Subchronic Intraperitoneal Administration Research Articles

Effect of human mesenchymal stem cell secretome administration on morphine self-administration and relapse in two animal models of opioid dependence

The present study investigates the possible therapeutic effects of human mesenchymal stem cell-derived secretome on morphine dependence and relapse. This was studied in a new model of chronic voluntary morphine intake in Wistar rats which shows classic signs of morphine intoxication and a severe naloxone-induced withdrawal syndrome. A single intranasal-systemic administration of MSCs secretome fully inhibited (>95%; p < 0.001) voluntary morphine intake and reduced the post-deprivation relapse intake by 50% (p < 0.02). Since several studies suggest a significant genetic contribution to the chronic use of many addictive drugs, the effect of MSCs secretome on morphine self-administration was further studied in rats bred as high alcohol consumers (UChB rats). Sub-chronic intraperitoneal administration of morphine before access to increasing concentrations of morphine solutions and water were available to the animals, led UChB rats to prefer ingesting morphine solutions over water, attaining levels of oral morphine intake in the range of those in the Wistar model. Intranasally administered MSCs secretome to UChB rats dose-dependently inhibited morphine self-administration by 72% (p < 0.001); while a single intranasal dose of MSC-secretome administered during a morphine deprivation period imposed on chronic morphine consumer UChB rats inhibited re-access morphine relapse intake by 80 to 85% (p < 0.0001). Both in the Wistar and the UChB rat models, MSCs-secretome administration reversed the morphine-induced increases in brain oxidative stress and neuroinflammation, considered as key engines perpetuating drug relapse. Overall, present preclinical studies suggest that products secreted by human mesenchymal stem cells may be of value in the treatment of opioid addiction.

Neuropsychopharmacological profiling of scoparone in mice

Scoparone (6,7-dimethoxycoumarin) is a simple coumarin from botanical drugs of Artemisia species used in Traditional Chinese Medicine and Génépi liquor. However, its bioavailability to the brain and potential central effects remain unexplored. We profiled the neuropharmacological effects of scoparone upon acute and subchronic intraperitoneal administration (2.5–25 mg/kg) in Swiss mice and determined its brain concentrations and its effects on the endocannabinoid system (ECS) and related lipids using LC–ESI–MS/MS. Scoparone showed no effect in the forced swimming test (FST) but, administered acutely, led to a bell-shaped anxiogenic-like behavior in the elevated plus-maze test and bell-shaped procognitive effects in the passive avoidance test when given subchronically and acutely. Scoparone rapidly but moderately accumulated in the brain (Cmax < 15 min) with an apparent first-order elimination (95% eliminated at 1 h). Acute scoparone administration (5 mg/kg) significantly increased brain arachidonic acid, prostaglandins, and N-acylethanolamines (NAEs) in the FST. Conversely, subchronic scoparone treatment (2.5 mg/kg) decreased NAEs and increased 2-arachidonoylglycerol. Scoparone differentially impacted ECS lipid remodeling in the brain independent of serine hydrolase modulation. Overall, the unexpectedly potent central effects of scoparone observed in mice could have toxicopharmacological implications for humans.

A CYTOLOGICAL STUDY OF IMPRINT SMEARS (TOUCH PREPARATION CYTOLOGY) TO EVALUATE THE TOXICITY OF METAL-CONTAINING NANOPARTICLES IN EXPERIMENTAL ANIMALS

Introduction. Touch preparation cytology is a well-known technique widely used in clinical practice. It can be also applied for an express assessment of cyto-morphological effects of metal-containing nanoparticles in experimental animals. Material and methods. We’ve studied 144 imprint smears (of the liver, kidneys, lungs, tracheobronchial and mesenteric lymph nodes) taken from 52 rats, weighed 280-300 g, aged 3.5 months. This was done following a subchronic intraperitoneal administration of TiO2, Al2O3, and SiO2 nanoparticles, in a range of doses, and a subacute (5-times) inhalational exposure to 1 mg/m3 NiO NPs. Leishman stain was used. Cytological markers were studied at х100/х1000 magnification, using a Carl Zeiss Primo Star microscope, with a USCMOS camera for visualization. The count was done for every 200 cells of lung, liver and kidney specimens and for every 100 cells of lymph node tissue. The differences between the group means (in case of quantitative results) were analyzed using a Student’s t-test. The differences between the group means were considered statistically significant if the probability of those differences being accidental didn’t exceed 5% (р &lt; 0,05). Results. We report the principal results obtained in a cytological study of imprint smears (touch preparations) of rat organs following the exposure to metal-containing nanoparticles. The main types of cellular responses were determined. Degenerative and dystrophic changes were observed in touch preparations of the liver, kidneys, and lungs following administration of nanoparticles in a range of doses and by various routes of exposure. Hyperergic inflammatory responses were seen upon the exposure to nickel oxide nanoparticles. A local cellular immune response was observed as an increase of macrophage percentage in imprint smears of some organs. Conclusion. The use of touch preparation cytology together with histological examination of tissue specimens expand opportunities for a more relevant morphological and quantitative analysis when studying the toxic effects of metal-containing nanoparticles.

ПРИМЕНЕНИЕ ЦИТОЛОГИЧЕСКОГО МЕТОДА ИССЛЕДОВАНИЯ МАЗКОВ У ЭКСПЕРИМЕНТАЛЬНЫХ ЖИВОТНЫХ ДЛЯ ОЦЕНКИ ТОКСИЧЕСКОГО ДЕЙСТВИЯ МЕТАЛЛОСОДЕРЖАЩИХ НАНОЧАСТИЦ

Introduction. Touch preparation cytology is a well-known technique widely used in clinical practice. It can be also applied for an express assessment of cyto-morphological effects of metal-containing nanoparticles in experimental animals. Material and methods. We’ve studied 144 imprint smears (of the liver, kidneys, lungs, tracheobronchial and mesenteric lymph nodes) taken from 52 rats, weighed 280-300 g, aged 3.5 months. This was done following a subchronic intraperitoneal administration of TiO2, Al2O3, and SiO2 nanoparticles, in a range of doses, and a subacute (5-times) inhalational exposure to 1 mg/m 3 NiO NPs. Leishman stain was used. Cytological markers were studied at х100/х1000 magnification, using a Carl Zeiss Primo Star microscope, with a USCMOS camera for visualization. The count was done for every 200 cells of lung, liver and kidney specimens and for every 100 cells of lymph node tissue. The differences between the group means (in case of quantitative results) were analyzed using a Student’s t-test. The differences between the group means were considered statistically significant if the probability of those differences being accidental didn’t exceed 5% (р < 0,05). Results. We report the principal results obtained in a cytological study of imprint smears (touch preparations) of rat organs following the exposure to metal-containing nanoparticles. The main types of cellular responses were determined. Degenerative and dystrophic changes were observed in touch preparations of the liver, kidneys, and lungs following administration of nanoparticles in a range of doses and by various routes of exposure. Hyperergic inflammatory responses were seen upon the exposure to nickel oxide nanoparticles. A local cellular immune response was observed as an increase of macrophage percentage in imprint smears of some organs. Conclusion. The use of touch preparation cytology together with histological examination of tissue specimens expand opportunities for a more relevant morphological and quantitative analysis when studying the toxic effects of metal-containing nanoparticles.

The novel element in the mechanism of endogenous regulation of depressive-like states

It was shown previously that cyclo-prolylglycine, an endogenous neuropeptide, is a positive AMPA receptor modulator and is able to increase the content of BDNF in neurons. In the present work it was shown that cyclo-prolylglycine at a dose of 1 mg/kg with subchronic intraperitoneal administration reduces the time of animal immobility to passive control, from 167.6 to 83.6 s on the 12th day of the experiment using the model of learned helplessness in rats. That indicates the presence of antidepressant-like activity. The results of the study allow us to consider that cyclo-prolylglycine is a link in the physiological regulation of a depressive-like state.

A New Component in the Mechanism of Regulation of Endogenous Depressive-Like States.

It was shown previously that cycloprolylglycine, an endogenous neuropeptide, is a positive AMPA receptor modulator and is able to increase the content of BDNF in neurons. In the present study, using the model of learned helplessness in rats, we showed that cycloprolylglycine at a dose of 1 mg/kg at subchronic intraperitoneal administration reduced the time of animal immobility to passive control values (from 167.6 to 83.6 s) on day 12 of the experiment. This indicates the presence of antidepressant-like activity. The results of the study allow us to consider cycloprolylglycine as a component in the physiological regulation of the depression-like state.

A comparative study of the effects of mexidolum and mildronatum on the physical performance of experimental animals

To evaluate the effects of mexidolum on physical performance using acute and subchronic administration in experimental animals. The investigation was carried out using 123 male white outbred mice. The forced swim test was used to assess the effects of the drugs on the physical performance of mice. A single intraperitoneal administration of 50 and 100 mg/kg mexidolum and subchronic intraperitoneal administration of 100 mg/kg mexidolum significantly enhances the physical performance of animals in the forced swim test. Subchronic intraperitoneal administration of 100 mg/kg of the comparison drug mildronatum enhances the physical performance of animals, while intraperitoneal administration at a lower dose (50 mg/kg) has no effect. The effect of mexidolum at a dose of 50 and 100 mg/kg is comparable with the effect of mildronatum in a dose of 100 mg/kg.

Effect of sub-chronic intraperitoneal administration of aminoguanidine on the memory and hippocampal apoptosis-related genes in diabetic rats

Memory impairment is a common disorder in diabetes mellitus which is associated with hippocampal neuronal apoptosis. The present study was conducted to examine the effect of one-week intraperitoneal (ip), administration of aminoguanidine (AG) on passive avoidance learning (PAL) and Bcl-2 family gene expression in the hippocampus of rats. Sixty male rats were divided into ten groups: non-diabetic/diabetic animals with/without AG (50, 100, 200 and 400 mg/kg, ip) treatment for one week. PAL and Bcl-2 family genes were examined. AG (100 and 200 mg/kg) improved both memory and Bax, Bak, Bcl-2 and Bcl-xl deficiency significantly in diabetic rats. AG treatment also ameliorated the diabetes-induced changes in (Bcl-2+Bcl-xl)/(Bak+Bax) ratios considerably. These results propose that one-week ip administration of AG may recover the deficit cognition in diabetic rats via enhancing (Bcl-2+Bcl-xl)/(Bak+Bax) proportions (Tab. 2, Fig. 4, Ref. 55).

Original Nerve Growth Factor Mimetic Dipeptide GK-2 Restores Impaired Cognitive Functions in Rat Models of Alzheimer’s Disease

Dipeptide mimetic of the nerve growth factor (NGF) loop 4, hexamethylenediamide bis-(N-monosuccinyl- glutamyl-lysine) (GK-2), was synthesized at the V.V. Zakusov Scientific Research Institute of Pharmacology of the Russian Academy of Medical Sciences. GK-2 exhibited in vitro neuroprotective activity at nanomolar concentrations, was efficient in animal models of the Parkinson's disease, ischemic and hemorrhagic stroke, and global cerebral ischemia at doses of 0.01-5 mg/kg (intraperitoneally) and 10 mg/kg (per os). The mnemotropic effects of subchronic intraperitoneal administration of GK-2 on rat models of the Alzheimer's disease are described in this paper. Dipeptide GK-2 at a dose of 1 mg/kg is found to decrease the habituation deficit induced by the septo-hippocampal pathway transsection and, at a dose of 0.5 mg/kg, to significantly prevent spatial memory impairment in Morris water maze induced by intracerebral injection of streptozotocin. Thus, GK-2, an original dipeptide mimetic of NGF, acts on models of the Alzheimer's disease upon systemic administration.

Colocalization of glucagon-like peptide-1 (GLP-1) receptors, glucose transporter GLUT-2, and glucokinase mRNAs in rat hypothalamic cells: evidence for a role of GLP-1 receptor agonists as an inhibitory signal for food and water intake.

This study was designed to determine the possible role of brain glucagon-like peptide-1 (GLP-1) receptors in feeding behavior. In situ hybridization showed colocalization of the mRNAs for GLP-1 receptors, glucokinase, and GLUT-2 in the third ventricle wall and adjacent arcuate nucleus, median eminence, and supraoptic nucleus. These brain areas are considered to contain glucose-sensitive neurons mediating feeding behavior. Because GLP-1 receptors, GLUT-2, and glucokinase are proteins involved in the multistep process of glucose sensing in pancreatic beta cells, the colocalization of specific GLP-1 receptors and glucose sensing-related proteins in hypothalamic neurons supports a role of this peptide in the hypothalamic regulation of macronutrient and water intake. This hypothesis was confirmed by analyzing the effects of both systemic and central administration of GLP-1 receptor ligands. Acute or subchronic intraperitoneal administration of GLP-1 (7-36) amide did not modify food and water intake, although a dose-dependent loss of body weight gain was observed 24 h after acute administration of the higher dose of the peptide. By contrast, the intracerebroventricular (i.c.v.) administration of GLP-1 (7-36) amide produced a biphasic effect on food intake characterized by an increase in the amount of food intake after acute i.c.v. delivery of 100 ng of the peptide. There was a marked reduction of food ingestion with the 1,000 and 2,000 ng doses of the peptide, which also produced a significant decrease of water intake. These effects seemed to be specific because i.c.v. administration of GLP-1 (1-37), a peptide with lower biological activity than GLP-1 (7-36) amide, did not change feeding behavior in food-deprived animals. Exendin-4, when given by i.c.v. administration in a broad range of doses (0.2, 1, 5, 25, 100, and 500 ng), proved to be a potent agonist of GLP-1 (7-36) amide. It decreased, in a dose-dependent manner, both food and water intake, starting at the dose of 25 ng per injection. Pretreatment with an i.c.v. dose of a GLP-1 receptor antagonist [exendin (9-39); 2,500 ng] reversed the inhibitory effects of GLP-1 (7-36) amide (1,000 ng dose) and exendin-4 (25 ng dose) on food and water ingestion. These findings suggest that GLP-1 (7-36) amide may modulate both food and drink intake in the rat through a central mechanism.

Model systems for detecting the hepatic toxicity of pyrrolizidine alkaloids and pyrrolizidine alkaloid N-oxides

Indicine N-oxide (INO) is a pyrrolizidine alkaloid (PA) with antitumor activity in animals and humans. Prior studies showed that despite the known hepatic toxicity of the PAs, INO did not produce hepatic toxicity in animals but caused unpredictable lethal hepatic toxicity in humans. In this study we have attempted to find a model system for predicting the hepatotoxic potential of antitumor PAs. Primary cultures of rat hepatocytes showed toxicity only with the most hepatotoxic PAs such as lasiocarpine, but did not detect toxicity with other PAs. Subchronic intraperitoneal administration of PAs to weanling rats and adult mice produced, in surviving animals, hepatic megalocytosis and centrilobular necrosis with heliotrine (H) and 9-O-( R(−)-2-(4′-chlorophenyl)-2-hydroxybutyryl)retronecine N-oxide (RC1NO) but only megalocytosis with INO. Thus, despite previous reports, weanling rats offered no advantage over adult mice for detecting significant hepatic toxicity with PAs. Phenobarbital pretreatment of the mice did not increase the hepatic toxicity of any of the PAs. Subchronic oral administration of PAs to adult mice produced hepatic megalocytosis and centrilobular necrosis in surviving animals with H and RC1NO and megalocytosis with INO. Animals that died acutely following oral administration of INO showed hepatic centrilobular necrosis. Administration of several courses of INO intravenously to dogs produced histological evidence of centrilobular hemorrhagic necrosis. It is concluded that there is no single animal model that will predict hepatic toxicity of the type seen in humans with the antitumor PAs. A combination of studies using adult mice and dogs and lethal doses of the PAs offers the best way of detecting potential hepatic toxicity.