but extremely high doses may not be advisable.

Acute and sub-acute toxicological assessment of the aqueous seed extract of Persea Americana Mill (lauraceae) in rats

The aqueous seed extract of Persea americana Mill (Lauraceae) is used by herbalists in Nigeria for the management of hypertension. As part of our on-going scientific evaluation of the extract, we designed the present study to assess its acute and sub-acute toxicity profiles in rats. Experiments were conducted to determine the oral median lethal dose (LD50) and other gross toxicological manifestations on acute basis. In the sub-acute experiments, the animals were administered 2.5 g/kg (p.o) per day of the extract for 28 consecutive days. Animal weight and fluid intake were recorded during the 28 days period. Terminally, kidneys, hearts, blood/sera were obtained for weight, haematological and biochemical markers of toxicity. Results show that the LD50 could not be determined after a maximum dose of 10 g/kg. Sub-acute treatment with the extract neither affected whole body weight nor organ-tobody weight ratios but significantly increased the fluid intake (P < 0.0001). Haematological parameters and the levels of ALT, AST, albumin and creatinine were not significantly altered. However, the concentration of total proteins was significantly increased in the treated group. In conclusion, the aqueous seed extract of P. americana is safe on sub-acute basis but extremely high doses may not be advisable

Increased superoxide dismutase and Na+, K+-ATPase activities in aortic strips from potassium-adapted rats: implication for altered vascular reactivity.

The contributions of superoxide dismutase (SOD) and Na(+), K(+)-ATPase to the altered vascular reactivity in potassium-adapted rats were investigated to test the hypothesis that smooth muscle hyperpolarisation may be involved. Isometric contractions to noradrenaline (NA), 5-hydroxytryptamine (5-HT), and relaxations to acetylcholine (ACh), levcromakalim (LEV) and sodium nitroprusside (SNP), were measured in aortic rings from potassium-adapted rats. Pieces of the aortae were also excised from the animals and assayed for SOD and Na(+), K(+)-ATPase. Maximum contractile responses were significantly attenuated (P<0.05) in aortic rings from the potassium-adapted rats to NA and 5-HT, while relaxations were also significantly augmented (P<0.05) in the same rings to LEV and SNP, but not to ACh. Both SOD and Na(+), K(+)-ATPase activities were significantly higher (P<0.05) in the aortae from the potassium-adapted rats compared to controls. It is concluded that the alteration in vascular smooth muscle reactivity may be due to hyperpolarisation caused by the activities of SOD and Na(+), K(+)-ATPase.