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To preclinically study the effectiveness of new antihypertensive drugs, various animal hypertension models are used. However, most of them do not correspond to primary hypertension, which develops in people with age. We used male Wistar rats of 4, 10, 12 and 18 months old. The animals were divided according to systolic blood pressure (SBP) into normotensive (SBP ≤ 114 mmHg) or hypertensive (SBP ≥ 115 mmHg). Within hypertensive animals, two cohorts were distinguished-with SBP below and above 125 mmHg. The animals received 100 µg/kg of taxifolin intraperitoneally for 7 days. A significant difference was shown between animals with SBP above and below 115 mmHg, as well as between cohorts of hypertensive animals with SBP above and below 125 mmHg within each age. The number of animals with elevated SBP increased with age both for clusters with an SBP above 115 mmHg and for cohorts with an SBP above 125 mmHg. Administration of taxifolin led to a significant decrease in the SBP only in hypertensive animals. A physiological model of age-related hypertension was obtained in male Wistar rats. It has been shown that hypertension develops and worsens with age. In preclinical studies, it should be taken into account that drugs may have different effects depending on the initial SBP of the animals.

Background/Objectives : Intratracheal administration of bleomycin (BLM) to laboratory rodents is a standard, widely used technique used to model pulmonary fibrosis (PF). BLM, as a modeling agent, is produced mainly in the form of two salts-sulfate and chloride. We compared the results of modeling PF in SD rats by intratracheal administration of BLM sulfate and BLM chloride. Methods : Healthy mature male SD rats were used. PF was modeled by intratracheal administration of BLM sulfate and BLM chloride at a dose of 3 mg/kg. The criteria for the development of PF included body weight gain, changes in respiratory parameters, relative lung weight, cellular composition of broncho-alveolar fluid (BALF), histological assessment of the severity of PF with trichrome Masson staining. Results : Intratracheal administration of both BLM salts led to the development of pronounced PF, which was determined by changes in all of the measured parameters relative to control animals. There were no significant differences between the BLM sulfate and BLM chloride groups in body weight gain, hydroxyproline content, and histological evaluation. However, significant differences were identified in the cellular composition of BALF-a significant increase in alveolar macrophages and neutrophils levels in animals treated with BLM sulfate. Conclusions : Intratracheal administration of both BLM salts led to the development of severe PF; however, the inflammatory process in animals receiving BLM sulfate was more pronounced and prolonged than in animals receiving BLM chloride, which in the former, when observed more than 21 days after modeling, can lead to more severe PF.

The development of novel anticoagulants requires a comprehensive investigational approach that is capable of characterizing different aspects of antithrombotic activity. The necessary experiments include both in vitro assays and studies on animal models. The required in vivo approaches include the assessment of pharmacokinetic and pharmacodynamic profiles and studies of hemorrhagic and antithrombotic effects. Comparison of anticoagulants with different mechanisms of action and administration types requires unification of the experiment scheme and its adaptation to existing laboratory conditions. The rodent thrombosis models in combination with the assessment of hemostasis parameters and hematological analysis are the classic methods for conducting preclinical studies. We report an approach for the comparative study of the activity of different anticoagulants in vivo, including the investigation of pharmacodynamics and the assessment of hemorrhagic effects (tail-cut bleeding model) and pathological thrombus formation (inferior vena cava stenosis model of venous thrombosis). The reproducibility and uniformity of our set of experiments were illustrated on unfractionated heparin and dabigatran etexilate (the most common pharmaceuticals in antithrombic therapy) as comparator drugs and an experimental drug variegin from the tick Amblyomma variegatum . Variegin is notorious since it is a potential analogue of bivalirudin (Angiomax, Novartis AG, Basel, Switzerland), which is now being actively introduced into antithrombotic therapy.

A short synthetic peptide from the C-terminal part of the caveolin-3 structure was tested for experimental autoimmune encephalomyelitis (EAE) treatment in rats. The structure-function similarity established between the novel synthetic peptide of pCav3 and the well-known immunomodulator immunocortin determined pCav3's ability to reduce EAE symptoms in Dark Agouti (DA) rats injected with pCav3 (500 µg/kg). pCav3 was found to interfere with the proliferation of lymphocytes extracted from the LNs of DA rats primed with homogenate injection, with IC 50 = 0.42 μM (2.35 mcg/mL). pCav3 affected EAE in a very similar manner as immunocortin. The high degree of homology between the amino acid sequences of pCav3 and immunocortin corresponded well with the therapeutic activities of both peptides, as demonstrated on EAE. The latter peptide, possessing a homologous structure to pCav3, was also tested on EAE to explore whether there were structural restrictions between these peptides implied by the MHC-involved cell machinery. Consequently, immunocortin was further examined with a different autoimmune disease model, collagen-induced arthritis (CIA), established in Sprague-Dawley rats. CIA was established using an intentionally different genetic platform than EAE. Based on the results, it was concluded that the effectiveness of pCav3 and immunocortin peptides in EAE rat model was almost identical, but differed in the rat model of rheumatoid arthritis; thus, efficacy may be sensitive to the MHC type of animals used to establish the autoimmune disease model.

α7-Type nicotinic acetylcholine receptor (α7-nAChR) promotes the growth and metastasis of solid tumors. Secreted Ly6/uPAR-Related Protein 1 (SLURP-1) is a specific negative modulator of α7-nAChR produced by epithelial cells. Here, we investigated mechanisms of antiproliferative activity of recombinant SLURP-1 in epidermoid carcinoma A431 cells and activity of SLURP-1 and synthetic 21 a.a. peptide mimicking its loop I (Oncotag) in a xenograft mice model of epidermoid carcinoma. SLURP-1 inhibited the mitogenic pathways and transcription factors in A431 cells, and its antiproliferative activity depended on α7-nAChR. Intravenous treatment of mice with SLURP-1 or Oncotag for 10 days suppressed the tumor growth and metastasis and induced sustained changes in gene and microRNA expression in the tumors. Both SLURP-1 and Oncotag demonstrated no acute toxicity. Surprisingly, Oncotag led to a longer suppression of pro-oncogenic signaling and downregulated expression of pro-oncogenic miR-221 and upregulated expression of KLF4 protein responsible for control of cell differentiation. Affinity purification revealed SLURP-1 interactions with both α7-nAChR and EGFR and selective Oncotag interaction with α7-nAChR. Thus, the selective inhibition of α7-nAChRs by drugs based on Oncotag may be a promising strategy for cancer therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shlepova, Shulepko, Shipunova, Bychkov, Kukushkin, Chulina, Azev, Shramova, Kazakov, Ismailova, Palikova, Palikov, Kalabina, Shaykhutdinova, Slashcheva, Tukhovskaya, Dyachenko, Murashev, Deyev, Kirpichnikov, Shenkarev and Lyukmanova.)

Introduction: Pharmacokinetic characteristics as well as cognitive-enhancing nootropic activity of latrepirdine (Dimebon ® ) in relationship with its polymorphic forms have been studied in SD and Wistar rats. Methods: The pharmacokinetics of six polymorphs (A, B, C, D, E, F) of latrepirdine were studied in male SD rats after 7 days of oral administration in corn oil at a dose of 10 mg/kg once a day. Blood and brain samples were taken on the 7th day of administration at 15 min, 30 min, 60 min and 120 min after administration and analyzed for latrepirdine content by LC-MS. The cognitive-enhancing nootropic effect was studied in male and female Wistar rats after 9 days of oral administration in corn oil at a dose of 10 mg/kg, after prior administration of scopolamine, an agent that causes memory impairment similar to that in Alzheimer's disease. The animals' cognitive function was studied in the passive avoidance test. Results: When studying the pharmacokinetics, the highest bioavailability both in the blood and in the brain was demonstrated by polymorph E, whose AUC was the highest relative to other polymorphs. In the study of the cognitive-enhancing nootropic effect, polymorph E also showed the highest activity, whose values of the latent period of entering the dark chamber did not differ from control animals, and differed from other polymorphs. Conclusion: Thus, the crystal structure has been shown to play a key role in the bioavailability and efficacy of latrepirdine, and polymorph E has also been shown to be a promising drug for the treatment of neurodegenerative diseases associated with memory impairment, such as Alzheimer's disease., Competing Interests: Author BG was employed by the company Bigespas Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gorin, Tukhovskaya, Ismailova, Slashcheva, Lenina, Petrov, Kazeev and Murashev.)

To simulate acute lung injury (ALI) in SD male rats they we administered intratracheally with lipopolysaccharide (LPS) followed by hyperventilation of the lungs (HVL), which lead to functional changes in the respiratory system and an increase in the blood serum concentration of inflammatory cytokines. LPS + HVL after 4 h lead to pronounced histological signs of lung damage. We have studied the effectiveness of Derinat ® when administered intramuscularly at dose of 7.5 mg/kg for 8 days in the ALI model. Derinat ® administration lead to an increase in the concentration of most of the studied cytokines in a day. In the ALI model the administration of Derinat ® returned the concentration of cytokines to its original values already 48 h after LPS + HVL, and also normalized the parameters of pulmonary respiration in comparison with animals without treatment. By the eighth day after LPS + HVL, respiratory parameters and cytokine levels, as well as biochemical and hematological parameters did not differ between groups, while histological signs of residual effects of lung damage were found in all animals, and were more pronounced in Derinat ® group, which may indicate stimulation of the local immune response. Thus, the administration of Derinat ® stimulates the immune response, has a pronounced protective effect against cytokinemia and respiratory failure caused by ALI, has immunomodulatory effect, and also stimulates a local immune response in lung tissues. Thus, Derinat ® is a promising treatment for ALI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Palikova, Palikov, Novikova, Slashcheva, Rasskazova, Tukhovskaya, Danilkovich, Dyachenko, Belogurov Jr., Kudriaeva, Bugrimov, Krasnorutskaya and Murashev.)

The aim of the study was to investigate the effect of AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on the consequences of metabolic syndrome and type 2 diabetes induced by the consumption of a high-fat diet (HFD) in male C57Bl/6 mice. Additionally, the animals from group 6 were administered Methotrexate (MTX) at a dose of 1 mg/kg in parallel with AICAR, which slows down the metabolism of AICAR. The animals were recorded with signs of metabolic syndrome and type 2 diabetes mellitus by recording their body weights, glucose and insulin levels, and the calculating HOMA-IRs. At the end of the study, at the end of the 13th week, during necropsy, the internal organs were assessed, the masses of the organs were recorded, and special attention was paid to visceral fat, assessing its amount and the mass of the fat surrounding epididymis. The biochemical parameters and histology of the internal organs and tissues were assessed. The animals showed signs of metabolic syndrome and type 2 diabetes, namely, weight gain, hyperglycemia, hyperinsulinemia, an increase in the amount and mass of abdominal fat, and metabolic disorders, all expressed in a pathological change in biochemical parameters and pathological changes in internal organs. The AICAR treatment led to a decrease in body weight, a decrease in the amount and mass of abdominal fat, and an improvement in the pathomorphological picture of internal organs. However, some hepatotoxic effects were observed when the animals, on a received standard diet (STD), were treated with AICAR starting from the first day of the study. The additional administration of MTX, an AICAR metabolic inhibitor, did not improve its efficacy. Thus, AICAR has therapeutic potential for the treatment of metabolic syndrome and type 2 diabetes.

Male Wistar rats aged 10 months were assigned to groups according to the initial level of systolic BP: hypertensive (systolic BP >115 mm Hg) and normotensive (systolic BP <115 mm Hg). The animals were injected intraperitoneally with 100 μg/kg taxifolin daily for 7 days. Systolic BP and HR were measured on the next day after single taxifolin administration and on the next day after 7-day injection course. In the group of hypertensive animals, systolic BP markedly decreased on the next day after the first injection; this decrease became even more pronounced (to the level of normotensive animals) at the end of the taxifolin course. In the group of normotensive animals, systolic BP remained unchanged. Hence, we demonstrate the possibility of course administration of taxifolin for BP normalization in hypertensive patients., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

The development of new herbal preparations for the treatment of urolithiasis is an urgent task of medical science. Ficus have attracted the attention of pharmacologists due to a wide range of biological properties, including antioxidant, anti-inflammatory, antibacterial and antifungal activity. We studied the effectiveness of Ficus tikoua Bur. in SD rats in which urolithiasis was induced by 6 weeks of oral administration of ethylene glycol 0.5% ad libitum instead of drinking water. Administration of the extract of Ficus tikoua Bur., as well as comparative drug Cystone ® after modeling of urolithiasis lead to the restoration of diuresis and the concentration of inorganic phosphates starting from the 6th week of the experiment. The use of the Ficus tikoua Bur. extract for 6 weeks, both during the modeling of urolithiasis and during the recovery period, led to the restoration of the percentage of lymphocytes in the blood, content of sodium, chlorine and inorganic phosphates in the blood to the control level. Thus, the extract of Ficus tikoua Bur. seems to be a promising drug for effective treatment of the initial stages of the development of urolithiasis., Competing Interests: Author PW is employed by Chengdu SinoPharmTech Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bervinova, Palikov, Mikhailov, Palikova, Borozdina, Kazakov, Rudenko, Tukhovskaya, Dyachenko, Slashcheva, Goryacheva, Sadovnikova, Kravchenko, Kalabina, Shinelev, Wu and Murashev.)

The success in treatment of venous thromboembolism and acute coronary syndromes using direct thrombin inhibitors has stimulated research aimed at finding a new anticoagulant from haematophagous organisms. This study deals with the comparison between hirudin-1 from Hirudomedicinalis (desirudin), being the first-known and most well-studied natural anticoagulant, along with recombinant analogs of haemadin from the leech Haemadipsa sylvestris , variegin from the tick Amblyomma variegatum , and anophelin from Anopheles albimanus . These polypeptides were chosen due to their high specificity and affinity for thrombin, as well as their distinctive inhibitory mechanisms. We have developed a universal scheme for the biotechnological production of these recombinant peptides as pharmaceutical substances. The anticoagulant activities of these peptides were compared using the thrombin amidolytic activity assay and prolongation of coagulation time (thrombin time, prothrombin time, and activated partial thromboplastin time) in mouse and human plasma. The preliminary results obtained suggest haemadin as the closest analog of recombinant hirudin-1, the active substance of the medicinal product Iprivask (Aventis Pharmaceuticals, USA) for the prevention of deep venous thrombosis in patients undergoing elective hip or knee replacement surgery. In contrast, variegin can be regarded as a natural analog of bivalirudin (Angiomax, The Medicines Company), a synthetic hirudin-1 derivative certified for the treatment of patients undergoing percutaneous coronary intervention and of patients with unstable angina pectoris after percutaneous transluminal coronary angioplasty.

Background and Objectives : Mutual effect of the preliminary and therapeutic intranasal treatment of SD rats with DSIP (8 days) on the outcome of focal stroke, induced with intraluminal middle cerebral occlusion (MCAO), was investigated. Materials and Methods : The groups were the following: MCAO + vehicle, MCAO + DSIP, and SHAM-operated. DSIP or vehicle was applied nasally 60 (±15) minutes prior to the occlusion and for 7 days after reperfusion at dose 120 µg/kg. The battery of behavioral tests was performed on 1, 3, 7, 14, and 21 days after MCAO. Motor coordination and balance and bilateral asymmetry were tested. At the end of the study, animals were euthanized, and their brains were perfused, serial cryoslices were made, and infarction volume in them was calculated. Results : Although brain infarction in DSIP-treated animals was smaller than in vehicle-treated animals, the difference was not significant. However, motor performance in the rotarod test significantly recovered in DSIP-treated animals. Conclusions : Intranasal administration of DSIP in the course of 8 days leads to accelerated recovery of motor functions.

A structural analogue of the DSIP, peptide KND, previously showed higher detoxification efficacy upon administration of the cytotoxic drug cisplatin, compared to DSIP. DSIP and KND were investigated using the model of acute myocardial infarction in male SD rats and the model of acute focal stroke in C57Bl/6 mice. A significant decrease in the myocardial infarction area was registered in KND-treated animals relative to saline-treated control animals (19.1 ± 7.3% versus 42.1 ± 9.2%). The brain infarction volume was significantly lower in animals intranasally treated with KND compared to the control saline-treated animals (7.4 ± 3.5% versus 12.2 ± 5.6%). Injection of KND in the first minute of reperfusion in the models of myocardial infarction and cerebral stroke reduced infarction of these organs, indicating a pronounced cardioprotective and neuroprotective effect of KND and potentiality for the treatment of ischemia-reperfusion injuries after transient ischemic attacks on the heart and brain, when administered during the reperfusion period. A preliminary pilot study using the model of myocardial infarction with the administration of DSIP during occlusion, and the model of cerebral stroke with the administration of KND during occlusion, resulted in 100% mortality in animals. Thus, in the case of ischemia-reperfusion injuries of the myocardium and the brain, use of these peptides is only possible during reperfusion.

Tuberculosis is known to be the biggest global health problem, causing the most deaths by a single infectious agent. Vaccine-development efforts are extremely important. This paper represents the results of the first-in-human trial of recombinant subunit tuberculosis vaccine GamTBvac in a Phase I study. GamTBvac is a new BCG booster candidate vaccine containing dextran-binding domain modified Ag85a and ESAT6-CFP10 MTB antigens and CpG ODN adjuvant, formulated with dextrans. Safety and immunogenicity of GamTBvac were estimated in an open-label clinical trial on 60 Mycobacterium tuberculosis uninfected (MTB-uninfected) volunteers previously-vaccinated with Bacillus Calmette-Guérin vaccine (BCG). The candidate vaccine had an acceptable safety profile and was well-tolerated. Three different vaccine doses with a double-immunization scheme were assessed for immunogenicity and induced a significant increase in IFN-γ in-house IGRA response and IgG ELISA analysis. Among them, the half dose vaccine group (containing DBD-ESAT6-CFP10, 12.5 μg; DBD-Ag85a, 12.5 μg; CpG (ODN 2216), 75 μg; DEAE-Dextran 500 kDa, 250 μg; and Dextran 500 kDa, 5 mg) provided high, early and stable in time immune response specific to both protein antigen fusions and is proposed for the further studies., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of this study; in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Changes in BP and HR were assessed after exposures increasing activity of angiotensin-converting enzyme: ionizing radiation, NO synthase inhibitor (L-NAME), and dexamethasone. Effects of dihydroquercetin and angiotensin-converting enzyme inhibitor enalapril on activity of this enzyme, BP, and HR were also evaluated under these exposures. Wistar male rats were subjected to X-ray irradiation in a dose of 2.5 Gy. Angiotensin-converting enzyme activity in the aorta sections was determined by Hip-His-Leu hydrolysis. BP and HR were recorded using a non-invasive tail-cuff method and PowerLab 8/35 software. BP and HR were not altered with the increase in activity of angiotensin-converting enzyme after irradiation. In case of prolonged (7 days) treatment with NO synthase inhibitor and dexamethasone, the increase in enzyme activity was accompanied by elevation of BP and, in the case of NO synthase inhibitor, HR reduction. Dihydroquercetin normalized the enzyme activity and lowered BP, but not to the normal level. Enalapril normalized BP, increased by NO synthase inhibitor solution intake; at the same time, the angiotensinconverting enzyme activity decreased more than 2-fold in comparison with the normal.

Azemiopsin (Az), a linear peptide from the Azemiops feae viper venom, contains no disulfide bonds, is a high-affinity and selective inhibitor of nicotinic acetylcholine receptor (nAChR) of muscle type and may be considered as potentially applicable nondepolarizing muscle relaxant. In this study, we investigated its preclinical profile in regard to in vitro and in vivo efficacy, acute and chronic toxicity, pharmacokinetics, allergenic capacity, immunotoxicity and mutagenic potency. The peptide effectively inhibited (IC 50 ~ 19 nM) calcium response of muscle nAChR evoked by 30 μM (EC 100 ) acetylcholine but was less potent (IC 50 ~ 3 μM) at α7 nAChR activated by 10 μM (EC 50 ) acetylcholine and had a low affinity to α4β2 and α3-containing nAChR, as well as to GABA A or 5HT₃ receptors. Its muscle relaxant effect was demonstrated at intramuscular injection to mice at doses of 30-300 µg/kg, 30 µg/kg being the initial effective dose and 90 µg/kg-the average effective dose. The maximal muscle relaxant effect of Az was achieved in 10 min after the administration and elimination half-life of Az in mice was calculated as 20-40 min. The longest period of Az action observed at a dose of 300 µg/kg was 55 min. The highest acute toxicity (LD 50 510 μg/kg) was observed at intravenous injection of Az, at intramuscular or intraperitoneal administration it was less toxic. The peptide showed practically no immunotoxic, allergenic or mutagenic capacity. Overall, the results demonstrate that Az has good drug-like properties for the application as local muscle relaxant and in its parameters, is not inferior to the relaxants currently used. However, some Az modification might be effective to extend its narrow therapeutic window, a typical characteristic and a weak point of all nondepolarizing myorelaxants., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript and in the decision to publish the results.

Introduction: It is important that the method of anesthesia of mice does not considerably alter the animal's physiological and metabolic status before terminal blood sampling taken in order to analyze clinical pathology parameters., Methods: Hematology, hemostasis, and clinical chemistry parameters were compared in male and female BALB/c mice exposed to either tiletamine-zolazepam-xylazine (TZX) anesthesia or euthanasia in carbon dioxide (CO 2) chamber to reveal an alternative method of anesthesia vs. the recommended CO 2 inhalation. Blood samples were taken from the inferior vena cava., Results: Clinical blood parameters in mice exposed to CO 2 inhalation or TZX anesthesia proved to be substantially different. The TZX group had lower activated partial thromboplastin time (APTT) and fibrinogen (statistically in males and tending in females) and lower platelets (PLT), red blood cells (RBC), hemoglobin (HGB), and white blood cells (WBC) in both sexes. TZX anesthesia resulted in lower blood serum concentrations of total protein, albumin and globulins, creatinine in males (higher in females); cholesterol, triglycerides, alanine aminotransferase (АLT) and alkaline phosphatase (AP) in both sexes, and bilirubin in males. The calcium level decreased in TZX-anesthetized males and females while the phosphates decreased only in females. The volume of serum obtained from females of TZX group was approximately two times higher than in the CO 2 -anesthetized group, with the degree of hemolysis tending to decrease., Discussion: The studied method of mouse anesthesia, followed by terminal blood sampling and analysis of clinical pathology parameters, suggests that TZX is a good alternative to CO 2 inhalation in toxicological and other nonclinical studies. The differences in hemostasis, hematology, and clinical chemistry parameters between these groups are supposedly associated with alterations in physiological and metabolic status of mice under conditions of increasing hypoxia, respiratory standstill, and circulatory arrest after CO 2 inhalation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

It is suggested that anti-inflammatory cytokine interleukin-10 (IL-10) mediates the delayed protective effects through activation of Jak-Stat3, PI3K-Akt and NF-κB signaling pathways. However, our previous experiments have demonstrated that IL-10 is capable to exert the rapid neuroprotective action through modulation of hypoxia-induced intracellular Ca(2+) ([Ca(2+)]i) response. The first purpose of the present study was to evaluate the neuroprotective effects of IL-10 using three models of the ischemic insults in rats: permanent middle cerebral artery occlusion, ischemia in acute hippocampal slices in vitro and ischemia in cultured hippocampal cells in vitro. The second purpose of the study was to elucidate a role of [Ca(2+)]i changes in the mechanisms underlying IL-10 elicited protection of neurons and astrocytes from ischemia-induced death in cultures of primary hippocampal cells. The data presented here shown that anti-inflammatory cytokine IL-10 is capable to induce a resistance of the brain cells to ischemia-evoked damages in in vivo and in vitro models of the ischemic insults in rats. This protective effect in cultured hippocampal cells is developed rapidly after application of IL-10 and strongly associated with the IL-10 elicited elimination of [Ca(2+)]i response to ischemia. Thus, our results provide the evidence that anti-inflammatory cytokine IL-10, in addition to an activation of the canonical signaling pathways, is capable to exert the rapid neuroprotective effects through transcription-independent modulation of ischemia-induced intracellular Ca(2+) responses in the brain cells., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Apolipoprotein E (apoE) is the primary apolipoprotein synthesized in the brain in response to injury with known neuroprotective effects exerted through antioxidant, antiinflammatory, antiexcitotoxic, and neurotrophic mechanisms. We have previously demonstrated that COG1410, an apoE mimetic peptide, exerts neuroprotective and antiinflammatory effects in a murine model of traumatic brain injury (TBI). As in TBI, ischemia-reperfusion injury is a component of acute stroke, which displays a pharmacogenetic association with the APOE4 gene. Using an intraluminal middle cerebral occlusion (MCAO) model in rats, we found that a single intravenous injection of COG1410 at 120 min post-MCAO significantly improved vestibulomotor function, decreased poststroke locomotor asymmetry, and decreased infarct volume of the ipsilateral hemisphere. These results support further exploration of a novel apoE-mimetic peptide, COG1410, as a therapeutic treatment for stroke., ((c) 2008 Wiley-Liss, Inc.)

Changes in blood pressure and sympathetic nerve activity induced by local injection of endothelin-1 into the rostroventrolateral medulla were studied in narcotized stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive WKY rats. Endothelin-1 produced similar biphasic response in both rat strains: a transient increase in blood pressure and sympathetic nerve activity followed by progressive hypotension and bradycardia. Pretreatment with ETB-receptor antagonist BQ788 inhibited sympathetic activation induced by endothelin-1, while pretreatment with the ETA-receptor antagonist N-acetyl-[D-Trp16]-endothelin-1 abolished the subsequent hypotension. The antihypotensive effect of ETA-receptor blockade was most effective in normotensive rats. Our findings suggest that cardiovascular disorders in SHRSP rats can be related to peculiarities in the rostroventrolateral medullar endothelin system.