An evaluation of the efficacy of monensin against Fasciola hepatica in the albino rat

The in vivo efficacy of monensin against Fasciola hepatica was determined in the albino rat. The results were variable, with monensin generally showing greater activity against juvenile (two-week-old) than adult (12-week-old) flukes. Significant (p less than 0.005) reductions in worm burdens were obtained only following treatment of adult flukes with 2 X 10 mg/kg monensin (52.9% efficacy), and of juvenile flukes with 1 X 10 mg/kg (42.4% efficacy) and 2 X 10 mg/kg (56.23% efficacy). Monensin administered in the diet (200 ppm) had a negligible effect on juvenile and adult fluke burdens. Prophylactic treatment of rats with monensin (100 ppm) produced a 45.5% efficacy, but this was not statistically significant. At doses of 1 X 5 mg/kg and 2 X 2.5 mg/kg, monensin had little effect on egg output by F. hepatica. No clear relationship was established between egg output and worm burden, and so faecal egg counting was not a reliable indicator of fluke burdens in the rat.     

Endothelin-induced sudden death and the possible involvement of platelet activating factor (PAF)

Endothelin (5 nmol/kg, i.v.) caused a transient hypotension followed by a lasting hypertension in rats. However, an abrupt fall in the blood pressure was observed in most rats 6 to 30 min after the injection of endothelin and sudden death followed with lethality noted over 60 min. An abnormal electrocardiogram (ECG) (ventricular arrhythmias) was observed in rats injected with endothelin. Endothelin (i.v.) also caused sudden death in mice. Pretreatment (5 or 60 min) with specific PAF antagonists, CV-6209 (0.1-3 mg/kg, i.v.) and WEB 2086 (30 mg/kg, p.o.), and a calcium channel blocker, diltiazem (60 mg/kg, p.o.) prevented death and attenuated the ECG changes induced by endothelin, but CV-6209 did not prevent the blood pressure changes induced by endothelin. CV-6209 (0.5-3 mg/kg, i.v.), WEB 2086, diltiazem and dexamethasone (5 mg/kg, i.v.) protected mice against the death induced by endothelin. On the other hand, aspirin (cyclooxygenase inhibitor, 100 mg/kg, p.o.) did not protect mice from the death. Thus, endothelin is a highly toxic peptide with cardiotoxic effects, and PAF may be involved in the pathogenesis of the sudden death.     

Effects of six fasciolicides against Fascioloides magna In white-tailed deer

Thirty-three white-tailed deer (Odocoileus virginianus) of various ages, both sexes, and in good physical condition were captured for anthelmintic evaluation of six compounds against the large American liver fluke, Fascioloides magna. Based on fluke mortality, hexachlorophene administered at the rate of 12 to 26 mg/kg of body weight was lethal to 5 of 10 mature flukes in seven deer. Nitroxynil at 11 to 24 mg/kg inhibited egg production, but did not kill mature flukes in eight deer. Rafoxanide at 12 to 25 mg/kg killed 6 of 8 (75%) immature flukes in eight deer, but was not effective against 17 mature flukes. Clioxanide at 16 to 38 mg/kg, diamphenethide at 255 to 280 mg/kg, and hexachloroethane at 463 to 629 mg/kg were not effective against F. magna in four, two and four deer, respectively. There was no indication that treatment with fasciolicides at the higher dose rates was more efficacious than at the lower dose rates. Detection of fluke eggs in the feces was a reliable method for diagnosing the presence of mature F. magna in deer prior to treatment, but was not reliable for measuring fasciolicidal activity of all compounds tested.     

Are all "cytoprotective" drugs gastroprotective?

The effect of three--structurally different--groups of compounds was compared against gastric mucosal damages induced by ethanol or prostaglandin (PG) synthesis inhibitors, as well as against carrageenan-induced inflammation. All the compounds studied--SH-compounds (cysteamine, 2,3-dimercaptosuccinic acid, D,L-penicillamine), SH-blocking N-ethylmaleimide (NEM) and morphine-exerted dose-dependent inhibition on carrageenan edema test and against ethanol-induced gastric damage. Mucosal lesions induced by PG synthesis inhibitors (indomethacin 20 mg/kg, naproxen 75 mg/kg, piroxicam 60 mg/kg) were inhibited by drugs studied when the compounds were given before the damaging agents. However, when the drugs were injected 1 h after the inhibitors of PG synthesis opposite actions were observed; SH-compounds exerted protective, while NEM (2 mg/kg p.o.) and morphine (5 mg/kg p.o.) aggravating action. The results suggest that: 1. SH-compounds might have therapeutic importance in the treatment of gastric damage induced by prostaglandin synthesis inhibitors. 2. Reconsideration of the use of the term "cytoprotection" is necessary, since "cytoprotective" agents may aggravate mucosal damage in other ulcer model.     

Sister-chromatid exchange in spleenic lymphocytes of mice after exposure to nifurtimox or benznidazole

The induction of sister-chromatid exchange (SCE) was analyzed in spleenic lymphocytes of mouse after exposure to nifurtimox (NFX) or benznidazole (BZ). Lymphocytes from Swiss mice treated "in vivo" with 1200 and 2000 mg/kg NFX (p.o.) and then incubated "in vitro" with bromo-2'-deoxyuridine showed an increased frequency of SCE. No significant differences were observed in mice treated with 2000 mg/kg BZ (p.o.). The present and previous results obtained in this and other laboratories suggest that the effects observed should warn against the potential risk of NFX treatment in humans receiving this chemotherapeutic agent as a treatment for Chagas' disease.     

Role of Brain Regional GABA: Aldrin-Induced Stimulation of Locomotor Activity in Rat

Aldrin, a chlorinated hydrocarbon group of pesticide, is a well known central nervous system (CNS) stimulant. The CNS stimulating effect of aldrin is manifested in the form of an increase in locomotor activity (LA) of animals. Maximum increase in LA was observed at 2 h following aldrin (2-10 mg/kg, p.o.) treatment and this aldrin-induced increase in LA attained a peak at a dose of 10 mg/kg, p.o. Administration of aldrin (2 or 5 mg/kg/day, p.o.) enhanced LA of rats and reached a maxima after 12 consecutive days of treatment following which aldrin-induced LA was gradually reduced and restored to control value after 20 consecutive days of aldrin treatment. A single administration of aldrin (2-10 mg/kg, p.o.) reduced the GABA system in cerebellum, hypothalamus and pons-medulla. The treatment with aldrin (2 mg/kg/day, p.o.) for 12 consecutive days produced more inhibition in those brain regional GABA system than that observed with a single dose of aldrin. These results, thus, suggest that aldrin-induced inhibition of central GABA may be a cause of stimulation of LA with aldrin either at a single dose or for 12 consecutive days.     

Micronucleus test with 6-mercaptopurine monohydrate administered intraperitoneally and orally

The effect of route of administration on the induction of micronucleated polychromatic erythrocytes (MNPCEs) was examined. 6-Mercaptopurine monohydrate (6-MP) was administered intraperitoneally (i.p.) or orally (p.o.) to 2 strains of mice, MS/Ae and CD-1. From the results of an acute toxicity test and a pilot micronucleus test, the doses selected for the final micronucleus test were 12.5-100 mg/kg for the i.p. route and 25-200 mg/kg for the p.o. route. The sampling time was 48 h. Frequencies of MNPCEs increased dose-dependently by the i.p. route but peaked at 50 or 100 mg/kg for the p.o. route. 6-MP induced MNPCEs more efficiently after p.o. administration than after i.p. treatment in both strains.     

Hypoglycemic effect of Sclerocarya birrea {(A. Rich.) Hochst.} [Anacardiaceae] stem-bark aqueous extract in rats

This study was undertaken to evaluate the hypoglycemic effect of Sclerocarya birrea [(A. Rich.) Hochst.] subspecies caffra (Sond.) Kokwaro [family: Anacardiaceae] stem-bark aqueous extract in normal (normoglycemic) and in streptozotocin (STZ)-treated, diabetic Wistar rats. In one set of experiments, graded doses of S. birrea stem-bark aqueous extract (SB, 100-800 mg/kg p.o.) were separately administered to groups of fasted normal and fasted diabetic rats. In another set of experiments, a single dose of the plant aqueous extract (SB, 800 mg/kg p.o.) was used. The hypoglycemic effect of this single dose (SB, 800 mg/kg p.o.) of S. birrea stem-bark aqueous extract was compared with that of chlorpropamide (250 mg/kg p.o.) in both fasted normal and fasted diabetic rats. Following acute treatment, relatively moderate to high doses of S. birrea stem-bark extract (SB, 100-800 mg/kg p.o.) produced dose-dependent, significant reductions (P < 0.05-0.001) in the blood glucose concentrations of both fasted normal and fasted diabetic rats. Chlorpropamide (250 mg/kg p.o.) also produced significant reductions (P < 0.05-0.001) in the blood glucose concentrations of the fasted normal and fasted diabetic rats. Administrations of the single dose of S. birrea stem-bark aqueous extract (SB, 800 mg/kg p.o.) significantly reduced (P 0.01 < 0.001) the blood glucose levels of both fasted normal (normoglycemic) and fasted STZ-treated, diabetic rats. The results of this experimental animal study indicate that aqueous extract of Sclerocarya birrea possesses hypoglycemic activity, and thus lend credence to the suggested folkloric use of the plant in the management and/or control of adult-onset, type-2 diabetes mellitus in some African communities.     

In vitro and in vivo leishmanicidal activity of Dysoxylum binectariferum and its fractions against Leishmania donovani

The leishmanicidal effect of crude ethanolic extract of stem bark of Dysoxylum binectariferum and its fractions has been investigated against Leishmania donovani, the causative agent of visceral leishmaniasis. Ethanolic extract was lethal to promastigotes as well as amastigote forms in macrophage system at the concentration of 100 microg/ml. Chloroform fraction significantly inhibited promastigote multiplication and was also active against amastigotes in infected J774A.1 macrophages at 100 microg/ml. Hexane fraction was moderately active and the other fractions were inactive against both the forms. When tested in vivo in hamsters, ethanolic extract was toxic at 500 mg/kg whereas exhibited marginal activity (67.7+/-5.3%) at 250 mg/kg x 5, p.o. on day 7 post treatment (p.t.) which increases slightly (69+/-4.7) by day 30 p.t. Chloroform and n-hexane fractions exhibited 64.3+/-4% and 47.8+/-4.6% parasite inhibition at the dose of 100 mg/kg x 5 p.o., respectively. The pure compound, rohitukine, obtained from chloroform fraction showed weaker in vitro activity and was ineffective in infected hamsters. The lead potential of this plant need further investigations.     

Ramelteon (TAK-375) accelerates reentrainment of circadian rhythm after a phase advance of the light-dark cycle in rats

In vivo pharmacological effects of ramelteon (TAK-375), a novel, highly MT1/MT2-selective receptor agonist, were studied in rats to determine ramelteon's ability to reentrain the circadian rhythm after an abrupt phase advance. Experiments were also conducted to assess the potential cognitive side effects of ramelteon and its potential to become a drug of abuse. After an abrupt 8-h phase shift, ramelteon (0.1 and 1 mg/kg, p.o.) and melatonin (10 mg/kg, p.o.) accelerated reentrainment of running wheel activity rhythm to the new lightdark cycle. Ramelteon (3-30 mg/kg, p.o.) and melatonin (10-100 mg/kg, p.o.) did not affect learning or memory in rats tested by the water maze task and the delayed match to position task, although diazepam and triazolam impaired both of the tasks. Neither ramelteon (3-30 mg/kg, p.o.) nor melatonin (10-100 mg/kg, p.o.) demonstrated a rewarding property in the conditioned place-preference test, implying that MT1/MT2 receptor agonists have no abuse potential. In contrast, benzodiazepines and morphine showed rewarding properties in this test. The authors' results suggest that ramelteon may be useful for treatment of circadian rhythm sleep disorders without adverse effects typically associated with benzodiazepine use, such as learning and memory impairment, and drug dependence.     

Involvement of nitric oxide in the gastroprotective effects of an aqueous extract of Pfaffia glomerata (Spreng) Pedersen, Amaranthaceae, in rats

The plants belonging to Pfaffia genus are used in folk medicine to treat gastric disturbances. This study examined the effects of an aqueous extract of Pfaffia glomerata (Spreng) Pedersen (AEP) on the gastrointestinal tract. Wistar rats were pretreated orally (p.o.) with the AEP (125, 250, 500 and 1000 mg.kg(-1)) before induction of ulcers by hypothermic restraint stress (HRS, 3 h restraint stress at 4 degrees C), ethanol (ET, 70%; 0.5 ml/animal; p.o.) or indomethacin (IND, 20 mg.kg(-1); s.c.). Control animals received water (C) or ranitidine (60 mg.kg(-1)) p.o. The AEP protected rats against HRS and ET-induced ulcers, but was not able to protect the gastric mucosa against IND-induced ulcers. When injected into the duodenal lumen, the AEP reduced total acidity and both basal and histamine-stimulated acid secretion in pylorus-ligated rats. In addition, gastric secretion from AEP-treated animals exhibited increased concentrations of nitrite and nitrate. Treatment of animals with L-NAME (120 mg.kg(-1), p.o.) prevented both the reduction of total acidity and the increase in NOx levels promoted by AEP treatment. In conclusion, AEP effectively protected the gastric mucosa and inhibited gastric acid secretion in rats, probably by involving the histaminergic pathway and an enhanced production of nitric oxide in the stomach.     

Behavioral effects of sinomenine in murine models of anxiety

The present study was designed to investigate the putative anxiolytic-like effect of sinomenine in three experimental models of anxiety in male rats and mice. Use of the elevated plus-maze test revealed that sinomenine (20 and 40 mg/kg, p.o.) increased the percentage of open arm entries and diazepam (2 mg/kg, p.o.) increased the percentage of open arm entries, the percentage of time spent on open arms and total arm entries in mice. In the light/dark transition test, sinomenine (20 and 40 mg/kg, p.o.) increased time spent in the light area and diazepam (2 mg/kg, p.o.) increased time spent in the light area and the overall movements in mice. In the social interaction test, the sinomenine-treated animals significantly increased social interaction time in low light unfamiliar (7 mg/kg, p.o.) and high light unfamiliar conditions (7 and 14 mg/kg, p.o.) as well as diazepam (3 mg/kg, p.o.). Sinomenine (28 mg/kg, p.o.) can also decrease squares entered in rats in social interaction test under low light unfamiliar condition. In the open-field test, sinomenine (160 mg/kg) decreased squares entered in mice. Thus, these findings indicated that sinomenine exhibited anxiolytic-like effect.     

Efficacy of triclabendazole against natural infections of Fascioloides magna in wapiti.

Fourteen free-ranging adult wapiti (Cervus elaphus nelsoni) were captured in Banff National Park, Alberta (Canada) and held in captivity near Edmonton. A 24% suspension of triclabendazole at doses of 30 to 100 mg/kg body weight was drenched into the rumen of eight females and four males. Two male wapiti were used as untreated controls. Animals were killed and examined at 4 (n = 3), 6 (n = 4), or 8 (n = 4) wk after treatment. Efficacy was 90% against immature Fascioloides magna collected 4 wk after treatment and 98% against adult flukes collected 4, 6 or 8 wk after treatment. All 32 flukes recovered from control wapiti were active and apparently healthy. Treatment at 50 to 60 mg/kg is recommended against F. magna in wapiti. A protocol for treating infected wapiti is outlined.     

Evaluation of the antinociceptive action caused by ether fraction and a triterpene isolated from resin of Protium kleinii.

This study investigates the antinociception caused by i.p. and p.o. administration of ether fraction and the triterpene identified as urs-12-ene-3beta-16beta-diol, known as Brein, isolated from Protium kleinii in several models of nociception in mice. The systemic administration of ether fraction (0.3 to 10 mg/kg, i.p. or 3 to 60 mg/kg, p.o.) caused a dose-related antinociception when assessed against acetic acid-induced writhing, with mean ID50 values of 1.2 and 16.4 mg/kg, respectively. The ether fraction (5 to 60 mg/kg, i.p. or 30 to 300 mg/kg, p.o.) also produced dose-related inhibition of both phases of formalin induced licking. The mean ID50s values for the early phase were > 60.0 and 62.1 mg/kg, while for the late phase they were 15.4 and 60.0 mg/kg, respectively, given by i.p. and p.o. routes. The ether fraction (3 to 30 mg/kg, i.p. or 10 to 100 mg/kg, p.o.) produced significant inhibition of the neurogenic nociception caused by topical injection of capsaicin, with mean ID50 values of 6.2 and 16.0 mg/kg, respectively. Given orally (1 to 30 mg/kg) the ether fraction produced graded and pronounced inhibition of glutamate-induced hyperalgesia in mice with a mean ID50 value of 15.2 mg/kg. In contrast, the ether fraction failed to produce antinociception when assessed in the thermal model of pain, the tail flick and hot plate tests. The antinociception caused by the ether fraction, in contrast to that of morphine, was not reversed by naloxone when assessed in the formalin-induced licking. The ether fraction did not affect motor coordination or the core body temperature in mices. The triterpene Brein isolated from P. kleinii, given by i.p. route (10 to 100 mg/kg) produced dose-related inhibition of both phases of formalin induced-licking, with mean ID50s values of 15.3 and 20.6 for the early and the late phases, respectively. These data show that the active principle(s) present in the ether fraction from the resin of P. kleinii elicited pronounced antinociception when assessed by i.p. or p.o routes, against both inflammatory and neurogenic nociception. Such effects seem, at least in part, to be related to the presence of the triterpene Brein in the extract. The mechanisms responsible for the antinociceptive action are at this moment not completely understood, but the involvement of the opioid pathway seems unlikely.     

Effect of pentylenetetrazol on the carbaryl-induced changes of serotonin metabolism in rat-brain hypothalamus

Carbaryl (200 mg/kg or 400 mg/kg, p.o.) significantly elevated serotonin (5-HT) (57–109%) and 5-hydroxy-indoleacetic acid (5-HIAA) (60–78%) levels at 1.0 h in the hypothalamic region of adult male rat brain. Further, administration of carbaryl (200 mg/kg, p.o.) for different time intervals (0.5 h, 1.0 h, and 2.0 h) revealed that both 5-HT and 5-HIAA levels elevated maximally at 0.5 h in hypothalamus. These regional 5-HT and 5-HIAA levels were not significantly affected with pentylenetetrazol (PTZ) at any time after its treatment. But simultaneous administration of carbaryl (200 mg/kg, p.o.) and PTZ (60 mg/kg, s.c.) reduced the carbaryl-induced elevation of both 5-HT and 5-HIAA leveis. Measurement of (i) probenecid-induced (200 mg/kg, i.p.) accumulation and (ii) pargyline-induced (75 mg/kg, i.p.) depletion of hypothalamic 5-HIAA level in the absence or presence of carbaryl (200 mg/kg, p.o.) and/or PTZ (60 mg/kg, s.c.) revealed that (a) carbaryl enhanced the synthesis as well as the breakdown of 5-HT, (b) PTZ had no effect on either of these processes of 5-HT, and (c) carbaryl-induced increased catabolism of 5-HT became normal in the presence of PTZ.     

Repeated treatment with imipramine, fluvoxamine and tranylcypromine decreases the number of escape failures by activating dopaminergic systems in a rat learned helplessness test.

Chronic administration of antidepressants has been shown to reduce the number of escape failures in the rat learned helplessness test (LH). In the present study we investigated the role of D1, D2 and D3 receptors in mediating this effect. In our first series of experiments, we demonstrated that SKF38393, D1 receptor agonist, in a dose of 2.5 mg/kg (i.p.) and quinpirole, D2 receptor agonist in a dose of 0.5 mg/kg (i.p.), significantly decreased the number of escape failures in LH, and these were reversed by SCH23390 (0.015 mg/kg), D1 receptor antagonist, and by sulpiride (25 mg/kg), D2 receptor antagonist, respectively. In contrast, 7-OH-DPAT, a D3 receptor agonist, in a dose of 10 mg/kg (i.p.) did not affect the number of escape failures in LH. In a second series of experiments, we showed that eight days of repeated treatment with imipramine (10 mg/kg, p.o.), fluvoxamine (1.25 mg/kg, p.o.) and tranylcypromine (1.25 mg/kg, p.o.) significantly decreased the number of escape failures in LH. The decrease in escape failures seen with use of imipramine and tranylcypromine was reversed by sulpiride in LH, but not by SCH23390. On the other hand, the effect of fluvoxamine was reversed by both SCH23390 and sulpiride. These findings indicate that stimulation of D1 and D2 receptors decreased the number of escape failures in LH, respectively. Thus, D2 and/or D1 receptors are probably involved in the decreased number of escape failures in case of repeated treatment with antidepressants in LH.     

Dehydroevodiamine.HCl prevents impairment of learning and memory and neuronal loss in rat models of cognitive disturbance

We previously reported that dehydroevodiamine.HCl (DHED) has anticholinesterase and antiamnesic activities. To verify the effects of DHED on cognitive deficits further, we tested it on the scopolamine-induced amnesia model of the rat using the passive avoidance and eight-arm radial maze tests. A single (20 mg/kg p.o.) and repeated (10 mg/kg p.o.) administrations of DHED could significantly reverse the latency time shortened by scopolamine (1 mg/kg i.p.) to control level. The impaired spatial working memory induced by scopolamine (1 mg/kg i.p.) was also improved significantly by a single injection (6.25 mg/kg i.p.) and repeated administrations of DHED (10 mg/kg p.o.) in the eight-arm radial maze test. In addition, we examined the effects of DHED on the memory impairment and the histological changes of the brain after unilateral electrolytic lesion of the entorhinal cortex (EC) and middle cerebral artery occlusion in rats. The cognitive deficits caused by EC lesion and middle cerebral artery occlusion were improved significantly by repeated administrations of DHED (6.25 mg/kg i.p.) after EC lesion or ischemic insult once a day for 7 days in the passive avoidance test. Histological analysis showed that the neuronal loss in the DHED-treated group was notably reduced in the hippocampal area (CA1) of ischemic rats and in the dentate gyrus and hippocampal area (CA1 and CA3) of EC-lesioned rats compared with the nontreated group. The infarction area was decreased significantly by a single administration of DHED (6.25 mg/kg i.p.) 30 min before ischemic insult for 6 h. These results suggest that DHED might be an effective drug for not only the Alzheimer's disease type, but also the vascular type of dementia.     

Modification of the adjuvans arthritis by carrageenin, compound 48/80, histamine- and serotonin antagonists, non-steroid antiphlogistics as well as protease inhibitors and their possible relations to inflammation mediators]

1. Injections of carrageenin (1,25 mg/kg i.v.) from the 1st to the 3rd day and then each 2nd or 3rd day inhibited paw swelling in adjuvant arthritis of the rat during the time of treatment. Injections from the 11th to the 15th day were ineffective. The level of plasma kininogen was slightly decreased but the total complement serum level was significantly lowered. 2,5 and 3 mg carrageenin/kg respectively were toxic after repeated injections. After a single administration the levels of plasma kininogen and of total serum complement were decreased by 50% although paw swelling was not affected. 2. Pentosane polysulfoester (25 mg/kg i.v.) did not influence paw swelling despite daily administration from the 1st to the 17th day. Heparin (10 000 IE/kg i.v.) was likewise ineffective. 3. Single or repeated injections of compound 48/80 (0,125-0,5 mg/kg i.v.; 1-5 mg/kg i.p.; 3-6 mg/kg s.c.), reserpine (0,2 mg/kg i.p.), cyproheptadine (5 mg/kg i.v.), bromolysergic acid diethylamide (2 x 2 mg/kg i.v.) or metiamide (10 mg/kg i.v.) were without effect on paw swelling. Neither did compound 48/80 effect the complement serum level. 4. Daily administration of chloropromazine (4-10 mg/kg p.o.) or of promethazine (10-15 mg/kg s.c. or p.o.) inhibited paw swelling in the first phase of adjuvant arthritis but not in the second one. 5. The soybean trypsin inhibitor (15 mg/kg i.v.) inhibited paw swelling significantly up to the 4th day, the Kunitz inhibitor (25 000 E/kg i.v.) was ineffective. 6. The content of prostaglandin E of the inflamed paws was increased threefold in both phases of arthritis. The results are discussed with regard to the putative role of mediators of inflammation (histamine, serotonin, kinins, prostaglandins, lysosomal enzymes, lymphokines, complement).     

Effects of methylenechloride-soluble fraction of Japanese angelica root extract,ligustilide and butylidenephthalide,on pentobarbital sleep in group-housed and socially isolated mice

We previously showed that the extract of Japanese angelica root (JAR-E) reversed the decrease in pentobarbital (PB) sleep induced by isolation stress and yohimbine and methoxamine, stimulants of central noradrenergic systems, in mice. Here, we tested the effects of several fractions from JAR-E and ligustilide and butylidenephthalide, phthalide components of JAR-E, on PB sleep in isolated mice to elucidate the mechanism of the action of JAR-E. Methanol-soluble (Met-S) and -insoluble (Met-IS) fractions were obtained from JAR-E. Methylenechloride-soluble (MC-S) and -insoluble fractions (MC-IS) were prepared from Met-S. MCS (11.4–76 mg/kg, p.o.) reversed the isolation stress-induced decrease in PB sleep, but neither Met-IS (0.8–2.4 g/kg, p.o.) nor MC-IS (0.7–2 g/kg, p.o.) had the same effect. The i.p. administration of MC-S exhibited a similar activity to that observed after the p.o. administration of the same fraction. Ligustilide (5–20 mg/kg, i.p.) and butylidenephthalide (10–30 mg/kg, i.p.) reversed PB sleep decrease in isolated mice. Both components (20 mg/kg, i.p.) attenuated the suppressive effects of yohimbine (30 nmol, i.c.v.), methoxamine (200 nmol, i.c.v.) and a benzodiazepine inverse agonist FG7142 (10 mg/kg, i.p.) on PB sleep in group-housed mice. These results suggest the contribution of ligustilide and butylidenephthalide to the effect of JAR-E on PB sleep in isolated mice, and implicate central noradrenergic and/or GABA_a systems in the effects of these components.     

Prophylactic and Therapeutic Potential of Acetyl‐l‐carnitine against Acetaminophen‐Induced Hepatotoxicity in Mice

Prophylactic and therapeutic effects of acetylcarnitine against acetaminophen‐induced hepatotoxicity were studied in mice. To evaluate the prophylactic effects of acetylcarnitine, mice were supplemented with acetylcarnitine (2 mmol/kg/day per oral (p.o.) for 5 days) before a single dose of acetaminophen (350 mg/kg intraperitoneal (i.p.)). Animals were sacrificed 6 h after acetaminophen injection. Acetaminophen significantly increased the markers of liver injury, hepatic reactive oxygen species, and nitrate/nitrite, and decreased hepatic glutathione (GSH) and the antioxidant enzymes. Acetylcarnitine supplementation resulted in reversal of all biochemical parameters toward the control values. To explore the therapeutic effects of acetylcarnitine, mice were given a single dose of acetylcarnitine (0.5, 1, and 2 mmol/kg p.o.) 1.5 h after acetaminophen. Animals were sacrificed 6 h after acetaminophen. Acetylcarnitine administration resulted in partial reversal of liver injury only at 2 mmol/kg p.o. At equimolar doses, N‐acetylcystiene was superior as therapeutic agent to acetylcarnitine. However, acetylcarnitine potentiated the effect of N‐acetylcystiene in the treatment of acetaminophen toxicity.