Influence of original structural analogue of arginine-vasopressin(6–9), Ac-D-SPRG,on exploratory activity and level of anxiety of white rats

Influence of synthetic analogue of arginine-vasopressin (AVP), Ac-D-SPRG, on exploratory behavior and level of anxiety of white rats was investigated. Ac-D-SPRG was injected nasally in doses of 0.01, 0.1, 1.0, and 10.0 μg/kg in the volume of 1 μl per 10 g of body weight 5 min before the testing. The analogue caused depression of orientation and exploratory activity (OEA) and increase of anxiety level in animals. The contradictory literature data provide no opportunity to conclude unambiguously on mechanisms underlying bases of regulation of anxiety level and OEA from AVP but nevertheless confirm the participation of this hormone in a given process.     

The Protective Effect of Semax in a Model of Stress-Induced Impairment of Memory and Behavior in White Rats

The effect of acute restrained stress on cognitive functions and anxiety-like behavior in white rats has been studied; furthermore, the influence of the fragment ACTH(4–10) analog Semax on the stress effects was evaluated. It was shown that stress exposure leads to impaired retention of previously acquired food-motivated maze task as well as reduced anxiety-like behavior in the elevated plus maze in rats. Preliminary intraperitonial administration of Semax (0.1 mg/kg) attenuates cognitive impairment caused by acute restrained stress, but it does not affect stress-induced changes in anxiety.     

Neuroprotective effects of semax in MPTP-induced disturbances of brain dopamine system

Effects of an ACTH (4-10) analogue Semax (MEHFPGP) on behaviour of white rats with MPTP-induced disturbances of brain DA-system have been studied. It was shown that MPTP administration (25 mg/kg) reduced motor activity and auhmented the anxiety level in rats. Semax administration (daily intranasal 0.2 mg/kg) attenuated behaviour disturbances induced by neurotoxin. The observed protective action of Semax in rats with MFTP-induced DA system disturbances may be due to both its modulating influence on the brain DA system and peptide neuroprotective effects.     

Pharmacological Activity of Ruthenium Complexes trans-[RuCl2(L)4] (L = Nicotinic or i-Nicotinic acid) on Anxiety and Memory in Rats

Many biological properties have been attributed to ruthenium complex I (trans-[RuCl₂(nic)₄]) and ruthenium complex II (trans-[RuCl₂ (i-nic) ₄]) including nitric oxide synthase inhibition. In this study, we evaluated pharmacological effects of these complexes on anxiety and memory formation. Memory was evaluated with inhibitory avoidance and habituation to an open-field and anxiety was tested with elevated plus-maze. Adult male Wistar rats (250 to 350 g) received intraperitoneal injections of vehicle, ruthenium complex I (45.2, 90.4, or 180.7 μmol/kg), or ruthenium complex II (0.08, 4.5, or 13.6 μmol/kg) 30 min prior open-field training or elevated plus-maze test and 30 min or 0 h after training. No effects were observed in the anxiety parameters and habituation to an open-field. The ruthenium complexes impaired memory retention compared with vehicle group in the inhibitory avoidance, as when administrated 30 min prior as immediately after training. The memory impairment induced by ruthenium complexes may be due to their nitric oxide synthase inhibition capacity.     

Kinetics of semax penetration into the brain and blood of rats after its intranasal administration

The radioactive petide analogue Semax corresponding to the ACTH(4–10) sequence (Met-Glu-His-Phe-Pro-Gly-Pro) with a specific radioactivity of 56 Ci/mmol labeled with tritium at the C-terminal Pro was prepared. The labeled peptide was used for studying the kinetics of Semax penetration into rat brain and blood after its intranasal administration (50 μg/kg, 20 μl of solution) to nonbred white rats of body mass 200–250 g. It was demonstrated that 0.093% of the total introduced radioactivity per gram can be found in the rat brain 2 min after the administration, 80% of this radioactivity belonged to Semax, and the rest, to its metabolites. The peptide undergoes rapid enzymatic degradation, with the tripeptide Pro-Gly-Pro prevailing in biological samples relative to the total content of Semax and its metabolites.     

Effects of an inhibitor of adenosine deaminase,deoxycoformycin, and of nucleoside transport,propentofylline, on post-ischemic recovery of adenine nucleotides in rat brain

The effects of an adenosine deaminase inhibitor (deoxycoformycin, 500 μg/kg) and of an inhibitor of nucleoside transport (propentofylline, 10 mg/kg) on adenosine and adenine nucleotide levels in the ischemic rat brain were investigated. The brains of the rats were microwaved before, at the end of a 20 min period of cerebral ischemia (4 vessel occlusion+hypotension), or after 5, 10, 45, and 90 min of reperfusion. Deoxycoformycin increased brain adenosine levels during both ischemia and the initial phases of reperfusion. AMP levels were elevated during ischemia and after 5 min of reperfusion. ATP levels were elevated above those in the non-treated animals after 10 and 45 min of reperfusion. ADP levels were elevated above the non-drug controls at 90 min. These increases in ATP, ADP and AMP resulted in significant increases in total adenylates during ischemia, and after 10 min and 90 min of reperfusion. Propentofylline administration resulted in enhanced AMP levels during ischemia but did not alter adenosine or adenine nucleotide levels during reperfusion in comparison with non-treated controls.     

Dependence of long-lasting effects of the ACTH(4-10) analogue semax on the time of its neonatal administration

Long-lasting behavioural effects of chronic administration of synthetic ACT(4-10) analogue Semax (MEHFPGP) during early neonatal life were studied. The peptide was injected daily intraperitoneally in dose 0.05 mg/kg during the first, second or second-third weeks of postnatal development. It was shown that the peptide injections during the first week lead to a decrease and during second or second-third weeks--to an increase of exploratory activity in 4-8-week aged rats. Furthermore, the peptide adminictration at all times diminished anxiety and improved learning ability of adult rats. The data obtained show that Semax neonatal administration during the first three weeks of life modulates development of brain structures involved in regulation of exploration, anxiety and learning.     

Kinetics of Semax penetration into the brain and blood of rats after its intranasal administration

The radioactive peptide analogue Semax corresponding to the ACTH(4-10) sequence (Met-Glu-His-Phe-Pro-Gly-Pro) with a molar radioactivity of 56 Ci/mmol labeled with tritium at the C-terminal Pro was prepared. The labeled peptide was used for studying the kinetics of Semax penetration into rat brain and blood after its intranasal administration (50 microg/kg, 20 microl of solution) to nonbred white rats of body mass 200-250 g. It was demonstrated that 0.093% of the total introduced radioactivity per gram can be found in the rat brain 2 min after the administration, 80% of this radioactivity belonged to Semax, and the rest, to its metabolites. The peptide undergoes rapid enzymatic degradation, with the tripeptide Pro-Gly-Pro prevailing in biological samples relative to the total content of Semax and its metabolites.     

Effects of chronic Semax administration on exploratory activity and emotional reaction in white rats

Effects of chronic intranasal administration of ACTH(4-10) analog Semax (MEHFPGP) on exploratory activity, anxiety level, and depression-like behaviour were studied in white rats. The peptide was injected daily in dose 0.05 mg/kg during 10 or 14 days. It was shown that chronic Semax administration at 1-2 weeks induced anxiolytic and antidepressant effects but did not influenced the exploratory activity in non-stressogenic environment. The Semax effects may be the results of activation of the brain serotoninergic system as well as increased BDNF expression in the rat hippocampus.     

Effects of Octreotide in Chronically Mild Stressed Rats: Possible Role of Immune and Oxidative Stress Pathways

Impairment of neuroendocrine, immune and antioxidant defenses contribute to pathophysiology of stress-induced depression. Somatostatin executes diverse regulatory effects on endocrine, exocrine and neural functions; however, the possibility that octreotide, a synthetic somatostatin analogue might mitigate stress-induced depression remains elusive. Hence, the current study aimed to explore the immunomodulatory and antioxidant effects of octreotide in a model of chronic mild stress (CMS). This paradigm was performed by exposing rats to a combination of mild unpredictable stressors for 21 days. Fifty male Wistar rats were divided into five groups; (1) control receiving saline, (2) octreotide given to normal unstressed animals. The remaining three groups were subjected to (3) CMS alone or in combination with octreotide (4) 50 μg/kg or (5) 90 μg/kg. Octreotide increased sucrose preference index and attenuated CMS-induced increases in plasma adrenocorticotrophic hormone and corticosterone levels. In addition, octreotide decreased plasma tumor necrosis factor-alpha concentration. Moreover, it prevented CMS-induced oxidative damage by enhancing the antioxidant defenses superoxide dismutase, glutathione reductase and glutathione in the hippocampus. Furthermore, octreotide normalized the elevated malondialdehyde and lactate dehydrogenase levels in the hippocampus. These results demonstrate a possible antidepressant-like activity of octreotide in CMS due to its antioxidant/antiinflammatory aptitude.     

Long-lasting behavioral effects of chronic neonatal treatment with ACTH (4-10) analogue semax in white rat pups

It is well known that ACTH/MSH-like peptides (melanocortins) have neurotrophic and neuroprotective effects on the central and peripheral nervous systems in the early postnatal life. The aim of present work was to study consequences of the ACTH (4-10) analogue Semax influence on the developing brain. The work was carried out in white rat pups. The peptide (0.05 mg/kg, i/p) was injected daily on the 8th-21st postnatal days. Delayed long-lasting effects of such treatment on animal behavior were revealed. At the age of four to eight weeks, Semax-treated rats displayed elevated exploratory activity, decreased anxiety level and improved passive avoidance conditioning. The results suggest that neonatal Semax administration modulates the development of the central nervous system.     

Effects of Exogenous Selenium on Nicotine-Induced Oxidative Stress in Rats

The effect of two different doses of selenium [1 and 50 μg selenium/100 g body weight (wt)] on nicotine-induced oxidative damage in liver was investigated in experimental rats. Male albino rats were maintained for 60 days as follows: (1) control group (normal diet), (2) nicotine group (0.6 mg/kg body wt)/day, (3) high-dose selenium (50 μg/100 g body wt)/day, (4) high-dose selenium (50 μg/100 g body wt) + nicotine (0.6 mg/kg body wt)/day, (5) low-dose selenium (1 μg/100 g body wt)/day, and (6) low-dose selenium (1 μg/100 g body wt) + nicotine (0.6 mg/kg body wt)/day. Nicotine administration caused a decrease in the activity of antioxidant enzymes, an increase in the concentration of lipid peroxidation products and protein carbonyls and an increase in the activity of nitric oxide synthase compared to the control group. Coadministration of nicotine and selenium reduced the concentration of lipid peroxidation products and increased the activity of antioxidant enzymes compared to the nicotine group. Selenium also enhanced the metabolism of nicotine. The antioxidant effect was more significant in the group administered a low dose of selenium.     

Cardiovascular responses of the taurine-depleted rat to vasoactive agents

Summary. The objective of this study was to assess the effect of taurine-depletion on cardiovascular responses of rat to vasoactive agents. Male Wistar-Kyoto (WKY) rats were given either tap water (control) or 3% β-alanine (taurine-depleted) for three weeks. Thereafter, mean arterial pressure (MAP) and heart rate of the freely moving animal were measured in response to vasoactive agents. Administration of phenylephine (5–40 μg/kg/min; i.v.) resulted in a similar and significant increase in MAP but a reduction in heart rate in both control and taurine-depleted groups. On the other hand, administration of sodium nitroprusside (15–300 μg/kg/min; i.v.) elicited a similar and significant reduction in MAP but increased heart rate in both groups. Lack of a differential response to phenylephrine and sodium nitroprusside between the two groups suggests that baroreflex regulation of cardiovascular function is not adversely affected by taurine-depletion. Administration of angiotensin II (0.1–3.0 μg/kg/min; i.v.) resulted in a dose-related increase in the pressor response and a decrease in heart rate in both groups. However, angiotensin II-induced pressor response was reduced in the taurine-depleted compared to the control rats (p < 0.05); heart rate was similarly reduced in both groups. Acute exposure to β-alanine (3 g/kg; i.v., 30-minutes) did not alter angiotensin II-induced hemodynamic responses. Similarly, incubation of aortic rings with β-alanine (40 mM, 30 minutes) did not affect the contractile responses to angiotensin II. The results suggest that β-alanine, per se, does not affect angiotensin II-induced responses in rat. However, β-alanine-induced taurine depletion is associated with a reduction in the pressor response to angiotensin II without impairing baroreflex function. Received December 17, 1999/Accepted January 12, 2000     

Semax,An ACTH(4-10) Analogue with Nootropic Properties,Activates Dopaminergic and Serotoninergic Brain Systems in Rodents

Corticotrophin (ACTH) and its analogues, particularly Semax (Met-Glu-His-Phe-Pro-Gly-Pro), demonstrate nootropic activity. Close functional and anatomical links have been established between melanocortinergic and monoaminergic brain systems. The aim of present work was to investigate the effects of Semax on neurochemical parameters of dopaminergic- and serotonergic systems in rodents. The tissue content of 5-hydroxyindoleacetic acid (5-HIAA) in the striatum was significantly increased (+25%) 2 h after Semax administration. The extracellular striatal level of 5-HIAA gradually increased up to 180% within 1–4 h after Semax (0.15 mg/kg, ip) administration. This peptide alone failed to alter the tissue and extracellular concentrations of dopamine and its metabolites. Semax injected 20 min prior d-amphetamine dramatically enhanced the effects of the latter on the extracellular level of dopamine and on the locomotor activity of animals. Our results reveal the positive modulatory effect of Semax on the striatal serotonergic system and the ability of Semax to enhance both the striatal release of dopamine and locomotor behavior elicited by d-amphetamine. Special issue dedicated to Dr. Simo S. Oja.     

The participation of CCK-8-ergic mechanisms in the regulation of emotional behavior in rodents

Effects of CCK-8 receptor agonists caerulein and pentagastrin and CCK-8 receptor antagonist proglumide on exploratory and locomotor activity of mice and rats were studied. Systemic administration of caerulein (500 ng/kg 1 mcg/kg) decreased significantly the exploratory activity of mice in elevated plus-maze. This anxiogenic-like action of caerulein was attenuated by acute pretreatment with proglumide (1 and 15 mg/kg) but not with diazepam (up to 0.75 mg/kg). Proglumide slightly increased the exploratory activity of rats in plus-maze; on the other hand, caerulein and pentagastrin potently decreased the measures of exploration in this test. Caerulein (10-100 mcg/kg) and proglumide (1 and 15 mg/kg) inhibited 3H-pentagastrin binding in mice brain in in vivo experiments. The data obtained indicate that CCK-8-ergic mechanisms in brain play an important role in the generation of anxiety states in rodents.     

Anticonvulsant Efficacy of Drugs with Cholinergic and/or Glutamatergic Antagonism Microinfused into Area Tempestas of Rats Exposed to Soman

A group of antiparkinson drugs (benactyzine, biperiden, caramiphen, procyclidine, and trihexyphenidyl) has been shown to possess both anticholinergic and antiglutamatergic properties, making these agents very well suited as anticonvulsants against nerve agents. The first purpose of this study was to make a comparative assessment of the anticonvulsant potencies of the antiparkinson agents when microinfused (1 μl) into the seizure controlling area tempestas (AT) of rats 20 min before subcutaneous injection of soman (100 μg/kg). The second purpose was to determine whether cholinergic and/or glutamatergic antagonism was the effective property. The results showed that only procyclidine (6 μg) and caramiphen (10 μg) antagonized soman-induced seizures. Cholinergic, and not glutamatergic, antagonism was likely the active property, since atropine (100 μg), and scopolamine (1 μg) caused anticonvulsant effects, whereas MK-801 (1 μg), and ketamine (50 μg) did not. Soman (11 nmol) injected into AT resulted more frequently in clonic convulsions than full tonic–clonic convulsions. AT may serve as both a trigger site for soman-evoked seizures and a site for screening anticonvulsant potencies of future countermeasures. Special issue article in honor of Dr. Frode Fonnum.     

Effect of dietary nickel and iron on the trace element content of rat liver

The level and/or form of dietary iron, dietary nickel, and the interaction between them affected the trace element content of rat liver. Livers were from the offspring of dams fed diets containing 10–16 ng, or 20 μg, of nickel/g. Dietary iron was supplied as ferric chloride (30 μg/g) or ferric sulfate (30 μg, or 60 μg). In nickel-deprived rats fed 60 μg of iron/g of diet as ferric sulfate, at age 35 days, levels of iron and zinc were depressed in liver and the level of copper was elevated. At age 55 days, iron was still depressed, copper was still elevated, but zinc also was elevated. In rats fed 30 μg of iron/g of diet as ferric chloride, liver iron content was higher in nickel-deprived than in nickel-supplemented rats at 30, but not at 50, days of age. Also manganese and zinc were lower in nickel-deprived than in nickel-supplemented rats at age 35 days if their dams had been on experiment for an extended period of time (i.e., since age 21 days). Thus, the levels of copper, iron, manganese, and zinc in liver were affected by nickel deprivation, but the direction and extent of the affects depended upon the iron status of the rat.     

Influence of selenium (antioxidant) on gliclazide induced hypoglycaemia/anti hyperglycaemia in normal/alloxan-induced diabetic rats

Oxidative stress is involved in diabetes mellitus and its complications. Since diabetes is a stress-related disorder, supplementation with antioxidants may improve the condition. The purpose of this study is to know the effect of oral administration of selenium on blood glucose and its influence on gliclazide induced hypoglycaemia/antihyperglycaemia in normal and alloxan-induced diabetic rats. Albino rats of either sex were divided into three groups of six each. Group-I/II/III were treated with selenium 1/2 TD (0.9 μg/200 g rat)/TD (1.8 μg/200 g rat)/2TD (3.6 μg/200 g rat), respectively. Later group II was treated with gliclazide TD (1.44 mg/200 g rat)/selenium TD + gliclazide TD with a washout period of 1 week between the treatments. Diabetes was induced by alloxan monohydrate 100 mg/kg body weight i.p. A group of six rats showing fasting blood glucose levels ranging from 175–250 mg/dl were selected for the study. Rats were treated with selenium TD, gliclazide TD and selenium TD + gliclazide TD with a washout period of 1 week between the treatments. Selenium 1/2 TD and TD produced hypoglycaemia while 2TD produced hyperglycaemia. The combination of selenium TD with gliclazide TD, significantly enhanced the glucose lowering effect of gliclazide in normal and diabetic rats.     

CCK-8对内毒素休克大鼠肺脏细胞因子的抑制效应

观察八肽胆囊收缩素(cholecystokinin-octapeptide,CCK-8）改善脂多糖(lipopolysaccharide,LPS）引起的大鼠内毒素性休克（endotoxic shock,ES）过程中血清及肺脏细胞因子的变化,探讨p38比裂素活化蛋白激酶（p38 mito-gen-activated protein kinase,p38 MAPK）的信号转导作用。用生理多道记录仪观察尾静脉注入LPS(p38 mito-gen-activated protein kinase,p38 MAPK）的信号转导作用。用生理多道记录仪观察尾静脉注入 LPS（8mg/kg i.v.）复制的SD大鼠ES模型、LPS注入前10min尾静脉注入CCK-8(40ug/kg i.v.）、单独注入CCK-8(40Uug/kg i.v.）或生理盐水（对照）的四组大鼠平均动脉血压（MAP）的改变,应用ELISA试剂盒检测血清和肺脏中炎性细胞因子（TNF-a、IL-1β和IL-6）的变化。用Western blot检测肺脏p38 MAPK的表达。结果显示：CCK-8可改善LPS引起的大鼠MAP的下降。与对照组相比,LPS可显著增加血清和肺脏TNF-a、IL-1β和IL-6含量;CCK-8可显著抑制LPS诱导的血清和肺脏TNF-a、IL-1β和IL-6的增加。CCK-8可增加ES大鼠肺脏磷酸化p38 MAPK的表达。结果提示CCK-8可改善ES大鼠MAP的降低,并对肺脏促炎性细胞因子过量产生有抑制作用,p38MAPK可能参与了其信号转导机制。     

MK-329 blocks the inhibition of alcohol intake by CCK-8

Peripheral administration of sulfated cholecystokinin octapeptide (CCK-8) potently reduces alcohol intake, preference, and blood levels in rats. MK-329 (L-364,718 or Devazepide) acts at peripheral cholecystokinin (CCK_A) receptors to antagonize CCK-8's physiological and behavioral effects, such as pancreatic stimulation and inhibition of feeding. We determined whether CCK_A receptor blockade would also prevent CCK-8's alcohol satiety effect. Water-deprived female and male rats (n = 7 for each) received randomized combinations of intraperitoneal injections of MK-329 (0, 100, 200, or 400 μg/kg) followed by CCK-8 (0 or 4 μg/kg). Rats were then given access to 5% w/v ethanol for 30 min, followed by 30-min access to water, with food ad lib. MK-329 at all doses significantly (p < 0.05) reduced the suppression of alcohol intake and food intake by CCK-8. MK-329 alone increased alcohol intake at 400 μg/kg, and increased food intake, in females and males at 100 and 200 μg/kg, respectively. We concluded that CCK-8's alcohol and food satiation effects depend on specific, peripheral CCK_A receptors, and satiation of alcohol consumption and drinking-associated feeding reflect an endogenous functional interaction of CCK-8 with CCK_A receptors.