Fazal Subhan

Antispasmodic and bronchodilator activities of St John's wort are putatively mediated through dual inhibition of calcium influx and phosphodiesterase

The crude extract of aerial parts of St Johns wort (Hypericum perforatum) (Hp.Cr) and its fractions were studied in vitro for its possible spasmolytic and bronchodilator activities to rationalize some of its medicinal uses. In rabbit jejunum preparations, Hp.Cr caused a concentration‐dependent relaxation of both spontaneous and K+ (80 mm)‐induced contractions at a similar concentration range (0.1–1.0 mg/mL), similar to that produced by papaverine, whereas verapamil was relatively potent against K+‐induced contractions. Hp.Cr shifted the Ca2+ concentration–response curves (CRCs) to the right, similar to that caused by papaverine or verapamil and also caused leftward shift of isoprenaline‐induced inhibitory CRCs, similar to papaverine. In guinea‐pig tracheal preparations, Hp.Cr caused relaxation of carbachol and K+‐induced contractions at similar concentrations (0.01–0.3 mg/mL) and also shifted the isoprenaline‐induced inhibitory CRCs to the left, similar to that caused by papaverine. In rabbit aorta preparations at rest, Hp.Cr produced a moderate vasoconstriction, while exhibited vasodilator effect against phenylephrine and K+‐induced contractions. Papaverine and verapamil also produced similar non‐specific vasodilation, but were devoid of any vasoconstrictor effect. Hp.Cr caused suppression of atrial force of contractions at concentrations about 20 times higher than those that produced inhibitory effect in smooth muscle preparations, similar to papaverine. These results suggest that the spasmolytic effects of Hp.Cr are mediated through dual inhibition of calcium influx and phosphodiesterase (PDE)‐like mechanisms, which might explain the medicinal use of St Johns wort in the disorders of gastrointestinal and respiratory tracts. Furthermore, the presence of Ca2+ antagonist and PDE inhibitory‐like constituents might also be contributing to some extent in the well established use of plant in depression.

Do antidepressants affect motivation in conditioned place preference

The positive motivational effects of a range of antidepressants/neurotransmitter reuptake inhibitor compounds were studied using conditioned place preference. These agents included amitriptyline (2.5-10 mg/kg), venlafaxine (5 and 10 mg/kg), sibutramine (5 and 10 mg/kg), fluoxetine (2.5-10 mg/kg), paroxetine (5-15 mg/kg) and sertraline (2.5-10 mg/kg). Male Wistar rats were place conditioned in a three-compartment box to vehicle or drug alternately for 8 days using a 30-min pretreatment time. Control animals received vehicle only. Cocaine (5 mg/kg) was used as a positive control for the procedure. Significant place preference (P<0.05) was observed with paroxetine (15 mg/kg), fluoxetine (5 and 10 mg/kg), sertraline (2.5-10 mg/kg) and cocaine. Venlafaxine and sibutramine, serotonin/noradrenaline reuptake inhibitors, produced no place conditioning, while the highest dose of the tricyclic antidepressant, amitriptyline (10 mg/kg), produced signs of place aversion. The role of serotonin in reward pathways and differences in serotonin, noradrenaline and dopamine reuptake-inhibiting properties of these compounds may explain why only the serotonin-selective reuptake inhibitors produced place preference in this study.

Molecularly Characterized Solvent Extracts and Saponins from Polygonum hydropiper L. Show High Anti-Angiogenic, Anti-Tumor, Brine Shrimp, and Fibroblast NIH/3T3 Cell Line Cytotoxicity

Polygonum hydropiper is used as anti-cancer and anti-rheumatic agent in folk medicine. This study was designed to investigate the anti-angiogenic, anti-tumor, and cytotoxic potentials of different solvent extracts and isolated saponins. Samples were analyzed using GC, Gas Chromatography–Mass Spectrometry (GC–MS) to identify major and bioactive compounds. Quantitation of antiangiogenesis for the plants samples including methanolic extract (Ph.Cr), its subsequent fractions; n-hexane (Ph.Hex), chloroform (Ph.Chf), ethyl acetate (Ph.EtAc), n-Butanol (Ph.Bt), aqueous (Ph.Aq), saponins (Ph.Sp) were performed using the chick embryo chorioallantoic membrane (CAM) assay. Potato disc anti-tumor assay was performed on Agrobacterium tumefaciens containing tumor inducing plasmid. Cytotoxicity was performed against Artemia salina and mouse embryonic fibroblast NIH/3T3 cell line following contact toxicity and MTT cells viability assays, respectively. The GC–MS analysis of Ph.Cr, Ph.Hex, Ph.Chf, Ph.Bt, and Ph.EtAc identified 126, 124, 153, 131, and 164 compounds, respectively. In anti-angiogenic assay, Ph.Chf, Ph.Sp, Ph.EtAc, and Ph.Cr exhibited highest activity with IC50 of 28.65, 19.21, 88.75, and 461.53 μg/ml, respectively. In anti-tumor assay, Ph.Sp, Ph.Chf, Ph.EtAc, and Ph.Cr were most potent with IC50 of 18.39, 73.81, 217.19, and 342.53 μg/ml, respectively. In MTT cells viability assay, Ph.Chf, Ph.EtAc, Ph.Sp were most active causing 79.00, 72.50, and 71.50% cytotoxicity, respectively, at 1000 μg/ml with the LD50 of 140, 160, and 175 μg/ml, respectively. In overall study, Ph.Chf and Ph.Sp have shown overwhelming results which signifies their potentials as sources of therapeutic agents against cancer.

Neuroprotective and Anti-Aging Potentials of Essential Oils from Aromatic and Medicinal Plants

The use of essential oils (EOs) and their components is known since long in traditional medicine and aromatherapy for the management of various diseases, and is further increased in the recent times. The neuroprotective and anti-aging potentials of EOs and their possible mechanism of actions were evaluated by numerous researchers around the globe. Several clinically important EOs and their components from Nigella sativa, Acorus gramineus, Lavandula angustifolia, Eucalyptus globulus, Mentha piperita, Rosmarinus officinalis, Jasminum sambac, Piper nigrum and so many other plants are reported for neuroprotective effects. This review article was aimed to summarize the current finding on EOs tested against neurodegenerative disorders like Alzheimer disease (AD) and dementia. The effects of EOs on pathological targets of AD and dementia including amyloid deposition (Aβ), neurofibrillary tangles (NFTs), cholinergic hypofunction, oxidative stress and glutamatergic abnormalities were focused. Furthermore, effects of EOs on other neurological disorders including anxiety, depression, cognitive hypofunction epilepsy and convulsions were also evaluated in detail. In conclusion, EOs were effective on several pathological targets and have improved cognitive performance in animal models and human subjects. Thus, EOs can be developed as multi-potent agents against neurological disorders with better efficacy, safety and cost effectiveness.

Potentiation of opioid-induced conditioned place preference by the selective serotonin reuptake inhibitor fluoxetine.

The ability of the selective serotonin reuptake inhibitor, fluoxetine, to modify the effects of morphine, N-((S)-2-benzyl-3[(S) 2-amino-4-methylthio)butyldithio-]-1-oxopropyl)-L-alanine benzylester (RB 120; mixed inhibitor of enkephalin metabolism), and 4-¿[2-[[3-(1H-indol-3-yl))-2-methyl-1-oxo-2-[[(tricyclo[3,3,1,1] dec-2-yloxy) carbonyl] amino¿ propyl] amino]-1-phenylethyl] amino¿-4-oxo-[R-(R*,R*)]-butanoate N-methyl-D-glucamine (CI 988; cholecystokinin receptor subtype [CCK(2)] antagonist), was assessed using conditioned place preference. RB 120 and morphine both induced significant, dose-dependent conditioned place preference, whilst CI 988 failed to elicit conditioned place preference. A subthreshold dose of fluoxetine (2.5 mg/kg) potentiated the morphine submaximal response. Notably, the combination of a subthreshold dose of fluoxetine (2.5 mg/kg) with RB 120 (5 mg/kg) or CI 988 (3 mg/kg) was devoid of any significant conditioned place preference properties. Fluoxetine may act via enhanced serotonergic activity to modulate enkephalinergic tone. Agents that increase enkephalinergic tone more directly such as RB 120 and CI 988, at submaximal doses, did not induce conditioned place preference when co-administered with fluoxetine. These data suggest that fluoxetine, in combination with CI 988 or RB 120, might prove to be a beneficial treatment strategy for opioid drug addiction, though further studies are necessary.

Terpenoid Content of Valeriana wallichii Extracts and Antidepressant-like Response Profiles

Three extracts of Valeriana wallichii DC (Valerianaceae) rhizome and fluoxetine were studied for antidepressant‐like activity in two behavioral models, namely the forced swim test (FST) and the tail suspension test (TST). Fluoxetine as well as methanolic and aqueous extracts of V. wallichii induced monophasic dose‐related decrements in immobility times in both tests. However, the aqueous‐ethanolic fraction induced a biphasic dose‐response profile since it produced a graded effect up to 200 mg/kg but the highest dose (250 mg/kg) was inactive in the FST. This extract also exhibited significantly reduced activity at 200 mg/kg compared to lower doses in the TST. The highest doses of aqueous‐ethanolic extract also reduced locomotor activity which will have led to a negative functional interaction with antidepressant‐like effects. Qualitative phytochemical analysis revealed that the aqueous‐ethanolic extract of V. wallichii was the only separated rhizome fraction containing terpenoids. Furthermore, since the methanolic and aqueous extracts were active in the tests, it is suggested that the antidepressant‐like action of this herbal plant is not contingent upon its terpenoid constituents. Copyright

A Bacoside Containing Bacopa monnieri Extract Reduces Both Morphine Hyperactivity Plus the Elevated Striatal Dopamine and Serotonin Turnover

Bacopa monnieri (BM) has been used in Ayurvedic medicine as a nootropic, anxiolytic, antiepileptic and antidepressant. An n‐butanol extract of the plant (nBt‐ext BM) was analysed and found to contain Bacoside A (Bacoside A3, Bacopaside II and Bacopasaponin C). The effects of the BM extract were then studied on morphine‐induced hyperactivity as well as dopamine and serotonin turnover in the striatum since these parameters have a role in opioid sensitivity and dependence. Mice were pretreated with saline or nBt‐ext BM (5, 10 and 15 mg/kg, orally), 60 min before morphine administration and locomotor activity was subsequently recorded. Immediately after testing, striatal tissues were analysed for dopamine (DA), serotonin (5HT) and their metabolites using HPLC coupled with electrochemical detection. The results indicated that nBt‐ext BM significantly (p < 0.001) decreased locomotor activity in both the saline and morphine treated groups. Additionally, nBt‐ext BM significantly lowered morphine‐induced dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5‐hydroxyindole acetic acid (5‐H1AA) upsurges in the striatum but failed to affect DA, 5‐HT and their metabolites in the saline treated group. These findings suggest that nBt‐ext BM has an antidopaminergic/serotonergic effect and may have potential beneficial effects in the treatment of morphine dependence. Copyright

Evaluation of antidiabetic and antihyperlipidemic activity of Artemisia indica linn (aeriel parts) in Streptozotocin induced diabetic rats

ETHNOPHARMACOLOGICAL RELEVANCE Diabetes mellitus is a major metabolic disorder affecting a huge population all over the world. Artemisia species have been extensively used for the management of diabetes in folkloric medicine. The present study is designed to investigate the antidiabetic and antihyperlipidemic effects of aeriel parts of Artemisia indica. MATERIALS AND METHODS Hydromethanolic crude extracts, chloroform, ethyl acetate and n-butanol fractions of aerial parts of Artemisia indica were tested for their antidiabetic potential in Streptozotocin (STZ) (50mg/kg, i.p.) induced diabetic Sprague-Dawley rats. Blood glucose level, body weight, serum lipid profile and activities of liver enzymes were determined. The extracts were further subjected to preliminary phytochemical analysis. RESULTS A daily oral dose of hydromethanolic crude extracts (200 and 400mg/kg b.w.) and chloroform fraction (200mg/kg b.w.) of Artemisia indica for 15 days showed a significant reduction in blood glucose level which was comparable to that of the standard antidiabetic drug, glibenclamide (500 μg/kg, p.o.). Artemisia indica extracts also showed reduction in total cholesterol, triglycerides and low density lipoproteins as well as serum creatinine level, serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT) and alkaline phosphatase (ALP) in diabetic rats. CONCLUSION According to the results Artemisia indica possesses hypoglycemic, antihyperlipidemic and valuable effects on liver and renal functions in diabetic rats, which seems to validate its traditional usage.

Anti-Alzheimer’s Studies on β-Sitosterol Isolated from Polygonum hydropiper L.

The family Polygonaceae is known for its traditional use in the management of various neurological disorders including Alzheimer’s disease (AD). In search of new anti-AD drugs, β-sitosterol isolated from Polygonum hydropiper was subjected to in vitro, in vivo, behavioral and molecular docking studies to confirm its possibility as a potential anti-Alzheimer’s agent. The in vitro AChE, BChE inhibitory potentials of β-sitosterol were investigated following Ellman’s assay. The antioxidant activity was tested using DPPH, ABTS and H2O2 assays. Behavioral studies were performed on a sub-strain of transgenic mice using shallow water maze (SWM), Y-maze and balance beam tests. β-sitosterol was tested for in vivo inhibitory potentials against cholinesterase’s and free radicals in the frontal cortex (FC) and hippocampus (HC). The molecular docking study was performed to predict the binding mode of β-sitosterol in the active sites of AChE and BChE as inhibitor. Considerable in vitro and in vivo cholinesterase inhibitory effects were observed in the β-sitosterol treated groups. β-sitosterol exhibited an IC50 value of 55 and 50 μg/ml against AChE and BChE respectively. Whereas, the activity of these enzymes were significantly low in FC and HC homogenates of transgenic animals. Molecular docking studies also support the binding of β-sitosterol with the target enzyme and further support the in vitro and in vivo results. In the antioxidant assays, the IC50 values were observed as 140, 120, and 280 μg/ml in the DPPH, ABTS and H2O2 assays respectively. The free radicals load in the brain tissues was significantly declined in the β-sitosterol treated animals as compared to the transgenic-saline treated groups. In the memory assessment and coordination tasks including SWM, Y-maze and balance beam tests, β-sitosterol treated transgenic animals showed gradual improvement in working memory, spontaneous alternation behavior and motor coordination. These results conclude that β-sitosterol is a potential compound for the management of memory deficit disorders like AD.

Effect of fasting during Ramadan on serum lithium level and mental state in bipolar affective disorder.

The Muslims fast every year during the month of Ramadan. A fasting day can last 12–17 h. The effects of fasting on serum lithium levels and the mood changes in patients suffering from bipolar affective disorder during Ramadan are not well studied. We aimed to compare the serum lithium levels, side effects, toxicity and mental state in patients suffering from bipolar affective disorder and on prophylactic lithium therapy before, during and after Ramadan. Sixty-two patients meeting the International Classification of Diseases, Tenth Revision, Research Diagnostic Criteria of bipolar affective disorder receiving lithium treatment for prophylaxis were recruited in a tertiary care teaching hospital in Peshawar, Pakistan. Serum lithium, electrolytes, Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were assessed at three points, 1 week before Ramadan, midRamadan and 1 week after Ramadan. The side effects and toxicity were measured by a symptoms and signs checklist. There was no significant difference in mean serum lithium levels at three time points (preRamadan=0.45±0.21, midRamadan=0.51±0.20 and postRamadan=0.44±0.23 milli equivalents/litre, P=0.116). The scores on HDRS and YMRS showed significant decrease during Ramadan (F=34.12, P=0.00, for HDRS and F=15.6, P=0.000 for YMRS). The side effects and toxicity also did not differ significantly at three points. In conclusion, the patients who have stable mental state and lithium levels before Ramadan can be maintained on lithium during Ramadan. Fasting in an average temperature of 28°C for up to 12 h per day did not result in elevated serum lithium levels or more side effects and did not have adverse effects on mental state of patients suffering from bipolar affective disorder.