Hypoglycaemic and anti-diabetic activity of stem bark extracts Erythrina indica in normal and alloxan-induced diabetic rats

The objective of the study is to investigate the alcoholic (AlcE) and aqueous (AqsE) extracts of stem bark of Erythrina indica (Papilionaceae) for hypoglycaemic effects in normal and diabetic rats. Diabetes was induced in rats by a single dose administration of alloxan (120 mg/kg, i.p.) or by injecting dexamethasone (10 mg/kg, i.p.) for 10 days. In normal rats, AlcE and AqsE had significantly decreased the blood glucose level (BGL) in a dose dependent manner after repeated administration for 7 days. In alloxan-induced diabetic rats, both the extracts decreased blood sugar levels with significant improvement in glucose tolerance and body weight at the end of 1st, 2nd and 3rd week after test extract treatment. In case of dexamethasone induced insulin resistant diabetic rats, repeated administration of AlcE and AqsE inhibited the increase in blood glucose level and improved glucose tolerance induced by dexamethasone as compared to dexamethasone induced diabetic rats. These results suggest that both extracts possess hypoglycaemic activity in normal as well as in diabetic rats. Among AlcE and AqsE, AqsE possesses better hypoglycaemic activity than AlcE in all the models. Preliminary phytochemical investigations revealed that alcoholic extracts contain carbohydrates, alkaloids, flavonoids, saponins, phytosterols, phenolics and tannins. Aqueous extract contains carbohydrates, alkaloids, flavonoids, glycosides, phytosterols and triterpenoids. These phytoconstituents may be responsible for the hypoglycaemic activity of the plant.     

The mechanism of the hypothermic effect of amantadine in rats and mice

Amantadine (25–100 mg kg^?1, i.p.) given to rats at an ambient temperature of 4°, or mice at 21°, caused a marked fall in rectal temperature. Prior administration of pimozide (1–2 mg kg^?1, s.c.) did not block hypothermia due to amantadine in rats or mice; in contrast, hypothermia due to apomorphine (2 mg kg^?1, i.p.) and piribedil (10–40 mg kg^?1, i.p.) in rats was blocked by pimozide pretreatment. Amphetamine (5 mg kg^?1, i.p.) given 2 h after reserpine (2 mg kg^?1, i.p.) caused a reversal of the hypothermic effect of reserpine in mice, but a reversal was not obtained with amantadine (50 mg kg^?1, i.p.). Direct injection of amantadine (4–8 mg kg^?1) into the cerebral ventricles (i.c.v.) of mice caused marked hypothermia which was not blocked by pimozide, but intravenous injection of the same dose of amantadine did not cause hypothermia. Rimantadine, a congener of amantadine but without anti-parkinsonian activity, also caused pimozide insensitive hypothermia in mice at doses of 50 mg kg^?1, intraperitoneally or 2–4 mg kg^?1, intracerebroventricularly. The main conclusion drawn from these results is that in causing hypothermia amantadine acts in the cns but not on dopamine receptors.     

The Effect on Plasma Glucose,Insulin and Glucagon Levels of Treatment of Diabetic Rats with the Medicinal Plant Rhazya stricta and with Glibenclamide,Alone and in Combination

Because many diabetic patients in the United Arab Emirates use medicinal plants as a supplement to treatment with insulin or oral hypoglycaemic agents, the effect on plasma glucose, insulin and glucagon concentrations of simultaneous treatment of streptozotocin-diabetic rats with Rhazya stricta extract and glibenclamide has been examined. Treatment of control rats with the extract at oral doses of 0.5, 20 and 4.0 g kg^? did not significantly affect the concentration of glucose, insulin or glucagon for up to 4 h after administration of the extract. The same doses in diabetic rats reduced the glucose level 1 h (2 and 4 gkg^?) and 2h (4 gkg^?) after administration of the extract. This was accompanied by significant increases in insulin concentration 1, 2 and 4 h after administration of the extract at doses of 2 and 4 gkg^?. Glibenclamide (2.5, 5.0 and 10.0 mgkg^?) dose-dependently reduced glucose and glucagon levels, and increased that of insulin in normal and diabetic rats. Simultaneous treatment of normal and diabetic rats with the plant extract (0.5, 20 and 5.0 gkg^?) and glibenclamide (5.0 mg kg^?) significantly exacerbated the effects on glucose, insulin and glucagon induced by the extract or by glibenclamide when given separately. When the plant extract was given at doses of 0.5, 2 and 4 g kg^? per day for 6 consecutive days the glucose level was reduced by approximately 6, 8 and 30%, respectively. No significant effect was seen on the levels of cholesterol or protein. These results imply that co-administration of the extract with glibenclamide might adversely interfere with glycaemic control in diabetic patients.     

The novel nootropic compound DM232 (UNIFIRAM) ameliorates memory impairment in mice and rats

The favorable pharmacological profile exhibited by piracetam stimulated the synthesis of related compounds potentially endowed with a higher nootropic potency. The antiamnesic and procognitive activity of DM232 (unifiram), a new compound structurally related to piracetam, was investigated. Mouse passive avoidance and rat Morris water maze and Social learning tests were employed. DM232 (0.001–1 mg kg^?1 i.p. – 0.01–0.1 1 mg kg^?1 p.o.) prevented amnesia induced by scopolamine (1.5 mg kg^?1 i.p.), mecamylamine (20 mg kg^?1 i.p.), baclofen (2 mg kg^?1 i.p.), and clonidine (0.125 mg kg^?1 i.p.). Furthermore, The antiamnesic effect of the investigated compound was comparable to that exerted by well‐known nootropic drugs such as piracetam (30–100 mg kg^?1 i.p.), aniracetam (100 mg kg^?1 p.o.), rolipram (30 mg kg^?1 p.o.), and nicotine (5 mg kg^?1 i.p). DM232 (0.1 mg kg^?1 i.p.) was also able to prevent amnesia induced by scopolamine (0.8 mg kg^?1 i.p.) in the rat Morris watermaze test. In the rat social learning test, DM232 (0.1 mg kg^?1 i.p.) injected in adults rats reduced the duration of active exploration of the familiar partner in the second session of the test. DM232, similarly to piracetam, reduced the duration of hypnosis induced by pentobarbital. At the highest effective doses, the investigated compound did not impair motor coordination (rota rod test), nor modified spontaneous (Animex). These results indicate DM232 (unifiram) as a novel cognition enhancer, strictly related to piracetam‐like compounds, able to ameliorate memory impairment at doses about 1,000 times lower than the most active available nootropic compounds. Drug Dev. Res. 56:23–32, 2002. © 2002 Wiley‐Liss, Inc.     

Behavioural Profile of Two Potential Antidepressant Pyridazine Derivatives Including Arylpiperazinyl Moieties in Their Structure,in Mice

The potential antidepressant effects of two pyridazine derivatives, 5-benzyl 6-methyl 2-[4-(3-trifluoro-methyl phenyl) piperazin-1-yl] methylpyridazin-3-one (PC4) and 5-benzyl 6-methyl 2-[4-(3-chlorophenyl) piperazin-1-yl] methylpyridazin-3-one (PCI3), were evaluated using classical psychopharmacological tests in mice. The intraperitoneal LD50 values of PC4 and PC13 were respectively 1125·8 and 429-6mg kg^?1. Only at intraperitoneal doses of 100mg kg^?1 did PC4 or PC13 significantly decrease locomotor activity. Both compounds (5–20 mg kg^?1, i.p.) reduced the duration of immobility of mice in the forced swimming test, antagonized reserpine (2–5 mg kg^?1, i.p.)-induced ptosis, and potentiated reserpine (2–5 mg kg^?1, i.p.)-induced hypothermia. PC4 and PCI3 (20mg kg^?1, i.p.) partly reversed hypothermia induced by low dose apomorphine (5 mg kg^?1, s.c.) but were less effective for higher doses of apomorphine (16 mg kg^?1, s.c). At 200 mg kg^?1, intraperitoneal PC13 enhanced the toxic effects of yohimbine (30 mg kg^?1, s.c), while PC4 was inactive. Head twitches produced either by L-5-hydroxytryptophan (4 mg kg^?1, i.p.) in mice pretreated with pargyline (100mg kg^?1, i.p.) or by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3 mg kg^?1, i.p.) were antagonized by both pyridazine derivatives (20 mg kg^?1, i.p.). PC4 and PC13 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (50 < ED50 < 5-5mg kg^?1, i.p.) and in the hot-plate test (10 to 37% of analgesia at 10 mg kg^?1, i.p.). These antinociceptive effects were not significantly diminished by naloxone (1 mg kg^?1, i.p.). Furthermore, acute intraperitoneal administration of both compounds (20 mg kg^?1 for PC4 and 5mg kg^?1 for PC13) potentiated morphine (7–5 mg kg^?1, s.c.) analgesia in the hot-plate test. Thus, these results suggest that PC4 and PC 13 possess potential antidepressant effects related to different aminergic mechanisms, especially at the 5-HT₂ receptor level.     

Evaluation of antidiabetic properties of cactus pear seed oil in rats

Context: Cactus pear (Opuntia ficus-indica (L.) Mill. (Cactaceae)) is a medicinal plant widely used to treat diabetes.

Objective: This work investigates the hypoglycemic and antihyperglycemic effect of cactus pear seed oil (CPSO), its mechanism of action, and any toxic effects.

Materials and methods: The hypoglycemic effect of CPSO was evaluated in groups of six healthy Wistar rats given 1 or 2?ml?kg^?1 orally and compared with groups receiving glibenclamide (2?mg?kg^?1) or water. Glycemia was determined after 30, 60, 120, 240, and 360?min. The antihyperglycemic effect of CPSO was determined in healthy rats and in streptozotocin-induced diabetic rats (STZ); normal rats received 0.8?ml?kg^?1 CPSO, while diabetic rats received 1?ml?kg^?1 CPSO, their controls received water or 2?mg?kg^?1 glibenclamide. For the antihyperglycemic effect evaluation, all the animals were fasted for 16?h before treatment and received glucose orally at 1?g?kg^?1 30?min after treatment; blood was taken after 30, 90, 150, and 210?min. Intestinal glucose absorption was estimated in rat jejunum perfused with a solution containing 5.55?mmol?l^?1 glucose. Acute toxicity was determined in albino mice that received oral or intraperitoneal doses of 1, 3, or 5?ml?kg^?1 CPSO.

Results: CPSO (p.o.) decreased postprandial hyperglycemia (60?min after glucose loading), 40.33% and 16.01%, in healthy and STZ-diabetic glucose-loaded rats, respectively. CPSO, also, significantly decreased intestinal glucose absorption by 25.42%. No adverse effects were seen in mice administered CPSO at up to 5?ml?kg^?1.

Conclusion: CPSO is antihyperglycemic. The effect can be explained partly by inhibition of intestinal glucose absorption.     

Evaluation of BTS 67 582, a novel antidiabetic agent,in normal and diabetic rats

1. The effect of BTS 67 582, a novel antidiabetic agent, has been evaluated on plasma glucose and plasma insulin in normal and streptozotocin-induced diabetic rats.
2. BTS 67 582 (3 to 300 mg kg⁻¹, p.o.) caused a dose- and time- dependent reduction in plasma glucose and an increase in plasma insulin in both fasted and glucose-loaded normal rats. The ED₅₀ for the glucose lowering effect of BTS 67 582 in fasted rats was 37.6, 18.4 and 18.5 mg kg⁻¹ at 1, 2 and 4 h after administration respectively.
3. In streptozotocin-induced (50 mg kg⁻¹, i.v.) diabetic rats, BTS 67 582 (37–147 mg kg⁻¹, p.o.) caused significant reductions of plasma glucose following a glucose load, whereas glibenclamide (100 mg kg⁻¹, p.o.) was ineffective. BTS 67 582 significantly increased plasma insulin compared to controls whereas glibenclamide did not.
4. BTS 67 582 did not displace [³H]-glibenclamide from its binding sites in rat brain, guinea-pig ventricle or the HIT-T15 insulinoma β-cell line. BTS 67 582 does not therefore appear to modulate its action via an effect on the ‘sulphonylurea'' receptor.
5. In fasted rats, the glucose lowering effect of BTS 67 582 (100 mg kg⁻¹ p.o.) and glibenclamide (1 mg kg⁻¹, p.o.) were antagonized by diazoxide (30 mg kg⁻¹, i.p.). In addition BTS 67 582, like glibenclamide, caused a dose-dependent rightward shift of cromakalim-induced relaxation of noradrenaline precontracted rat aortic strips, suggesting the involvement of K_ATP channels.
6. In summary, BTS 67 582 produces a blood glucose-lowering effect in normal and streptozotocin-induced diabetic rats associated with increased insulin concentrations. This effect appears to be due to a blockade of ATP-sensitive potassium channel activity via a different binding site to that of glibenclamide.

     

Alagebrium attenuates acute methylglyoxal-induced glucose intolerance in Sprague-Dawley rats

Background and purpose:

Alagebrium is a breaker of cross-links in advanced glycation endproducts. However, the acute effects of alagebrium on methylglyoxal (MG), a major precursor of advanced glycation endproducts have not been reported. MG is a highly reactive endogenous metabolite, and its levels are elevated in diabetic patients. We investigated whether alagebrium attenuated the acute effects of exogenous MG on plasma MG levels, glucose tolerance and distribution of administered MG in different organs in Sprague-Dawley rats.

Experimental approach:

We measured MG levels (by HPLC), glucose tolerance, adipose tissue glucose uptake, GLUT4, insulin receptor and insulin receptor substrate 1 (IRS-1) protein expression, and phosporylated IRS-1 in rats treated with MG at doses of either 17.25 mg·kg⁻¹ i.p. (MG-17 i.p.) or 50 mg·kg⁻¹ i.v. (MG-50 i.v.) with or without alagebrium, 100 mg·kg⁻¹ i.p.

Key results:

Alagebrium attenuated the increased MG levels in the plasma, aorta, heart, kidney, liver, lung and urine after MG administration. In MG-treated rats, glucose tolerance was impaired, plasma insulin levels were higher and insulin-stimulated glucose uptake by adipose tissue was reduced, relative to the corresponding control groups. In rats treated with MG-50 i.v., GLUT4 protein expression and IRS-1 tyrosine phosphorylation were decreased. Alagebrium pretreatment attenuated these effects of MG. In an in vitro assay, alagebrium reduced the amount of detectable MG.

Conclusions and implications:

Alagebrium acutely attenuated MG-induced glucose intolerance, suggesting a possible preventive role for alagebrium against the harmful effects of MG.     

Ameliorative effect of Aegle marmelos leaf extract on early stage alloxan-induced diabetic cardiomyopathy in rats

Objective: The pathogenesis of diabetic cardiomyopathy (DCM) is complex, and the therapeutic options available to treat DCM are limited. The present study was designed to investigate the effect of Aegle marmelos (L.) Correa (Rutaceae) leaf extract on early stage DCM in alloxan-induced diabetic rats.

Methods: Diabetes was induced in Wistar rats (150–200?g) by injecting alloxan (150?mg kg^?1; i.p.). Ethanol extract of A. marmelos leaves was administered at varying doses (100, 200, and 400?mg kg^?1) and tolbutamide (100?mg kg^?1) as standard. Fasting blood glucose (FBG), total cholesterol, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), lactate dehydrogenase (LDH) and creatine kinase (CK) were determined by standard methods.

Results: A. marmelos extract (AME) was found to decrease the levels of FBG, total cholesterol, TBARS, LDH and CK, and increase the levels of GSH, CAT and SOD dose dependently as compared to diabetic control groups. The maximum dose-dependent decrease in TBARS (63.46%), LDH (34.04%), CK (53.14%), and increase in GSH (64.91%), CAT (59.34%), SOD (69.65%) was evident at an optimum dose of 200?mg kg^?1. Histopathological studies revealed salvage in the morphological derangements as indicated by absence of necrosis and marked decrease in inflammatory cells in AME-treated groups as compared to diabetic control.

Conclusions: The present investigations conclude that treatment with AME attenuates the severity and improves the myocardium in the early stages of alloxan-induced DCM at a dose of 200?mg kg^?1.     

Chronic Administration Does Not Alter the Pharmacokinetic Profile of l-Dopa in the Rat

Abstract— Chronic administration of l-dopa (200 mg kg^?1 day^?1 for 12 months) plus carbidopa (25 mg kg^?1 day^?1) or carbidopa (25 mg kg^?1 day^?1) alone did not alter the t½, AUC_0–∞ k₁₀, k₁₂, k₂₁, CL_p or Vd_ss of l-dopa following intra-aortic (i.a.) administration (50 mg kg^?1) alone or after carbidopa (25 mg kg^?1, i.p.) pretreatment, or the t½, AUC_0–∞, t_max or the bioavailability (F) of l-dopa (50 mg kg^?1) administered orally, alone or after acute pretreatment with carbidopa (25 mg kg^?1 i.p.). The peripheral metabolism of l-dopa was unaltered by chronic administration of l-dopa plus carbidopa or carbidopa alone as measured by unaltered AUC_{0·360 min} for 3-O-methyldopa, dopamine, DOPAC or homovanillic acid in the plasma of rats following acute administration of l-dopa (50 mg kg^?1, p.o. or i.a.) alone or following pretreatment with carbidopa, and unaltered hepatic dopa decarboxylase activity.     

Comparative study of the antagonism of bemegride and picrotoxin on behavioural depressant effects of diazepam in rats and mice

Experiments carried out on rats and mice showed that bemegride and diazepam acted as antagonists. Bemegride (at doses ranging from 4 to 16 mg.kg^?1 i.p.) counteracted diazepam (8 mg.kg^?1 i.p.)-induced hypokinesia and amnesic-like activity, diazepam (4 mg.kg^?1 i.p.)-induced motor inco-ordination and diazepam (2 mg.kg^?1 i.p.)-induced reduced grip strength. A GABA receptor blocking agent, picrotoxin (2–4 mg.kg^?1 i.p.) also markedly antagonized all (except for hypokinesia) these diazepam effects. Diazepam (1. 2, 4, 8 mg.kg^?1 i.p.) exerted similar dose-related antagonisms on bemegride (24 mg.kg^?1 i.p.) and on picrotoxin (8 mg.kg^?1 i.p.)-induced seizures. Both antagonisms were observed at lower doses than were required for strychnine (6 mg.kg^?1 i.p.)-induced seizures inhibition. Picrotoxin/ diazepam antagonism seems to further support the possibility of a gabaminergic mechanism of action of benzodiazepines depressant effects. Bemegride/diazepam antagonism is discussed in terms of a possible inhibitory role of bemegride on gabaminergic transmission.     

Vitis vinifera L. grape skin extract activates the insulin-signalling cascade and reduces hyperglycaemia in alloxan-induced diabetic mice

Objectives This study examined the effect of Vitis vinifera grape skin extract (ACH09) on hyperglycaemia and the insulin‐signalling cascade in alloxan‐treated mice. Methods Glycaemia, serum insulin and Western blot analysis of insulin cascade proteins were evaluated in the gastrocnemius muscles of four groups of adult mice: control, ACH09 (200 mg/kg per day, p.o.), alloxan (300 mg/kg, i.p.) and alloxan + ACH09. Insulin secretion in isolated pancreatic islets was also studied. Key findings Glycaemia values in the alloxan + ACH09 and ACH09 groups were significantly lower than in the alloxan‐treated and control groups, respectively. Increased insulin resistance (HOMA index) was observed in the alloxan‐treated group but not in the alloxan + ACH09 group. Insulin receptor content and Akt phosphorylation were significantly greater in the alloxan + ACH09 group compared with the alloxan‐treated group. The glucose transporter (GLUT‐4) content was reduced in alloxan‐treated mice compared with the control group, while alloxan + ACH09 and ACH09‐treated mice showed a significant increase in GLUT‐4 content. ACH09 treatment did not change glucose‐induced insulin secretion in isolated pancreatic islets. Conclusions The results suggest that ACH09 has hypoglycaemic and antihyperglycaemic effects that are independent of an increase in insulin release but are probably dependent on an increase in insulin sensitivity resulting from an activation of the insulin‐signalling cascade in skeletal muscle.     

N‐acetylcysteine improves renal hemodynamics in rats with cisplatin‐induced nephrotoxicity

This work investigated the effect of N‐acetylcysteine (NAC), on renal hemodynamics in cisplatin (CP)‐induced nephrotoxicity in Wistar–Kyoto (WKY) rats. The animals were divided into four groups (n = 5 or 6). The first and second groups received normal saline (control) and intraperitoneal (i.p.) N‐acetylcysteine (500 mg kg^?1 per day for 9 days), respectively. The third and fourth groups were given a single intraperitoneal (i.p.) injection of CP (5 mg kg^?1) and an i.p. injection of CP (5 mg kg^?1) together with i.p. NAC (500 mg kg^?1 per day for 9 days), respectively. At the end of the experiment, rats were anesthetized and blood pressure and renal blood flow were monitored, followed by intravenous (i.v.) injection of norepinephrine (NE) for measurement of renal vasoconstrictor responses. CP caused a significant reduction in renal blood flow but did not affect NE‐induced renal vasoconstriction. In addition, CP significantly increased plasma concentrations of urea and creatinine and urinary N‐acetyl‐β‐D ‐glucosaminidase (NAG) activity and kidney relative weight. CP decreased body weight and creatinine clearance. Histopathologically, CP caused remarkable renal damage compared with control. NAC alone did not produce any significant change in any of the variables measured. However, NAC significantly ameliorated CP‐induced hemodynamic, biochemical and histopathological changes. The concentration of platinum in the kidneys of CP ? NAC treated rats was less than in CP‐treated rats by 37%. The results show that administration of i.p. NAC (500 mg kg^?1 per day for 9 days) reversed the renal hemodynamic changes as well as the biochemical and histopathological indices of CP‐induced nephrotoxicity in WKY rats. Copyright © 2009 John Wiley & Sons, Ltd.     

Mechanisms Involved in the Antinociceptive Effect in Mice of the Hydroalcoholic Extract of Siphocampylus verticillatus

The antinociception caused by the hydroalcoholic extract of Siphocampylus verticillatus (Campanulaceae) has been investigated in chemical and thermal models of nociception in mice. We have also assessed some of the mechanisms underlying the antinociceptive effect of the extract. The hydroalcoholic extract of S. verticillatus (60–1000 mg kg^?1, i.p. or p.o.) produced dose-related, significant and long-lasting (6 to 8 h) inhibition of acetic acid-induced abdominal constriction in mice, with ID50 values of 204 and ～1000 mg kg^?1, respectively. In the formalin test, the extract (100–1000 mg kg^?1), given either intraperitoneally or orally, resulted in graded inhibition of both phases of formalin-induced pain, being about 2- to 4-fold more potent in attenuating the second phase of the pain. The calculated mean ID50 (mg kg^?1) values for the earlier and the later phases were: 491 and 186 and 640 and 441, respectively. In addition, the extract (60–1000 mg kg^?1, i.p. or p.o.) caused marked and dose-related inhibition of capsaicin-induced neurogenic pain with mean ID50 values of 420 and 485 mg kg^?1, respectively. The hydroalcoholic extract, at the same doses, did not significantly affect the performance of animals in the rota-rod test, nor did it have any analgesic effect in the tail-flick or hot-plate tests. The treatment of animals with naloxone (5 mg kg^?1, s.c.) significantly reversed the analgesic effect of both morphine (5 mg kg^?1, s.c.) and the extract (300 mg kg^?1, i.p.) when assessed against acetic acid-induced abdominal constrictions. The treatment of animals with l-arginine (600 mg kg^?1, i.p.) significantly attenuated the antinociceptive effects of N^G-nitro-l-arginine (l-NOARG) (75 mg kg^?1, i.p.), of the hydroalcoholic extract (600 mg kg^?1, i.p.) or of morphine (5 mgkg^?1, s.c.), when analysed against the formalin test. In addition, adrenalectomy of animals 7 days before the tests significantly reversed the antinociception caused by the hydroalcoholic extract (300 mg kg^?1, i.p.) in the formalin-induced pain. These data show that the hydroalcoholic extract of S. verticillatus has significant and long-lasting oral antinociception when assessed against both neurogenic and inflammatory models of nociception in mice. The precise mechanism responsible for the analgesic effect of the extract still remains unclear, but a great part of this effect seems to be partly related to an opioid-like action and involvement of the l-arginine-nitric oxide pathway. Finally, the antinociception caused by the hydroalcoholic extract of S. verticillatus is modulated by adrenal hormones.     

Central and Cardiovascular Effects of the Alcoholic Extract of the Leaves of Carica papaya

Abstract

The central effects of an alcoholic extract of Carica papaya leaf were investigated in male rats. The extract (≥ 10 mg kg^?1, i.p.) induced a dose-dependent sedative effect. The extract (≥ 5 mg kg, i.p.) also induced central muscle relaxation. The behavioral effects of the extract were associated with an initial desynchronization of the electroencephalogram (EEG) and an increased activity of the electromyogram (EMG). This was followed by a deactivating pattern in the optic chiasma while the EMG activity was diminished. The extract at doses ≥50 mg kg^?1 (i.p.) completely protected the rats against pentylenetetrazol-induced seizures, while doses of 5 mg kg^?1 (i.p.) gave 50% protection. The extract at doses of 100 and 200 mg kg^?1 (i.p.) also gave 100% protection against maximal electroshock-induced convulsions.     

Differential effects of adrenaline and noradrenaline on the hepatic expression of immediate early genes in mice

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Glibenclamide Antagonizes the Inhibitory Effect of Morphine on Gall Bladder Emptying

Egg yolk-induced gall-bladder emptying in mice was used to investigate the effect of glibenclamide and minoxidil (ATP-dependent K⁺-channel modulators) on biliary tract effects of morphine. The inhibitory effect of morphine (1–4 mg kg^?l, i.p.) on egg yolk-induced gall-bladder emptying was completely blocked by pretreatment with naloxone (2 mg kg^?l, i.p.) or glibenclamide (0.65 mg kg^?l, i.p.) whereas, pretreatment with minoxidil (0.65 mg kg^?1, i.p.) did not modify the inhibitory effect of morphine on gall-bladder emptying. Our results suggest that biliary-tract actions of morphine are mediated through glibenclamide-sensitive K⁺ channels similar to those involved in the analgesic action of morphine.     

Potent Antinociceptive Activity of a Hydroalcoholic Extract of Phyllanthus corcovadensis

Abstract— This study analyses the analgesic effect of a hydroalcoholic extract (HE) from Phyllanthus corcovadensis in several models of pain in mice. HE (3–60 mg kg^?1, i.p.) or (100–500 mg kg^?1, p.o.) caused a graded and potent analgesic effect against the abdominal constriction response caused by acetic acid and acetylcholine with an ID50 of about 3 and 100 mg kg^?1, respectively. In the tail-flick model HE (up to 500 mg kg^?1, p.o.) was without effect, while morphine (1–10 mg kg^?1, s.c.) caused a graded increase in pain latency (ID50, 3 mg kg^?1). HE (1–300 mg kg^?1) given both intraperitoneally and orally caused a potent and graded inhibition of the second phase of formalin-induced persistent pain in mice with an ID50 of 1 and 80 mg kg^?1, respectively. In contrast, morphine (1–5 mg kg^?1, s.c.) inhibited both phases of formalin-induced pain with an ID50 of 2·5 mg kg^?1. Indomethacin (1–10 mg kg^?1, i.p.) only inhibited the second phase of formalin-induced pain with an ID50 of about 3 mg kg^?1. The analgesic effect of indomethacin, but not that caused by morphine and HE was accompanied by a graded inhibition of formalin-induced mouse paw oedema. In addition, HE up to 1 g kg^?1 failed to prevent carrageenan- and dextran-induced rat hindpaw oedema. It is concluded that HE exhibits a potent antinociceptive profile, either when given intraperitoneally or orally. The mechanisms that underly its analgesic effect are unclear at present, but appear to be unrelated to inhibition of synthesis of arachidonic acid via cyclo-oxygenase or to activation of opioid receptors.     

An α-adrenoceptor-mediated mechanism of hypoactivity induced by β-amyrin palmitate

Abstract— Inhibitory effects of β-amyrin palmitate in locomotor activity of mice were studied by combining this compound with α-adrenergic agonists or antagonists and a dopaminergic agonist. β-Amyrin palmitate (2·5, 5·0 and 10·0 mg kg^?1, i.p.) decreased locomotor activity of mice in a dose-dependent manner. It enhanced hypoactivity of mice treated with clonidine (0·025 mg kg^?1, i.p.) and antagonized hyperactivity produced by phenylephrine (40 μg, i.c.v.). The inhibitory action of β-amyrin palmitate was not affected by yohimbine (1·5 mg kg^?1, i.p.), but was potentiated by prazosin (0·75 mg kg^?1, i.p.). When combined with a dopaminergic agonist, apomorphine (2·0 mg kg^?1, i.p.), β-amyrin palmitate (5·0 and 10·0 mg kg^?1, i.p.) did not affect locomotor stimulation produced by apomorphine. These results suggest that β-amyrin palmitate might inhibit α₁-adrenoceptors.     

Changes in vascular reactivity in experimental hypertensive animals following treatment with indapamide

Indapamide at doses of 8–16 mg kg^?1 day^?1, orally, lowered arterial blood pressure (9–26 mm Hg) in conscious renal hypertensive cats during a two week treatment period. The antihypertensive effect was sustained for 5–7 h after dosing and was not accompanied by reflex tachycardia. Antihypertensive responses to injection of clonidine (20 μg, i.c.v.) were significantly enhanced one week after the completion of indapamide treatment but had returned to normal two weeks later. In DOCA/saline hypertensive rats, administration of indapamide 10 mg kg^?1 day^?1, orally, or hydrochlorothiazide, 5 mg kg^?1 day^?1, intraperitoneally, for 10 days produced similar falls in blood pressure (40–45 mm Hg) as measured by an indirect method. Pressor responses to intravenous noradrenaline or tyramine or electrical stimulation of the sympathetic outflow in the pithed rat preparation were much reduced by pretreatment with indapamide (10 mg kg^?1, orally) for 10 days. However, cardiovascular reactivity was unaffected by hydrochlorothiazide pretreatment (5 mg kg^?1 day^?1, i.p.). Isolated perfused mesenteric artery***/preparations from indapamide-treated rats showed no changes in reactivity to noradrenaline, 5-hydroxytryptamine or adenosine-5′-triphosphate from those of control DOCA/saline hypertensive rats. Isolated portal veins from rats pretreated with indapamide showed contractile responses to noradrenaline similar to those of control animals although the frequency of spontaneous contractions was reduced in the former group. The results support a vascular site of action for indapamide and suggest a mode of action different from that of hydrochlorothiazide.