Clinical and Experimental Pharmacology and Physiology最新文献

{"title":"Myrtenol complexed with β-cyclodextrin ameliorates behavioural deficits and reduces oxidative stress in the reserpine-induced animal model of Parkinsonism.","authors":"Suellen Silva-Martins, Jose Ivo Araújo Beserra-Filho, Amanda Maria-Macêdo, Ana Cláudia Custódio-Silva, Beatriz Soares-Silva, Sara Pereira Silva, Rafael Herling Lambertucci, Regina Helena Silva, José Ronaldo Dos Santos, Sathiyabama Rajiv Gandhi, Lucindo José Quintans-Júnior, Alessandra Mussi Ribeiro","doi":"10.1111/1440-1681.13563","DOIUrl":"https://doi.org/10.1111/1440-1681.13563","url":null,"abstract":"Current pharmacological approaches to treat Parkinson’s disease have low long‐term efficacy and important adverse side effects. The development of new pharmacological therapies has focused on novel plant‐derived phytochemicals. The alcoholic monoterpene myrtenol has been isolated from several plant species, and has anxiolytic, analgesic, anti‐inflammatory and antioxidant actions. Our study evaluated the neuroprotective potential of myrtenol complexed with β‐cyclodextrin (MYR) on a progressive parkinsonism model induced by reserpine (RES) in mice. The complexation with cyclodextrins enhances the pharmacological action of monoterpenes. Male Swiss mice were treated daily with MYR (5 mg/kg, p.o.) and with RES (0.1 mg/kg, s.c.) every other day during 28 days. Behavioural evaluations were conducted across treatment. At the end of the treatment, immunohistochemistry for tyrosine hydroxylase (TH) and oxidative stress parameters were evaluated. Chronic MYR‐treatment protected against olfactory sensibility loss, restored short‐term memory and decreased RES‐induced motor impairments. Moreover, this treatment prevented dopaminergic depletion and reduced the oxidative status index in the dorsal striatum. Therefore, MYR ameliorated motor and non‐motor impairments in the progressive animal model of parkinsonism, possibly by an antioxidant action. Additional research is needed to investigate the mechanisms involved in this neuroprotective effect.","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 11","pages":"1488-1499"},"PeriodicalIF":0.0,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13563","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39277012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"General anaesthetics as 'awakening agents'? Re-appraising the evidence for suggested 'pressure reversal' of anaesthesia.","authors":"Ben M George,&nbsp;Jaideep J Pandit","doi":"10.1111/1440-1681.13554","DOIUrl":"https://doi.org/10.1111/1440-1681.13554","url":null,"abstract":"<p><p>Increasing ambient pressure has been suggested to reverse general anaesthesia and provides support for the 'lipid theory'. Anaesthetic dissolution into cell membranes is said to cause their expansion to a critical volume. This triggers a sequence of events as basis of a unitary theory of anaesthestic mechanism. Pressure is argued to restore membrane volume to below critical level, reversing this process. We wished to review the original literature to assess internal consistency within and across papers, and to consider if alternative interpretations were possible. A literature search yielded 31 relevant 'pressure reversal' papers for narrative review, and 8 papers that allowed us to re-plot original data more consistently as 'dose-response' curves for the anaesthetics examined. Original studies were heterogenous for end-points, pressure ranges, species, and agents. Pressure effects were inconsistent, with narcosis at certain pressures and excitation at others, influenced by carrier gas (e.g., nitrogen vs helium). Pressure reversal (a right- or downward-shift on the re-plotted dose-response curves) was evident, but only in some species and at certain pressures and anaesthetic concentrations. However, even more striking was a novel 'awakening' effect of anaesthetics: i.e., anaesthetics reversed the narcotic effect of pressure, but this was limited to certain pressures at generally low anaesthetic concentrations. Contrary to the established view, 'pressure reversal' is not a universal phenomenon. The awakening effect of anaesthetics - described here for the first time - has equal evidence to support it, within the same literature, and is something that cannot be fully explained. Pressure cannot meaningfully be used to gain insight into anaesthetic mechanisms because of its heterogenous, non-specific and unpredictable effects on biological systems.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 11","pages":"1454-1468"},"PeriodicalIF":0.0,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13554","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39222821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of metformin on hypothalamic-pituitary-thyroid axis activity in postmenopausal women with untreated non-autoimmune subclinical hypothyroidism.","authors":"Robert Krysiak,&nbsp;Karolina Kowalcze,&nbsp;Bogusław Okopień","doi":"10.1111/1440-1681.13542","DOIUrl":"https://doi.org/10.1111/1440-1681.13542","url":null,"abstract":"<p><p>Metformin was found to reduce elevated thyrotropin levels in subjects with hypothyroidism. The impact on thyrotropin levels was stronger in women receiving oral contraceptive pills than in women not using any contraception. The aim of the present study was to determine whether physiological levels of oestradiol determine the effect of metformin on hypothalamic-pituitary-thyroid axis activity. The study population included 40 postmenopausal women with prediabetes and untreated non-autoimmune subclinical hypothyroidism, using (group A; n = 18) or not using (group B; n = 22) oestradiol replacement therapy. Over the entire study periods, all subjects were treated with metformin (2.55-3.00 g daily). Plasma levels of glucose, lipids, insulin, thyrotropin, free thyroxine, free triiodothyronine, prolactin, gonadotropins and oestradiol were measured, while the structure parameters of thyroid homeostasis and the degree of insulin sensitivity were calculated at the beginning of the study and 6 months later. At entry, both groups differed in gonadotropin and oestrogen levels. Despite improving insulin sensitivity, thyrotropin levels and Jostel's thyrotropin index in both study groups, these effects were stronger in group A than group B. Only in group A, metformin increased SPINA-GT, while only in group B the drug decreased FSH levels. Levels of the other variables remained at a similar level throughout the study. The effect of treatment on thyrotropin levels correlated with its baseline values, as well as with the improvement of insulin sensitivity. The results obtained suggest that the impact of metformin on hypothalamic-pituitary-thyroid axis activity depends on the oestrogen status of patients.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 11","pages":"1469-1476"},"PeriodicalIF":0.0,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13542","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39246032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-intensity pulsed ultrasound prevents prolonged hypoxia-induced cardiac fibrosis through HIF-1α/DNMT3a pathway via a TRAAK-dependent manner.","authors":"Kun Zhao,&nbsp;Liqing Weng,&nbsp;Tianhua Xu,&nbsp;Chuanxi Yang,&nbsp;Jing Zhang,&nbsp;Gehui Ni,&nbsp;Xiasheng Guo,&nbsp;Juan Tu,&nbsp;Dong Zhang,&nbsp;Wei Sun,&nbsp;Xiangqing Kong","doi":"10.1111/1440-1681.13562","DOIUrl":"https://doi.org/10.1111/1440-1681.13562","url":null,"abstract":"<p><p>Hypoxia-induced cardiac fibrosis is an important pathological process in cardiovascular disorders. This study aimed to determine whether low-intensity pulsed ultrasound (LIPUS), a novel and safe apparatus, could alleviate hypoxia-induced cardiac fibrosis, and to elucidate the underlying mechanisms. Hypoxia (1% O₂ ) and transverse aortic constriction (TAC) were performed on neonatal rat cardiac fibroblasts and mice to induce cardiac fibrosis, respectively. LIPUS irradiation was applied for 20 minutes every 6 hours for a total of 2 times in vitro, and every 2 days from 1 week before surgery to 4 weeks after surgery in vivo. We found that LIPUS dose-dependently attenuated hypoxia-induced cardiac fibroblast phenotypic conversion in vitro, and ameliorated TAC-induced cardiac fibrosis in vivo. Hypoxia significantly upregulated the nuclear protein expression of hypoxia-inducible factor-1α (HIF-1α) and DNA methyltransferase 3a (DNMT3a). LIPUS pre-treatment reversed the elevated expression of HIF-1α, and DNMT3a. Further experiments revealed that HIF-1α stabilizer dimethyloxalylglycine (DMOG) hindered the anti-fibrotic effect of LIPUS, and hampered LIPUS-mediated downregulation of DNMT3a. DNMT3a small interfering RNA (siRNA) prevented hypoxia-induced cardiac fibrosis. Results also showed that the mechanosensitive protein-TWIK-related arachidonic acid-activated K⁺ channel (TRAAK) messenger RNA (mRNA) expression was downregulated in hypoxia-induced cardiac fibroblasts, and TAC-induced hearts. TRAAK siRNA impeded LIPUS-mediated anti-fibrotic effect and downregulation of HIF-1α and DNMT3a. Above results indicated that LIPUS could prevent prolonged hypoxia-induced cardiac fibrosis through TRAAK-mediated HIF-1α/DNMT3a signalling pathway.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 11","pages":"1500-1514"},"PeriodicalIF":0.0,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13562","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39271448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological characterization of the chronic phase of the monoiodoacetate-induced rat model of osteoarthritis pain in the knee joint.","authors":"Felicity Y Han,&nbsp;David A Brockman,&nbsp;Janet R Nicholson,&nbsp;Laura Corradini,&nbsp;Maree T Smith","doi":"10.1111/1440-1681.13551","DOIUrl":"https://doi.org/10.1111/1440-1681.13551","url":null,"abstract":"<p><p>For patients with osteoarthritis (OA) of the knee, pain is the most debilitating symptom. Although it has been proposed that the chronic phase of the monoiodoacetate (MIA)-induced rodent model of knee joint pain may be superior to other chronic or acute OA models for assessing the analgesic efficacy of novel molecules, relatively few pharmacological studies have been conducted in the chronic phase of this model. Hence, this study was designed to use pharmacological methods to characterize the chronic phase of the MIA-induced rat model of knee joint OA pain. Rats received a single intraarticular injection of MIA at 2.5 mg or vehicle (saline) into the left (ipsilateral) knee joint. Pain behaviour was assessed by measuring paw withdrawal thresholds (PWTs) in the hindpaws pre-MIA injection and twice-weekly until study completion on day 42. Mechanical allodynia was fully developed in the ipsilateral hindpaws (PWTs ≤6 g) from day 7 and it persisted until day 42. MIA-injected rats with PWTs ≤6 g in the ipsilateral hindpaws received single doses of one of four clinically available drugs that represent four distinct pharmacological classes, viz gabapentin, amitriptyline, meloxicam and morphine, according to a 'washout' protocol with at least 48 hours between successive doses. Gabapentin evoked dose-dependent anti-allodynia as did morphine whereas amitriptyline and meloxicam were inactive. Our findings are aligned with clinical data showing that gabapentin and morphine alleviated OA pain in the knee. The lack of efficacy of amitriptyline is consistent with the loss of descending diffuse noxious inhibitory controls reported by others in this model.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 11","pages":"1515-1522"},"PeriodicalIF":0.0,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13551","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39194793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thromboxane-prostanoid receptor activation blocks ATP-sensitive potassium channels in rat aortas.","authors":"Jeimison D Santos,&nbsp;Michele Paulo,&nbsp;Juliana A Vercesi,&nbsp;Lusiane M Bendhack","doi":"10.1111/1440-1681.13557","DOIUrl":"https://doi.org/10.1111/1440-1681.13557","url":null,"abstract":"<p><p>K⁺ channel activation is one of the major mechanisms involved in vasodilation. Vasoconstrictor agonists such as angiotensin II promote ATP-dependent potassium channels (K_ATP ) dysfunction. This study evaluates whether thromboxane-prostanoid (TP receptor) activation by the agonist U46619 increases reactive oxygen species (ROS) production in rat aortas, which could contribute to K_ATP channel dysfunction and impaired NO-dependent vasodilation. TP receptor activation with the selective agonist U46619 increased ROS in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), but the TP receptor antagonist SQ29548 abolished this effect. ECs and VSMCs incubation with ROS scavengers like Tiron or PEG-Catalase impaired U46619-induced ROS production. U46619 at the concentrations of 0.1 and 1 µmol/L induced contractions with similar amplitude. K_ATP channel activation with pinacidil-induced relaxation was lower for the contractions induced with 0.1 or 1 µmol/L U46619 than with 10 nmol/L U46619. Acetylcholine-induced relaxation provided similar results. In aortas pre-contracted with 10 nmol/L U46619, neither Tiron (100 µmol/L) nor catalase (300 U/mL) affected pinacidil-induced relaxation. However, in aortas pre-contracted with 0.1 µmol/L U46619, catalase potentiated pinacidil-induced relaxation. Pinacidil potentiated acetylcholine-induced relaxation in aortas pre-contracted with 0.1 and 1 µmol/L U46619. Incubation with 10 nmol/L U46619 increased NO concentration in ECs. Taken together, these results show that high concentrations of the TP receptor agonist U46619 impair K_ATP channels, which is probably due to ROS production. It is likely that hydrogen peroxide is the ROS.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 11","pages":"1537-1546"},"PeriodicalIF":0.0,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13557","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39260181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the antifibrotic potential of N-acetyl seryl-aspartyl-lysyl-proline sequence peptides.","authors":"Vinasha Ramasamy,&nbsp;Mpiko Ntsekhe,&nbsp;Edward Sturrock","doi":"10.1111/1440-1681.13565","DOIUrl":"https://doi.org/10.1111/1440-1681.13565","url":null,"abstract":"<p><p>N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a physiological antifibrotic peptide that is hydrolysed by angiotensin I-converting enzyme (ACE). The beneficial antifibrotic effects of ACE inhibitors have been attributed, in part, to its inhibition of Ac-SDKP cleavage. There is indirect evidence that the SDK fragment of Ac-SDKP is the main component required for its antiproliferative action. However, the exact component of the physiological peptide that is responsible for its antifibrotic effect has yet to be determined. Ac-SDKP-derived analogues that are resistant to ACE degradation may provide a new avenue for fibrosis therapy. We tested the antifibrotic potential of various Ac-SDKP peptide sequences and an analogue resistant to ACE degradation in lung fibroblasts. We investigated the contribution and molecular mechanism of action of the amino acid residues in the Ac-SDKP sequence to its antifibrotic effects, and the effects of Ac-SDKP peptides in the prevention of collagen deposition in cells. The Ac-DKP fragment moderately inhibited endothelin-1 (ET-1) mediated transforming growth factor-β (TGF- β) expression, and could be slowly cleaved by ACE, revealing a different sequence requirement for the antifibrotic action of Ac-SDKP. The Ac-SDψKP analogue (where the peptide bond between the aspartate and lysine is reduced) inhibited TGF-β/small mother against decapentaplegic (Smad)-3 signalling and collagen deposition. The Ac-SDKP peptide, in combination with ACEi, demonstrated a greater inhibition of hydroxyproline as compared to Ac-SDKP alone.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 11","pages":"1558-1565"},"PeriodicalIF":0.0,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13565","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39274287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of thymoquinone, a major constituent of Nigella sativa, in the treatment of inflammatory and infectious diseases.","authors":"Kaneez Fatima Shad,&nbsp;Wissam Soubra,&nbsp;Dennis John Cordato","doi":"10.1111/1440-1681.13553","DOIUrl":"https://doi.org/10.1111/1440-1681.13553","url":null,"abstract":"<p><p>Nigella sativa (N. sativa) is an annual flowering plant that has been used as a traditional remedy for many centuries. The seed possesses a large variety of compounds with thymoquinone (TQ) considered its major but not sole bioactive constituent. Supercritical fluid extraction, geographical location, and oxidative status of N. sativa produces the highest yield of essential oil content including TQ. Thymoquinone is lipophilic, heat and light sensitive with low oral bioavailability and rapid elimination that have significantly inhibited its pharmacological development. Novel developments in nanoparticulate-based oral administration, nasal spray and transdermal delivery may allow the clinical development of N. sativa and TQ as therapeutic agents. Animal and human studies indicate a potential role of N. sativa seed oil and TQ for a diverse range of disease processes including hypertension, dyslipidaemia, type 2 diabetes mellitus, arthritis, asthma, bacterial and viral infections, neurological and dermatological disorders, as it belongs to the group of pan-assay interference compounds. This review outlines the pharmacological properties of N. sativa and TQ and their potential wide application for a large variety of human diseases. The paper will focus on recent studies of the anti-inflammatory and antiviral properties that make N. sativa and TQ promising therapeutic agents targeting contemporary inflammatory and infectious diseases including Covid 19.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 11","pages":"1445-1453"},"PeriodicalIF":0.0,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13553","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39213732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beneficial and harmful effects of CB₁ and CB₂ receptor antagonists on chronotropic and inotropic effects related to atrial β-adrenoceptor activation in humans and in rats with primary hypertension.","authors":"Jolanta Weresa,&nbsp;Anna Pędzińska-Betiuk,&nbsp;Eberhard Schlicker,&nbsp;Grzegorz Hirnle,&nbsp;Maciej Mitrosz,&nbsp;Barbara Malinowska","doi":"10.1111/1440-1681.13560","DOIUrl":"https://doi.org/10.1111/1440-1681.13560","url":null,"abstract":"<p><p>We have previously shown that cannabinoid CB₁ and CB₂ receptor antagonists, AM251 and AM630, respectively, modulate cardiostimulatory effects of isoprenaline in atria of Wistar rats. The aim of the present study was to examine whether such modulatory effects can also be observed (a) in the human atrium and (b) in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Inotropic effects of isoprenaline and/or CGP12177 (that activate the high- and low-affinity site of β₁ -adrenoceptors, respectively) were examined in paced human atrial trabeculae and rat left atria; chronotropic effects were studied in spontaneously beating right rat atria. AM251 modified cardiostimulatory effects more strongly than AM630. Therefore, AM251 (1 μM) enhanced the chronotropic effect of isoprenaline in WKY and SHR as well as inotropic action of isoprenaline in WKY and in human atria. It also increased the inotropic influence of CGP12177 in SHR. AM630 (1 μM) decreased the inotropic effect of isoprenaline and CGP12177 in WKY, but enhanced the isoprenaline-induced inotropic effect in SHR and human atria. Furthermore, AM251 (0.1 and 3 μM) and AM630 (0.1 μM) reduced the inotropic action of isoprenaline in human atria. In conclusion, cannabinoid receptor antagonists have potentially harmful and beneficial effects through their amplificatory effects on β-adrenoceptor-mediated positive chronotropic and inotropic actions, respectively.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 11","pages":"1547-1557"},"PeriodicalIF":0.0,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13560","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39265185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apocynin prevents reduced myocardial nerve growth factor, contributing to amelioration of myocardial apoptosis and failure.","authors":"Xi Jie,&nbsp;Hong Yang,&nbsp;Ke Wang,&nbsp;Zong-Feng Zhu,&nbsp;Jia-Pu Wang,&nbsp;Li-Guo Yang,&nbsp;Zi-Jian Yang,&nbsp;Xiao-Juan Zhang,&nbsp;Ai-Ling Wang,&nbsp;Lu Li,&nbsp;Rui-Fang Chi,&nbsp;Fu-Zhong Qin,&nbsp;Bao Li,&nbsp;Bianai Fan","doi":"10.1111/1440-1681.13465","DOIUrl":"https://doi.org/10.1111/1440-1681.13465","url":null,"abstract":"<p><p>Reduced nerve growth factor (NGF) is associated with cardiac sympathetic nerve denervation in heart failure (HF) which is characterized by increased oxidative stress. Apocynin is considered an antioxidant agent which inhibits NADPH oxidase activity and improves reactive oxygen species scavenging. However, it is unclear whether apocynin prevents reduced myocardial NGF, leading to improvement of cardiac function in HF. In this study, we tested the hypothesis that apocynin prevents reduced myocardial NGF, contributing to amelioration of myocardial apoptosis and failure. Rabbits with myocardial infarction (MI) or sham operation were randomly assigned to receive apocynin or placebo for 4 weeks. MI rabbits exhibited left ventricular (LV) dysfunction, and elevation in oxidative stress, as evidenced by a decreased reduced-to-oxidized glutathione ratio and an increased 4-hydroxynonenal expression, and reduction in NGF and NGF receptor tyrosine kinase A (TrKA) expression in the remote non-infarcted myocardium. Apocynin treatment ameliorated LV dysfunction, reduced oxidative stress, prevented decreases in NGF and TrKA expression and reduced cardiomyocyte apoptosis after MI. In cultured H9C2 cardiomyocytes, hypoxia or hydrogen peroxide decreased NGF expression, and apocynin normalized hypoxia-induced reduction of NGF. Recombinant NGF attenuated hypoxia-induced apoptosis. Apocynin prevented hypoxia-induced apoptosis, and the suppressive effect of apocynin on apoptosis was abolished by NGF receptor TrKA inhibitor K252a. We concluded that apocynin prevented reduced myocardial NGF, leading to attenuation of cardiomyocyte apoptosis and LV remodelling and dysfunction in HF after MI. These findings suggest that strategies to prevent NGF reduction by inhibition of oxidative stress may be of value in amelioration of LV dysfunction in HF.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"48 5","pages":"704-716"},"PeriodicalIF":0.0,"publicationDate":"2021-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/1440-1681.13465","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25420486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}