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PubMed2005

[Protective effects of ligustrazine against photoreceptor cell injury induced by N-methyl-N-nitrosourea and its mechanism].

AIM: To study the protective effect of ligustrazine against photoreceptor cell injury induced by N-methyl-N-nitrosourea (MNU) in Sprague-Dawley (SD) rats. METHODS: Ligustrazine injections of different doses were injected intraperitoneally into 47-day female SD rats once a day and a single intraperitoneal injection of MNU 60 mg x kg(-1) was given to 50-day rats. At different intervals after MNU treatment,the animals were sacrificed. The apoptotic index of photoreceptor cells was calculated by TUNEL labeling at 24 h following MNU treatment; peripheral retinal damage was evaluated based on retinal thickness at the d 7 after MNU treatment, and the expression of c-jun and c-fos genes was detected by RT-PCR technique. RESULTS: Ligustrazine injection could remarkably increase total thickness of peripheral retina and decrease apoptotic index of photoreceptor cells induced by MNU in a dose-dependent manner. Compared with MNU-treated rats, the gene expression of c-jun and c-fos was time-dependently down-regulated in ligustrazine-treated group. CONCLUSION: Ligustrazine injection partially protects against MNU-induced retinal damage by down-modulating the expression of c-jun and c-fos genes to inhibit apoptosis of photoreceptor cells.

Animals↗
PubMedDate not supplied

Protection by polyI:polyC against infection with herpes simplex virus in mice pretreated with Corynebacterium parvum.

The effect of Corynebacterium parvum on the protection by polyinosinic-polycytidylic acid (polyI:polyC) against lethal infection with Herpes simplex virus type 1 (HSV) was studied in mice. Pretreatment with C. parvum resulted in prolonged survival times in all experiments. One third of the mice survived an infection with 100 LD50, whereas all mice died when treated with polyI:polyC alone. Increased protection was observed up to 6 weeks after pretreatment and only seen when both C. parvum and polyI:polyC were given at the same site of injection (intraperitoneally). Protection against HSV correlated with increased interferon (IFN) activities induced by polyI:polyC in the peritoneal cavity of C. parvum-pretreated mice. In these mice, natural killer cell activity of peritoneal exudate cells (PEC) was also augmented in response to polyI:polyC. Protection was markedly decreased by intraperitoneal injection of silica or of an antiserum against murine IFN. It appears that increased local levels of IFN presumably produced by macrophages in response to polyI:polyC in C. parvum-pretreated mice play the major role in the antiviral defence in our model and that activation of NK cells may be a secondary effect of IFN.

Adjuvants, Immunologic↗
PubMed1994

[In vivo study of the antilipoperoxidant effect of 3',5,7-trihydroxy-4'-methoxy flavone 7 rutinoside].

In 3-month-old Wistar rats carrageenan and CCl4 injected intraperitoneally induce an acute phase reaction which is characterized by a marked increase in alpha 1, alpha 2, beta serum globulins. This reaction corresponds to a large increase in these globulins in the first case and a smaller one in the second. A lipoperoxidant effect is demonstrated by the serum lipoprotein mobility as the lipoperoxidation index (in MDA units) or the decrease in serum vitamin A and E concentrations. This effect is also greater in the first case than in the second one. In the same way the lipoperoxidant effect is shown in liver microsomes but with a lower amplitude in the first case than in the second one. The treatment of rats by intraperitoneal injection of diosmine (150 mg/kg per week) during the 8 weeks which precede the injection of carrageenan or CCl4 results in: i) a marked decrease in the acute-phase reaction and a lower one in the lipoperoxidant effect, in serum; ii) a decrease in the CCl4 induced lipoperoxidant effect in liver microsomes. It may be concluded that diosmine, not injected at the same time as carrageenan or CCl4, but during the previous 8 weeks is sufficiently well distributed in the whole body to produce a marked inhibition of the acute phase reaction and a perceptible effect on lipoperoxidation. It may be considered an effective complement to the natural antioxidant defences of the organism (vitamins A and E).

Acute-Phase Reaction↗
PubMedDate not supplied

[Comparative assessment of antioxidant activity of para-aminobenzoic acid and emoxipin in retina].

Effect of para-aminobenzoic acid (PABA) on lipid peroxidation (LPO) in rat and guinea pig retina exposed to hypoxic hypoxia is studied. PABA was injected intraperitoneally and parabulbarly before and after hypoxic exposure. Antioxidant activities of PABA and emoxipin were compared. An intraperitoneal injection of PABA in a dose of 10 mg/kg 24 h before hypoxia virtually completely prevented accumulation of lipid peroxides and preserved catalase activity in the retina. Parabulbar injection of 0.01% PABA solution 1 h before hypoxia prevented LPO intensification, stabilized catalase activity in hypoxia, and protected the retina starting from the moment immediately after hypoxic exposure. The efficacy of 0.01% PABA is comparable with that of 1% emoxipin, and a 0.01% solution of emoxipin is less effective than PABA in the same concentration. PABA exerts an antioxidant effect after hypoxia by decreasing the abnormally high level of lipid peroxides and reducing catalase activity in the retina after parabulbar injection of the drug. All the studied concentrations of the drug (from 0.007 to 0.08%) are active, but the optimal dose for the retina is 0.04%. By its efficacy this concentration is equivalent to 1% emoxipin.

4-Aminobenzoic Acid↗
PubMed1999

Divergent effects of intracerebroventricular and peripheral leptin administration on feeding and hypothalamic neuropeptide Y in lean and obese (fa/fa) Zucker rats.

Leptin inhibits feeding and decreases body weight. It may act partly by inhibiting hypothalamic neurons that express neuropeptide Y, a powerful inducer of feeding and obesity. These neuropeptide Y neurons express the Ob-Rb leptin receptor and are overactive in the fatty (fa/fa) Zucker rat. The fa mutation affects the extracellular domain of the leptin receptor, but its impact on leptin action and neuropeptide Y neuronal activity is not fully known. We compared the effects of three doses of leptin given intracerebroventricularly and three doses of leptin injected intraperitoneally on food intake and hypothalamic neuropeptide Y mRNA, in lean and fatty Zucker rats. In lean rats, 4-h food intake was reduced in a dose-related fashion (P<0.01) by all intracerebroventricular leptin doses and by intraperitoneal doses of 300 and 600 microg/kg. Neuropeptide Y mRNA levels were reduced by 28% and 21% after the highest intracerebroventricular and intraperitoneal doses respectively (P<0. 01 for both). In fatty rats, only the highest intracerebroventricular leptin dose reduced food intake (by 22%; P<0. 01). Neuropeptide Y mRNA levels were 100% higher in fatty rats than in lean animals, and were reduced by 18% (P<0.01) after the highest intracerebroventricular leptin dose. Intraperitoneal injection had no effect on food intake and neuropeptide Y mRNA. The fa/fa Zucker rat is therefore less sensitive to leptin given intracerebroventricularly and particularly intraperitoneally, suggesting that the fa mutation interferes both with leptin's direct effects on neurons and its transport into the central nervous system. Obesity in the fa/fa Zucker rat may be partly due to the inability of leptin to inhibit hypothalamic neuropeptide Y neurons.

Animals↗
PubMed1995

Changes in eating behavior and thermogenic activity following inhibition of nitric oxide formation.

The effects of the inhibition of nitric oxide (NO) production on eating behavior and thermogenesis were evaluated in the present experiments. NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO production, was injected intraperitoneally or intracerebroventricularly, and food intake, oxygen consumption rate, and interscapular brown adipose tissue (BAT) temperature were evaluated in conscious rats. The firing rate of sympathetic nerves innervating interscapular BAT was recorded in urethan-anesthetized animals. L-NAME, intraperitoneally injected, decreased food intake, oxygen consumption, temperature, and firing rate of sympathetic nerves innervating interscapular BAT. Intracerebroventricular injection of L-NAME decreased food intake and enhanced oxygen consumption, temperature, and firing rate of sympathetic nerves innervating BAT. The latter changes were similar to those found after lateral hypothalamic lesions. The opposite changes in oxygen consumption, temperature, and sympathetic activity of BAT that followed L-NAME injection through the two different routes were probably due to different effects of the molecule on sympathetic output. Impaired brain production of NO, which followed intracerebroventricular L-NAME, directly increased sympathetic activity, whereas the same activity that followed intraperitoneal L-NAME was depressed by increased blood pressure, which was elicited by the impaired peripheral production of NO.

Adipose Tissue, Brown↗
PubMed1993

Possible explanations for the antagonism by nicotine against reserpine-induced depletion of monoamines in mouse brain.

The inhibitory effect of nicotine pretreatment on reserpine-induced depletion of monoamines in mouse brain was investigated. The depletion of brain monoamines by 24 h after intraperitoneal injection of reserpine (2 mg/kg) was dose-dependently inhibited by nicotine (0.3-10 mg/kg, s.c.) pretreatment 20 min before reserpine injection. This effect of nicotine was more marked on dopamine depletion than on noradrenaline or 5-hydroxytryptamine depletion. The nicotine pretreatment also inhibited the reserpine-induced hypothermia and decrease in the locomotor activity. When reserpine (2 mg/kg) was injected intraperitoneally, the inhibitory effect of nicotine (3 mg/kg, s.c.) on the reserpine-induced depletion of brain monoamines and heart noradrenaline was not antagonized by hexamethonium (8 mg/kg, s.c.) but rather potentiated by mecamylamine (2 mg/kg, s.c.). However, when reserpine (0.5 mg/kg) was injected intravenously, pretreatment with nicotine (3 mg/kg, s.c.) inhibited the reserpine-induced dopamine depletion only, and this effect of nicotine was completely blocked by mecamylamine but not by hexamethonium. These results suggest that inhibitory effect of nicotine on the intraperitoneal reserpine-induced depletion of brain monoamines is due to an inhibition of absorption of reserpine, and that central nicotinic action is also involved in the antagonism by nicotine of reserpine-induced dopamine depletion.

Animals↗
PubMed1996

Effect of magnesium sulfate on excitatory amino acid receptors in the rat brain. I. N-methyl-D-aspartate receptor channel complex.

OBJECTIVE: Our purpose was to determine the effect of peripherally administered magnesium sulfate on the N-methyl-D-aspartate receptor channel complex in the rat central nervous system. STUDY DESIGN: Six rats were injected intraperitoneally with 270 mg/kg magnesium sulfate, followed by 27 mg/kg every 20 minutes for 4 hours. Controls (n = 6) received saline solution. Six rats received intraperitoneal injections of magnesium sulfate (270 mg/kg) every 4 hours for 24 hours and 6 received saline solution. Six rats received intraperitoneal magnesium sulfate (270 mg/kg) every 12 hours for 2 weeks and 6 received saline solution. Rats were subsequently perfused and killed and their brains dissected and frozen. Cryostate sections were taken, labeled in vitro by one of three ligands for autoradiography assay, and mounted on tritium-sensitive film for 4 weeks. The ligands were tritiated glutamate agonist, N-methyl-D-aspartate binding site; tritiated glycine agonist, glycine binding site; and tritiated MK-801 noncompetitive antagonist, channel site. Optical density measurements of binding of 11 brain regions on each section were performed with an image analyzing system. RESULTS: N-methyl-D-aspartate receptor binding in the hippocampus was higher than in all other brain regions in all three experiments. Systemic administration of magnesium sulfate for 24 hours resulted in reduced tritiated glutamate binding, whereas long-term administration (2 weeks) resulted in significantly decreased tritiated glycine binding in all brain regions sampled. Binding of tritiated MK-801 was significantly increased in both short- and intermediate-term administration of magnesium sulfate. CONCLUSIONS: These data suggest that short-term magnesium sulfate administration results in increased inhibition of the ion channel. This effect is also continued with prolonged treatment, along with decreased sensitivity of the N-methyl-D-aspartate receptor channel complex to its agonists glutamate and glycine. This proposed time-dependent, twofold effect may provide insight into the mechanisms of magnesium sulfate's central anticonvulsant effect.

Animals↗
PubMed1996

Effect of magnesium sulfate on excitatory amino acid receptors in the rat brain. II. Kainate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors.

OBJECTIVE: Our purpose was to determine the effect of peripherally administered magnesium sulfate on kainate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in the rat brain. STUDY DESIGN: Six rats were injected intraperitoneally with 270 mg/kg magnesium sulfate, followed by 27 mg/kg every 20 minutes for 4 hours. Controls (n = 6) received saline solution. Six rats received intraperitoneal injections of magnesium sulfate (270 mg/kg) every 4 hours for 24 hours and six received saline solution. Then 6 rats received intraperitoneal magnesium sulfate (270 mg/kg) every 12 hours for 2 weeks and six received saline solution. Rats were subsequently perfused and killed; their brains were dissected and frozen. Cryostat sections were labeled in vitro for autoradiography assay. The ligands used were tritiated kainate agonist, kainate binding site; tritiated alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid agonist, and tritiated 6-cyano-7-nitroquinoxaline-2,3-dione antagonist, both at the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid binding site. RESULTS: Magnesium sulfate caused decreased binding of the agonist to the kainate receptor recognition site after both short-term and intermediate-term systemic administration, whereas long-term treatment resulted in increased binding. No significant consistent effect on the binding to the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor agonist site was recorded after magnesium administration. The receptor antagonist showed an increased binding after short-term treatment. Long-term administration also resulted in increased binding of the antagonist, an effect that was limited to the hippocampus. CONCLUSIONS: These data suggest down-regulation of the kainate receptor population during short- and intermediate-term magnesium sulfate treatment. However, long-term inhibition by magnesium resulted in up-regulation of the receptor population. The results may also reflect an increased inhibitory effect of magnesium sulfate on the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1988

Synergistic effects of adjuvants, endotoxin, and fasting on induction of diabetes with multiple low doses of streptozocin in rats.

Three weekly intraperitoneal injections of complete Freund's adjuvant (CFA) and, 1 day later, low-dose streptozocin (STZ; 25 mg/kg i.p.) have been reported to cause immune destruction of beta-cells and a gradual onset of diabetes mellitus. In this study, male Lewis rats were injected intraperitoneally with CFA and 1 day later with low-dose STZ; these were repeated at weekly intervals for 3 wk. The incidence of diabetes mellitus (nonfasted plasma glucose greater than 200 mg/dl) in wk 1, 2, 3, and 4 was 50, 80, 93, and 100%, respectively. Rats receiving either CFA or STZ only did not develop diabetes. Injections of either the components of CFA (incomplete Freund's adjuvant and Mycobacterium butyricum), another granuloma-inducing organism (Listeria monocytogenes), or endotoxin before STZ induced diabetes, but the onset was slower and the diabetes was less severe than with CFA and STZ. Because intraperitoneal CFA injections caused peritoneal irritation, acute weight loss, and hypoglycemia on the day after injection, we examined whether fasting alone potentiated low-dose STZ. Fasting for 24 h before and 24 h after low-dose STZ caused diabetes that was similar in rapidity of onset and severity to that induced with CFA and STZ. Administration of CFA subcutaneously before STZ did not cause hypoglycemia or weight loss but did cause diabetes. Thus, the fasting effect of intraperitoneal CFA was not responsible for the induction of diabetes with CFA and STZ. These data indicate that immunologic adjuvants, endotoxin, and fasting all potentiate the diabetogenic action of low-dose STZ.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Linear sweep voltammetry with carbon paste electrodes in the rat striatum.

Voltammetry has been widely used in attempts to measure catecholamine release in vivo. The voltammogram recorded in the rat striatum using carbon paste electrodes and linear sweep voltammetry with semidifferentiation consists of a number of separate peaks; changes in the height of the first of these peaks have been attributed to changes in catecholamine release. We have found that ascorbate, either microinjected into the striatum or injected intraperitoneally, increases the height of the first peak without changing its potential. Microinjection of dopamine or 3,4-dihydroxyphenylacetic acid, or intraperitoneal injection of 3,4-dihydroxyphenylalanine, caused a shift in the potential of peak 1 of 25-50 mV in a positive direction. Amphetamine, administered intraperitoneally to freely moving animals, caused an increase in the height of the first peak but did not change its potential. Oxidation potentials in vitro and the effect of other drugs on the voltammogram obtained in vivo were also measured. Peak 1 is caused by the oxidation of both ascorbate and catechols whose oxidation potentials differ by only 50 mV in vivo; the contribution of catechols in control animals is negligible. Shifts in the potential of peak 1 caused by drugs are not due to changes in the oxidation potentials of the components but to a change in their relative contributions. Therefore changes in the height of peak 1 with no change in position do not represent changes in the extracellular concentration of catechols but are due to changes in ascorbate concentration. Changes in the concentration of catecholamine-related compounds can be detected at potentials some 50 mV greater than that of the first peak.

Animals↗
PubMed1996

The mitotoxin, basic fibroblast growth factor-saporin, effectively targets human prostatic carcinoma in an animal model.

PURPOSE: The antitumor activity of the mitotoxin basic fibroblast growth factor-saporin (bFGF-SAP) against human prostatic carcinoma DU 145 was examined in athymic nude mice. Therapeutic efficacy was evaluated on the basis of dose, route of administration and treatment schedule. MATERIALS AND METHODS: Chemical conjugate or recombinant bFGF-SAP (0.02 to 50 micrograms/kg.) was administered by intravenous tail injection, intraperitoneal injection, or local or distal subcutaneous injection beginning 5 days (or 60 to 121 days for large tumor studies) after subcutaneous implantation of DU 145 cells. Tumor growth was monitored as long as 140 days by external caliper measurements. RESULTS: Recombinant bFGF-SAP, though less cytotoxic than its chemical conjugate form, effectively targeted DU 145 tumors growing as xenografts in nude mice in a dose-dependent manner. Antitumor response to treatment by intravenous, intraperitoneal, or distal subcutaneous injection suggested similar bioavailability of the mitotoxin administered by each route; local subcutaneous injection to the tumor site resulted in statistically better antitumor response. Schedules that included at least 1 bFGF-SAP treatment beyond day 23 increased long-term antitumor efficacy independent of total dose. Moreover, recombinant bFGF-SAP induced dramatic reduction of large, established tumors. CONCLUSIONS: These studies suggest a therapeutic potential for bFGF receptor-directed toxins in targeting prostate cancer; further, these data suggest that treatment of established tumors (> 3 weeks) results in qualitatively and quantitatively improved tumor responses.

Animals↗
PubMed1994

Postingestive alliesthesia produced by exogenous cholecystokinin and blocked by abdominal vagotomy.

Facial consummatory responses reflecting ingestive and aversive perceptions were studied and quantified in rats chronically implanted with oral catheters. A gustatory stimulus of 50 microliters of 1.75 M sucrose was injected into the mouth every 5 min during 65 min. At 5 min, 2 micrograms/kg exogenous cholecystokinin (CCK) was injected intraperitoneally. Typical ingestive facial consummatory responses were observed in response to sweet stimuli before the load. Aversive consummatory responses were observed in response to sweet stimuli after the intraperitoneal exogenous CCK (negative alliesthesia). Control intraperitoneal injection of saline was not followed by negative alliesthesia in response to sweet oral stimuli. In the last part of the experiment rats were vagotomized or underwent sham operation. When the vagotomized rats were again subjected to the same gustatory sessions, the intraperitoneal exogenous CCK was not followed by negative alliesthesia in response to sweet stimuli, whereas sham-operated rats presented a strong negative alliesthesia. These results in rats suggest that CCK mediates duodenal preabsorptive signal for alimentary alliesthesia. They also suggest that the effect is peripheral, with the vagus nerve as afferent pathway.

Animals↗
PubMedDate not supplied

Modification of tirapazamine-induced cytotoxicity in combination with mild hyperthermia and/or nicotinamide: reference to effect on quiescent tumour cells.

C3H/He and Balb/c mice bearing SCC VII or EMT6/KU tumours received continuous administration of 5-bromo-2'-deoxyuridine (BrdU) for 5 days to label all proliferating (P) cells. The tumours were locally heated at 40 degrees C for 60 min and/or the tumour-bearing mice received intraperitoneal injection of nicotinamide, and then tirapazamine (TPZ) was injected intraperitoneally. Sixty minutes after TPZ injection, the tumours were excised, minced and trypsinized. The tumour cell suspensions were incubated with cytochalasin-B (a cytokinesis-blocker), and the micronucleus (MN) frequency in cells without BrdU labelling (quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. The MN frequency in total (P+Q) tumour cells was determined from the tumours that were not pretreated with BrdU. The cytotoxicity of TPZ was evaluated in terms of the frequency of induced micronuclei in binuclear tumour cells (= MN frequency). In both tumour systems, the MN frequencies of Q cells were greater than those of total tumour cell populations. Mild heat treatment elevated the MN frequency in total and Q cells in both tumour systems, but the effect was more marked in Q cells. In total cells, mild heat treatment increased the MN frequency in EMT6/KU tumour cells more markedly than in SCC VII tumour cells. In contrast, in both tumour systems, nicotinamide decreased the MN frequency in both cell populations, with a greater influence on the total cells. The combination of TPZ and mild heat treatment may be useful for sensitizing tumour cells in vivo, including Q cells.

Animals↗
PubMed1994

Enhancement of a kappa-opioid receptor agonist-induced analgesia by L-tyrosine and L-tryptophan.

The effects of the methyl esters of L-tyrosine (L-Tyr-OMe) and L-tryptophan (L-Trp-OMe) on the analgesic action of trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidin)cyclohexyl]-benzene acetamide methane sulfonate (U-50,488H), a kappa-opioid receptor agonist, were determined in male Swiss-Webster mice using the tail-flick test. Intraperitoneal injections of U-50,488H produced a dose-dependent analgesic response. The analgesic response to all doses of U-50,488H was potentiated by L-Tyr-OMe at 200 mg/kg injected intraperitoneally 30 min prior to the injection of U-50,488H. The effect of various doses of L-Tyr-OMe (50, 100 and 200 mg/kg) on the analgesia produced by 20 mg/kg of U-50,488H was also determined. The lowest dose (50 mg/kg) of L-Tyr-OMe did not modify U-50,488H-induced analgesia but the two higher doses enhanced it significantly. L-Tyr-OMe by itself at all the doses tested had no effect on the tail-flick latency. L-Trp-OMe (200 mg/kg) enhanced the analgesic action of 10 and 20 mg/kg doses of U-50,488H but not that induced by a 5 mg/kg dose. The analgesia induced by 20 mg/kg of U-50,488H was potentiated by L-Trp-OMe at 100 and 200 mg/kg but not by a 50 mg/kg dose. L-Trp-OMe by itself also did not alter the tail-flick latency. Previously, the studies in this laboratory have shown that L-Try-OMe potentiates morphine, a mu-opioid receptor agonist-induced analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMedDate not supplied

Potentiation of kappa-opioid receptor agonist-induced analgesia and hypothermia by fluoxetine.

The effect of fluoxetine, a selective 5-HT reuptake inhibitor on the analgesic and hypothermic response of trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methane sulphonate (U-50,488H) and (+/-)-trans-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzo[b] thiophene-4-acetamide (PD 117302), kappa-opioid receptor agonists, was determined in female Sprague-Dawley rats using the tail-flick method and telethermometer, respectively. Intraperitoneal injections of U-50,488H (U50) and PD 117302 (PD117) produced a dose-dependent analgesic and hypothermic response. Fluoxetine (10 mg/kg, i.p.) by itself did not produce an analgesic response. The analgesic response to U50 (10, 20, and 40 mg/kg, i.p.) and PD117 (7.5, 15, and 22.5 mg/kg, i.p.) was potentiated by fluoxetine injected intraperitoneally 60 min prior to the injection of kappa-opioid agonists. Similarly, the hypothermic response of U50 (20 and 40 mg/kg, i.p.) and PD117 (7.5, 15, and 22.5 mg/kg, i.p.) was potentiated by fluoxetine. The results indicate that selective kappa-opioid receptor agonists-induced analgesia and hypothermia is potentiated by fluoxetine, suggesting the role of extracellular 5-HT in the kappa-opioid receptor-mediated analgesia and hypothermia.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2006

LPS inhibits fasted plasma ghrelin levels in rats: role of IL-1 and PGs and functional implications.

LPS injected intraperitoneally decreases fasted plasma levels of ghrelin at 3 h postinjection in rats. We characterized the inhibitory action of LPS on plasma ghrelin and whether exogenous ghrelin restores LPS-induced suppression of food intake and gastric emptying in fasted rats. Plasma ghrelin and insulin and blood glucose were measured after intraperitoneal injection of LPS, intravenous injection of IL-1beta and urocortin 1, and in response to LPS under conditions of blockade of IL-1 or CRF receptors by subcutaneous injection of IL-1 receptor antagonist (IL-1Ra) or astressin B, respectively, and prostaglandin (PG) synthesis by intraperitoneal indomethacin. Food intake and gastric emptying were measured after intravenous injection of ghrelin at 5 h postintraperitoneal LPS injection. LPS inhibited the elevated fasted plasma ghrelin levels by 47.6 +/- 4.9%, 58.9 +/- 3.3%, 74.4 +/- 2.7%, and 48.9 +/- 8.7% at 2, 3, 5, and 7 h postinjection, respectively, and values returned to preinjection levels at 24 h. Insulin levels were negatively correlated to those of ghrelin, whereas there was no significant correlation between glucose and ghrelin. IL-1Ra and indomethacin prevented the first 3-h decline in ghrelin levels induced by LPS, whereas astressin B did not. IL-1beta inhibited plasma ghrelin levels, whereas urocortin 1 had no influence. Ghrelin injected intravenously prevented an LPS-induced 87% reduction of gastric emptying and 61% reduction of food intake. These data showed that IL-1 and PG pathways are part of the early mechanisms by which LPS suppresses fasted plasma ghrelin and that exogenous ghrelin can normalize LPS-induced-altered digestive functions.

Animals↗
PubMed1992

Convulsive action and toxicity of uremic guanidino compounds: behavioral assessment and relation to brain concentration in adult mice.

Four guanidino compounds that are known to accumulate in uremia, namely creatinine, guanidine, guanidinosuccinic acid and methylguanidine, were administered intraperitoneally and intracerebroventricularly to adult albino mice and the compounds epileptogenic and toxic properties were behaviorally assessed. After intraperitoneal injection, brain concentration of the compounds as a function of injected dose was monitored additionally. Guanidino compound brain concentration was determined by cation exchange chromatography with fluorescence ninhydrin detection. After systemic administration, especially guanidinosuccinic acid and methylguanidine induced long-lasting generalized convulsions which gradually increased in severity. Increasing the dose injected intraperitoneally resulted in linear increase in brain concentration of the injected compounds, in parallel with increase in proportion of animals presenting with convulsions and/or severity of convulsions. Guanidinosuccinic acid brain concentration increased more slowly than that of the other 3 compounds and guanidinosuccinic acid also exerted its effect later than the others. Since none of the other metabolically related guanidino compounds determined was significantly increased in the brains of the injected animals, the observed behavior was most certainly induced by the compounds injected and not by some secondary metabolite. Epileptogenic properties of the four compounds were markedly and qualitatively different in systemic administration, but rather similar in intracerebral administration. A tentative epileptogenic potency order was inferred from the combined behavioral and biochemical results. All 4 of the compounds tested displayed the ability to induce full-blown clonic-tonic convulsions and they did so in a dose-related manner. Guanidinosuccinic acid appeared to be slightly more potent than methylguanidine, but both guanidinosuccinic acid and methylguanidine were considerably more potent than guanidine. Creatinine was many times less potent than the other 3 guanidino compounds. Revised epileptogenic potency order on the basis of guanidino compound brain concentration after systemic administration as well as potency order after intracerebral administration paralleled the potency order of these compounds in their GABA antagonism reported earlier. It was therefore postulated that the GABA antagonism of uremic guanidino compounds could underlie their epileptogenic character. Moreover, these compounds could very likely be at the basis of the neurological complications including epilepsy of uremic patients in whom they accumulate in physiological fluids and brain.

Animals↗