Guhong injection protects against focal cerebral ischemia–reperfusion injury via anti-inflammatory effects in rats

Guhong injection (GHI), composed of aceglutamide and safflower aqueous extract, has been used clinically for the treatment of cerebrovascular diseases such as cerebral embolism, hemorrhage and mental deterioration. In this paper, we reported the results of the first study on the anti-inflammatory effects of GHI in murine focal cerebral ischemia–reperfusion (I/R) injury. Adult male SD rats were randomly divided into six groups: Sham group, I/R group, GHI-L group (2.5 mL/kg), GHI-M group (5 mL/kg), GHI-H group (10 mL/kg) and Nimodipine group. I/R injury was induced by middle cerebral artery occlusion (MCAO) for 1.5 h followed by reperfusion for 24 h. Compared with I/R group, rats treated with GHI showed dose dependent reductions in neurological defect scores and cerebral infarct volume. GHI obviously down-regulated nitric oxide (NO), inducible NO synthase (iNOS), myeloperoxidase (MPO), interleukin-1β (IL-1β), TNF-α (tumor necrosis factor-α) and C reactive protein (CRP) levels in serum. Moreover, histological examination by H&E staining showed that clear cell outline, less vacuolated spaces and largely surviving neurons were observed in GHI-treated rats. The immunohistochemical staining revealed that GHI administration significantly diminished the positive expressions of intercellular cell adhesion molecule-1 (ICAM-1) and nuclear factor-κB p65 (NF-κB p65) in brain tissues. Western blot analysis for ICAM, NF-κB p65 and iNOS further solidified the above findings. All these results demonstrate that GHI exerts a strong and ameliorative effect on cerebral I/R injury in rats possibly through the inhibition of inflammation.     

Protective effect of palm vitamin E and α-tocopherol against gastric lesions induced by water immersion restraint stress in Sprague-Dawley rats

Objective:

Stress can lead to various changes in the gastrointestinal tract of rats. The present study was designed to compare the effect of palm vitamin E (PVE) and α-tocopherol (α-TF) supplementations on the gastric parameters important in maintaining gastric mucosal integrity in rats exposed to water immersion restraint stress (WRS). These parameters include gastric acidity, plasma gastrin level, gastric prostaglandin E₂ (PGE₂), and gastric lesions.

Materials and Methods:

Sixty male Sprague-Dawley rats (200-250 g) were divided into three equal groups: a control group, which received a normal rat diet (RC), and two treatment groups, receiving oral supplementation of either PVE or α-TF at 60 mg/kg body weight for 28 days. Each group was further divided into two groups: the nonstress and stress groups. The stress groups were subjected to 3.5 h of WRS once at the end of the treatment period. Blood samples were then taken to measure the gastrin level, after which the rats were killed. Gastric juice was collected for measurement of gastric acidity and gastric tissue was taken for measurement of gastric mucosal lesions and PGE₂.

Results:

Exposure to stress resulted in the production of gastric lesions. PVE and α-TF lowered the lesion indices as compared to the stress control group. Stress reduced gastric acidity but pretreatment with PVE and α-TF prevented this reduction. The gastrin levels in the stress group were lower as compared to that in the nonstress control. However, following treatment with PVE and α-TF, gastrin levels increased and approached the normal level. There was also a significant reduction in the gastric PGE₂ content with stress exposure, but this reduction was blocked with treatment with both PVE and α-TF.

Conclusion:

In conclusion, WRS leads to a reduction in the gastric acidity, gastrin level, and gastric PGE₂ level and there is increased formation of gastric lesions. Supplementation with either PVE or α-TF reduces the formation of gastric lesions, possibly by blocking the changes in the gastric acidity, gastrin, and gastric PGE₂ induced by stress. No significant difference between PVE and α-TF was observed.     

Intranasal recombinant human erythropoietin protects rats against focal cerebral ischemia

Erythropoietin （EPO） is a hematopoietic growth-factor with tissue -protective properties, and can protect animals from cerebral ischemic injury. However, the central nervous effects of EPO as a glycoprotein is limited by the potential complication resulted from its erythropoietic activity and the problem of the penetration through blood-brain barrier （BBB）. To avoid these limitations,     

Inhibition of TNF-α protects against hepatic ischemia–reperfusion injury in rats via NF-κB dependent pathway

Hepatic ischemia–reperfusion injury (I/R) is a serious health problem associated with liver transplantation, resection surgery, and various types of shock especially hemorrhagic shock. In the present investigation, the effect of inhibition of tumor necrosis factor-alpha (TNF-α) using pentoxifylline or infliximab against hepatic I/R injury induced in rats by 45-min ischemia and 1-h reperfusion was studied. It was observed that both pentoxifylline and infliximab-treated groups showed a significantly lower extent and severity of liver injury. This is attributed to (1) a decrease in oxidative stress markers, (2) reduction of the expression of TNF-α, TNF-α type-1 receptors, and nuclear factor kappa B (NF-κB). Thus TNF-α inhibition may be one of the therapeutic interventions to overcome the deleterious effects of I/R on liver via reduction of oxidative stress and inhibition of inflammatory cascade.     

Rosiglitazone, a PPAR-γ agonist, protects against striatal dopaminergic neurodegeneration induced by 6-OHDA lesions in the substantia nigra of rats

Rosiglitazone is a commonly prescribed insulin-sensitizing drug with selective agonistic activity at the peroxisome proliferator-activated receptor-γ (PPARγ). Previously, rosiglitazone was shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), an effect attributed to its anti-inflammatory properties. To elucidate the neuroprotective mechanisms of rosiglitazone, we investigated the effects of rosiglitazone on the expressions of striatal tyrosine hydroxylase (TH), cyclooxygenase-2 (COX-2) and glial fibrillary acidic protein (GFAP) in a 6-OHDA-lesioned rat PD model. Rosiglitazone (3mg/kg) was administered intraperitoneally at 24h and 30min prior to the creation of an intranigral 6-OHDA lesion. A reduction in TH protein expression began at 3days and a prominent decrease was observed at 7days post-lesion, and decreases of dopamine (DA) levels began at 1day post-lesion. In contrast, GFAP expression was significantly increased at 3days and preserved for up to7 days post-lesion and the patterns of GFAP expression was inversely correlated to changes in TH expression. Furthermore, COX-2 expression in the rostral striatum showed a significant increase at 6h post-lesion while that of the caudal striatum was increased at 12h. In the 6-OHDA-lesioned model, the activation of PPARγ by rosiglitazone significantly prevented TH protein expression reductions, and inhibited 6-OHDA-induced microglia activation in striatum. In addition, rosiglitazone attenuated in production of both COX-2 and TNF-α expression. In contrast, rosiglitazone pretreatment led to greater increases in striatal GFAP expression than 6-OHDA alone and changes in the expression of this protein preceded the changes that were seen with TH expression. These results suggest that the neuroprotection observed with rosiglitazone treatment may be partially due to the attenuation of COX-2 production and the strengthening of astrocyte function. Our results provide insight into the neuroprotective mechanisms of rosiglitazone against 6-OHDA-induced neuronal damages.     

Intracerebroventricular injection of a TRH analogue, γ-butyrolactone-γ-carbonyl-l-histidyl-prolinamide induces gastric lesions and gastric acid stimulation in rats

Summary The effects of TRH and its biologically stable analogue, -butyrolactone--carbonyl-l-histidyl-l-prolinamide (DN-1417), on gastric mucosa and acid secretion were examined in rats. Intracerebroventricular (ICV) injection of DN-1417 (0.1–10 g) caused a dose-dependent gastric lesion in the corpus and antrum 6 h after administration. The gastric lesions produced by 1 g of DN-1417 were more severe than those produced by ICV TRH (10 g), intravenous DN-1417 (200 g) and stress. Although the lesion-generating effect of TRH (10 g) tended to be reduced 6 h after the injection, that of DN-1417 (1 g) was sustained during 6 h. Atropine (0.1 and 1 mg/kg s.c.) inhibited DN-1417-induced gastric lesions in a dose-related manner while sulpiride (10 and 30 mg/kg s.c.), haloperidol (1 mg/kg i.p.), phentolamine (1 and 5 mg/kg s.c.) and yohimbine (5 mg/kg s.c.) did not prevent the lesions. ICV DN-1417 also stimulated basal gastric acid secretion and the effect was stronger and longer-lasting than that of TRH. Atropine (0.1 mg/kg s.c.) stopped DN-1417-stimulated gastric acid secretion. In conclusion, the possibility that TRH may be involved in the CNS modulation of gastric mucosal integrity deserves further attention. The enhanced potency of action of DN-1417 over TRH could make ICV injection of this peptide a useful tool for inducing centrally-mediated gastric lesions in rats.     

Pharmacodynamic interaction of 3α-hydroxymasticadienonic acid and diligustilide against indomethacin-induced gastric damage in rats

The aims of the study were to evaluate the pharmacodynamic interaction between 3α-hydroxymasticadienonic acid and diligustilide (DLG), isolated from the plants Amphiptherygium adstringens and Ligusticum porteri, respectively, using the indomethacin-induced gastric injury model, as well as their individual gastroprotective efficacy in this model. Male Wistar rats were orally administered with 3α-hydroxymasticadienonic acid, DLG or the mixture of 3α-hydroxymasticadienonic acid-DLG (at a fixed-ratio combination of 1:1, 1:3, and 3:1). Thirty minutes later, the gastric damage was induced by a single oral dose of indomethacin (30 mg/kg). Three hours later, the gastric injury (mm²) was determined. 3α-hydroxymasticadienonic acid and DLG as individual compounds showed a gastroprotective effect against indomethacin-induced gastric damage (p < .05). The effective dose (ED₅₀) values for each compound were 6.96 ± 1.25 mg/kg for 3α-hydroxymasticadienonic acid and 2.63 ± 0.37 mg/kg for DLG. The isobolographic analysis performed showed that the combination exhibited super-additive interaction as the experimental ED₅₀ values (Zexp) were lower than theoretical additive dose values (Zadd; p < .05). Our results identify the super-additive (synergist) interaction between 3α-hydroxymasticadienonic acid and DLG and the gastric safety of both compounds in the indomethacin—induced gastric injury model, suggesting their potential in the future as a strategy to decrease the gastric damage associated to the chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs).     

Acute inhalation toxicity of aliphatic (C1–C5) nitrites in rats

The 4-hr inhalation LC50 was determined for methyl-, ethyl-, n-propyl-, n-butyl-, isobutyl-, and isopentyl nitrite in Sprague-Dawley rats. LC50 values were 176, 160, 300, 420, 777, and 716 ppm, respectively. The dose-mortality curves were characterized by extremely steep slopes. Toxic signs observed during exposure included cyanosis, prostration, and rarely, convulsions. There were no effects of exposure on body weight gain during a 14-day postexposure observation period. Signs of pulmonary hemorrhage were apparent in rats which died during exposure but were much less prominent in rats sacrificed at study termination. No animals died after cessation of exposure, and rapid recovery was apparent after exposure. Concentration × Time (CT) relationships suggested that the actual concentration was more important than the “dose” in determining the lethal effects of inhalation exposure to nitrites. Because of the extremely steep dosemortality curves, the aliphatic nitrites are more hazardous than the LC50 values would indicate.     

Effects of peptidase inhibitors on anti-nociceptive action of dynorphin-(1–8) in rats

Previous in vitro studies showed that the degradation of dynorphin-(1-8) [dyn-(1-8)] by cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors (PIs), amastatin, captopril and phosphoramidon. In the present investigations, effects of the three PIs on the anti-nociception induced by the intra-third-ventricular (i.t.v.) administration of dyn-(1-8) were examined. The inhibitory effect of dyn-(1-8) on the tail-flick response was increased more than 100-fold by the i.t.v. pretreatment of rats with the three PIs. The inhibition produced by dyn-(1-8) in rats pretreated with any combination of two PIs was significantly smaller than that in rats pretreated with three PIs, indicating that any residual single peptidase could inactivate significant amounts of dyn-(1-8). The antagonistic effectiveness of naloxone, a relatively selective mu-opioid antagonist, indicates that dyn-(1-8)-induced inhibition of tail-flick response in rats pretreated with three PIs is mediated by mu-opioid receptors. Furthermore, mu-receptor-mediated inhibition induced by dyn-(1-8) was significantly greater than that produced by [Met5]-enkephalin in rats pretreated with three PIs. The data obtained in the present investigations together with those obtained in previous studies strongly indicate that dyn-(1-8) not only has well-known kappa-agonist activity but also has high mu-agonist activity.     

Hydrogen sulfide protects against bleomycin-induced pulmonary fibrosis in rats by inhibiting NF-κB expression and regulating Th1/Th2 balance

Hydrogen sulfide (H₂S) displays vasodilative, anti-oxidative, anti-inflammatory and cytoprotective activities. The objective of this study was to evaluate the inhibitory effect of H₂S on bleomycin (BLM)-induced pulmonary fibrosis in rats and its possible mechanisms. Fifty-four pathogen-free Male Wistar rats were randomly divided into three groups: control, BLM and H₂S treated groups with 18 rats in each group. Each group was then divided into three subgroups based on time of study (7, 14 and 28 day). Pulmonary fibrosis model was established by a single intratracheal instillation of BLM A₅ (5 mg/kg). While control rats received saline, rats of the treated group simultaneously were administered intraperitoneal injections of NaHS (the H₂S donor, 28 μmol/kg) once daily. BLM induced pulmonary inflammation and fibrosis, increased lung hydroxyproline levels, lung index, total cell counts, neutrophils and eosinophils counts and expression of NF-κB p65 in lung tissue, decreased lymphocytes and macrophages counts. In addition, Th1 response is suppressed as shown by diminished IFN-γ in bronchoalveolar lavage fluid (BALF) after BLM exposure, and enhancement of Th2 response is marked by increased IL-4 in BALF. H₂S administration significantly attenuated these effects. The findings reveal the therapeutic potential of H₂S for BLM-induced pulmonary fibrosis in male rats, which were at least partly due to inhibition NF-κB p65 expression and regulation of Th1/Th2 balance.     

Angiotensin 1 – 7 stimulation of platelet recovery

Introduction: Thrombocytopenia is an abnormally low number of platelets in the blood resulting from either too few platelets being produced or existing platelets being destroyed. Severe thrombocytopenia leads to excessive bleeding and can be the result of numerous medical conditions or a side effect of medications or treatments. Although platelet transfusions are typically administered to correct thrombocytopenia, transfusions represent a temporary and unsustainable solution. As there is a limited supply of platelet units available for transfusion, along with the significant financial cost and risk of infection, investigation to uncover mechanisms that boost platelet production may have important clinical and therapeutic implications. Treatment with angiotensin 1 – 7 (A(1 – 7)) has been shown in a preclinical and clinical evaluations to have a positive effect on platelet recovery.

Areas covered: The authors provide an overview of the current treatment options available for platelet recovery and highlight the need for alternatives. Following on, the authors discuss the use of A(1 – 7) as a potential therapeutic option for platelet recovery, including its safety and efficacy.

Expert opinion: Current evidence provides a good basis for continued research and evaluation of the benefits of A(1 – 7) treatment in stimulating platelet recovery following myelosuppression. A(1 – 7) therapy has the potential to make a significant contribution to healthcare by providing standalone and additive treatments to address unmet medical needs and life-threatening diseases by utilizing the regenerative arm of the renin–angiotensin system.     

Ergothioneine protects against neuronal injury induced by β-amyloid in mice

β-Amyloid peptides (Aβ) are neurotoxic and contribute to the development of Alzheimer’s disease (AD). Ergothioneine (EGT) has been shown to protect against loss of memory and learning abilities in mice. In this study, mice were orally fed EGT (0.5 or 2 mg/kg body weight) for 16 days before treatment (i.c.v) with a single dose of Aβ1–40 in the hippocampus. After resting for 12 days to restore the body weight, the mice were again fed EGT for additional 39 days. Active avoidance tests were conducted on days 37–39 (short-memory avoidance) and on days 37, 44 and 51 (long-memory avoidance). Water maze task was used to evaluate learning and memory abilities by acquisition test and retention test. In both long-memory avoidance and water maze tests, EGT significantly decreased the escape latency and increased the frequency of successful avoidance. Furthermore, EGT significantly prevented Aβ accumulation in the hippocampus and brain lipid peroxidation, restored acetylcholinesterase (AChE) activity, maintained glutathione/glutathione disulfide ratio and superoxide dismutase activity in brain tissues of Aβ1–40-teated mice. Thus, EGT can protect against Aβ-induced loss of memory and learning abilities in mice. Further studies are required to confirm the protective effects of EGT on the development or progression of AD.     

Neuroprotective effects of Schisandrin B against transient focal cerebral ischemia in Sprague–Dawley rats

Fruits of Schisandra have been traditionally used in East Asia for the treatment of dyspnea, cough, dysentery, insomnia, tonic-clonic seizures, and amnesia. Schisandrin B, a dibenzocyclooctadiene derivative isolated from Fructus Schisandrae, has been shown to produce antioxidant effect on rodent liver and heart. In the present study, we investigated the neuroprotective effects of Schisandrin B, a constituent drug of the fruit of Schisandra, against focal cerebral ischemia in rats. Schisandrin B (10, 30 mg/kg, i.p.) was twice administered 30 min before the onset of ischemia and 2 h after reperfusion. Schisandrin B 10 and 30 mg/kg treated groups showed infarct volumes reduced by 25.7% and 53.4%, respectively, 2 h after occlusion. Also, Schisandrin B treated animal treatment abrogated protein expression of TNF-α and IL-1β and degradation of MMP-2 and MMP-9 in ischemic hemispheres. These results suggest that Schisandrin B treatment provides a neuroprotective effect to rats after transient focal cerebral ischemia by inhibiting inflammation and by protecting against metalloproteinase degradation.     

Cellular mechanisms of β-carotene-induced gastric cytoprotection in indomethacin-treated rats

Indomethacin (IND) is a non-steroidal anti-inflammatory agent which is widely used in the treatment of various inflammatory disorders. The drug causes gastrointestinal injury in humans and experimental animals. The aim of these studies was to examine the time course correlation between the macroscopic appearance of mucosal damage, tissue level of PGE₂ and adenosine nucleotide metabolism during the development of indomethacin (IND)-induced mucosal damage and its prevention by β-carotene. The observations were carried out on both sexes of CFY-strain rats, weighing 180–200 g. Gastric mucosal damage was produced by subcutaneous administration of IND (20 mg/kg). β-Carotene (Hoffman-La Roche, Switzerland) was given intragastrically at the time of IND administration at doses of 0.01, 0.1, 1 and 10 mg/kg. The animals were sacrificed at 0, 1, 2, 3 and 4 h after IND administration when the number and severity of mucosal lesions were noted and the tissue levels of ATP, ADP, AMP, cAMP, lactate and PGE₂ were measured from the total homogenate of gastric mucosa. The ratio of ADP/ATP, the values of the adenylate pool (ATP+ADP+AMP), and ‘energy charge’ [(ATP+0.5ADP)/(ATP+ADP+AMP)] were calculated. It was found that: (a) gastric mucosal lesions appear macroscopically 2 h after IND administration; (b) the tissue level of ATP decreased, while ADP was increased 1 h after administration; (c) the most significant decrease in cAMP was found 1 h after IND administration, and thereafter its level returned to baseline; (d) β-carotene dose-dependently prevented the IND-induced mucosal damage and elevated the cAMP level, but it did not alter the mucosal PGE₂ level 3 or 4 h after IND administration; (e) β-carotene produced an elevation in ATP and a decrease in ADP level; (f) no significant changes were found in ‘energy charge’ of the gastric mucosa in IND-treated animals. The development of gastric mucosal damage due to IND was associated with increased energy liberation, i.e. transformation of ATP into ADP, and decreased ATP-cAMP transformation. The significant decrease in cAMP preceded the macroscopic appearance of mucosal damage. The increase in ATP-cAMP transformation is involved in the development of β-carotene-induced gastric cytoprotection.     

Scutellarin protects against Aβ-induced learning and memory deficits in rats: involvement of nicotinic acetylcholine receptors and cholinesterase

Aim:

To examine the protective effects of scutellarin (Scu) on rats with learning and memory deficit induced by β-amyloid peptide (Aβ).

Methods:

Fifty male Wistar rats were randomly divided into 5 groups: control, sham operation, Aβ, Aβ+Scu, and Aβ+piracetam groups. Aβ_25–35 was injected into the lateral ventricle (10 μg each side). Scu (10 mg/2 mL) or piracetam (10 mg/2 mL was intragastrically administered per day for 20 consecutive days following Aβ treatment. Learning and memory was assessed with Morris water maze test. The protein and mRNA levels of nicotinic acetylcholine receptor (nAChR) α4, α7, and β2 subunits in the brain were examined using Western blotting and real-time PCR, respectively. The activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the brain and plasma were measured using Ellman''s colorimetric method.

Results:

In Aβ group, the escape latency period and first platform cross was significantly increased, and the total number of platform crossings was significantly decreased, as compared with the control and the sham operation groups. Both Scu and piracetam treatment significantly reduced the escape latency period and time to cross platform, and increased the number of platform crosses, but there were no significant differences between Aβ+Scu and Aβ+piracetam groups. In Aβ group, the protein levels of nAChR α4 and α7 subunits in the cerebral cortex were significantly decreased by 42%–47% and 58%–61%, respectively, as compared to the control and the sham operation groups. Scu treatment caused upregulation of α4 and α7 subunit proteins by around 24% and 30%, respectively, as compared to Aβ group, but there were no significant differences between Aβ+Scu and Aβ+piracetam groups. The protein level of nAChR β2 subunit had no significant difference among different groups. The mRNA levels of nAChR α4, α7, and β2 subunits were not significantly changed. In Aβ group, the activities of AChE and BuChE in the brain were significantly increased, but were significantly decreased in the plasma, as compared to the control and the sham operation groups. Scu or piracetam treatment restored the activities in brain and plasma nearly to the levels in the control group.

Conclusion:

The results suggest that Scu may rescue some of the deleterious effects of Aβ, possibly by stimulating nAChR protein translation and regulating cholinesterase activity.     

Epigallocatechin-3-gallate,a green tea catechin,protects the heart against regional ischemia–reperfusion injuries through activation of RISK survival pathways in rats

Epigallocatechin-3-gallate (EGCG), the major catechin derived from green tea, has been shown to modulate numerous molecular targets in the setting of inflammation. This study aimed to determine whether EGCG protects against regional myocardial ischemia/reperfusion (I/R) injuries and its underlying mechanisms involving the role of reperfusion injury salvage kinase (RISK) pathways (PI3K-Akt and ERK 1/2) and GSK-3β or apoptotic kinases (p38 and JNK). The rats were subjected to I/R injuries consisting of 30 min ischemia followed by 2 h reperfusion. EGCG (10 mg/kg, intravenously) was administered alone or along with wortmannin (PI3K inhibitor, 0.6 mg/kg, intravenously) 5 min before the onset of reperfusion. Wortmannin was administered 10 min before the reperfusion. Infarct size was measured at the end of the reperfusion. The phosphorylation of Akt, GSK-3β, and MAPK kinases (ERK1/2, P38 and JNK) was determined by Western blotting after 10 min of reperfusion. EGCG reduced the infarct size compared with the control (25.4 ± 9.2 versus 43.2 ± 8.2 %, p < 0.05). Wortmannin alone did not affect the infarct size, but abolished the EGCG-induced infarct size limiting effect, indicating that EGCG may protect the heart by modulating the PI3K-Akt. EGCG significantly enhanced the phosphorylation of Akt and GSK-3β but not ERK1/2, while it reduced that of p38 and JNK. These results suggest that EGCG has a protective effect against regional myocardial I/R injuries through activation of the RISK pathway and attenuation of p38 and JNK. EGCG may have cardioprotective effects in patients undergoing surgeries prone to myocardial I/R injuries.     

Possible involvement of GLP-1(9�C36) in the regional haemodynamic effects of GLP-1(7�C36) in conscious rats

BACKGROUND AND PURPOSE

The incretin hormone, glucagon-like peptide (GLP)-1(7–36), is rapidly cleaved by dipeptidyl peptidase 4 (DPP-4) into GLP-1(9–36), and although it is agreed that most, if not all, of the metabolic effects are attributable to the intact peptide, the degree to which the cardiovascular effects are due to the cleavage product is unclear. The purpose of this study was to measure the regional haemodynamic effects of GLP-1(7–36), and determine the extent to which the cardiovascular effects of GLP-1(7–36) were influenced by DPP-4 inhibition and reproduced by GLP-1(9–36). Additional experiments investigated the involvement of autonomic mechanisms in the cardiovascular effects of GLP-1(7–36).

EXPERIMENTAL APPROACH

Regional haemodynamic effects of bolus doses and 4 h infusions of GLP-1(7–36) amide and GLP-1(9–36) amide were measured in conscious, chronically instrumented rats; the influence of DPP-4 inhibition and autonomic blockade on responses to GLP-1(7–36) were also assessed.

KEY RESULTS

Glucagon-like peptide-1(7–36) had clear regional haemodynamic effects comprising tachycardia, a rise in blood pressure, renal and mesenteric vasoconstriction and hindquarters vasodilatation, whereas GLP-1(9–36) was devoid of any cardiovascular actions. The effects of GLP-1(7–36) were enhanced by DPP-4 inhibition, and the tachycardia and hindquarters vasodilatation were β-adrenoceptor-mediated.

CONCLUSIONS AND IMPLICATIONS

In conscious rats, the cardiovascular effects of GLP-1(7–36) resemble those of the GLP analogue, exendin-4, and are attributable to the intact peptide rather than the cleavage product, GLP-1(9–36).     

Inhibitory α2-Adrenergic mechanism regulating gastric secretion in pylorus-ligated rats

Summary Several -adrenoceptor agonists given intracerebroventricularly or subcutaneously to rats were assessed for their effects on gastric secretion under condition of pylorus ligation. Intracerebroventricular injection of -adrenoceptor agonists reduced gastric secretion, in the following order (relative potency, clonidine = 1): oxymetazoline (100) > clonidine (1) > methoxamine (0.024) > phenylephrine (0.003). The antisecretory effects of oxymetazoline and clonidine given intracerebroventricularly were antagonized with yohimbine administered by the same route. Subcutaneous injection of -adrenoceptor agonists also reduced gastric secretion, in the following order (relative potency, clonidine = 1): clonidine (1) > oxymetazoline (0.3) phenylephrine (0.001) methoxamine (0.0006). Oxymetazoline, when given intracerebroventricularly, was most effective in decreasing the volume and titratable acidity of gastric secretion. Pretreatment with 6-hydroxydopamine intracerebroventricularly (250 g/rat × 2; 72 and 120 h before) reduced the antisecretory effect of clonidine given intracerebroventricularly. Thus, gastric secretion appears to be regulated in an inhibitory manner by ₂-, but not by ₁- in the central and peripheral nervous systems, in pylorus-ligated rats.     

Anti -addiction effects of agmatine against heroin self-administration in rats

Rationale： Drug abuse is serious and costly health problems. Present understanding that drug addiction is a chronic brain disease paves the way for pharmacotherapy. Unfortunately, few medications have proven effective for the treatment of addiction and dependence. Searching novel strategies of pharmacotherapy against drug addiction are challenging. Agmatine （ decarboxylated L - arginine）, an endogenous imidazoline receptor ligand, with multiple pharmacological profiles including its NMDA antagonistic properties, attracts the attention for its potential therapeutic efficacy for drug addiction.     

Mast cell- derived mediators protects PC12 cells against ischemia in vitro

We have previously demonstrated that brain mast cells degranulated under ischemia in in vivo or in vitro experiments. However the true role of mast cells in the brain ischemia is still known. In the present study, we investigated the effect of the mediators from the mast cell on neuronal cell line PC12 in an in vitro ischemic model oxygen - glucose deprivation （OGD）. The supernatant of mast cells was collected ofter 1h OGD, and then incubated with the PC12 cells under lh OGD. Results showed that by the incorporation of the mast cell - derived supernatants, the survival of PC12 cells markedly increased after OGD exposure with or without 24h reperfusion. Histamine H1 receptor antagonist pyrilamine significantly reversed the effect of the mast cell - derived supernatants, which indicated the participation of histamine in this process. However histamine itself did not increased the survival of PC12 cells after OGD.