作者: Ranno, Eugenia ; Spalloni, Alida ; Iyer, Anand M ; Aronica, Eleonora ; Longone, Patrizia ; Berretta, Antonio ; Bonaccorso, Carmela M ; D'Antoni, Simona ; Catania, Maria Vincenza ; Spatuzza, Michela ; Laureanti, Floriana ; Pellitteri, Rosalia

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor neurons (MNs) and astrogliosis. Recent evidence suggests that factors secreted by activated astrocytes might contribute to degeneration of MNs. We focused on endothelin-1 (ET-1), a peptide which is strongly up-regulated in reactive astrocytes under different pathological conditions. We show that ET-1 is abundantly expressed by reactive astrocytes in the spinal cord of the SOD1-G93A mouse model and sporadic ALS patients. To test if ET-1 might play a role in degeneration of MNs, we investigated its effect on MN survival in an in vitro model of mixed rat spinal cord cultures (MSCs) enriched of astrocytes exhibiting a reactive phenotype. ET-1 exerted a toxic effect on MNs in a time- and concentration-dependent manner, with an exposure to 100-200nM ET-1 for 48h resulting in 40-50% MN cell death. Importantly, ET-1 did not induce MN degeneration when administered on cultures treated with AraC (5μM) or grown in a serum-free medium that did not favor astrocyte proliferation and reactivity. We found that both ETA and ETB receptors are enriched in astrocytes in MSCs. The ET-1 toxic effect was mimicked by ET-3 (100nM) and sarafotoxin S6c (10nM), two selective agonists of endothelin-B receptors, and was not additive with that of ET-3 suggesting the involvement of ETB receptors. Surprisingly, however, the ET-1 effect persisted in the presence of the ETB receptor antagonist BQ-788 (200nM-2μM) and was slightly reversed by the ETA receptor antagonist BQ-123 (2μM), suggesting an atypical pharmacological profile of the astrocytic receptors responsible for ET-1 toxicity. The ET-1 effect was not undone by the ionotropic glutamate receptor AMPA antagonist GYKI 52466 (20μM), indicating that it is not caused by an increased glutamate release. Conversely, a 48-hour ET-1 treatment increased MN cell death induced by acute exposure to AMPA (50μM), which is indicative of two distinct pathways leading to neuronal death. Altogether these results indicate that ET-1 exerts a toxic effect on cultured MNs through mechanisms mediated by reactive astrocytes and suggest that ET-1 may contribute to MN degeneration in ALS. Thus, a treatment aimed at lowering ET-1 levels or antagonizing its effect might be envisaged as a potential therapeutic strategy to slow down MN degeneration in this devastating disease.

2013-04-01·Inflammation Research3区 · 医学

Endothelin-3 at low concentrations attenuates inflammatory responses via the endothelin B2 receptor

3区 · 医学

Article

作者: Keiichi Ebina ; Akira Sato

OBJECTIVEThe aim of this study was to clarify a role of endothelins (ETs: ET-1, -2, and -3) and their receptors (ETA, ETB1, and ETB2) in inflammatory responses.METHODSMale Wistar rats (180-220 g) were used. The effects of ETs in the absence or presence of the ETA antagonist BQ-123/the selective ETB2 antagonist BQ-788, and the effect of the selective ETB1 agonist IRL-1620 and the nonselective ETB agonist BQ-3020, on rat hind paw oedema induced by several proinflammatory substances were examined. The involvement of nitric oxide (NO) in the effects of ETs on the paw oedema was investigated using the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME).RESULTSET-3, which acts mainly on ETB, at low concentrations specifically inhibited platelet-activating factor (PAF)-induced paw oedema, whereas neither ET-1 nor ET-2, both of which act on ETA and ETB, showed inhibitory activity. The inhibition by ET-1 and ET-3 (each 0.5 pmol/paw) in the presence of BQ-123 (66.4 ± 6.7 % and 65.4 ± 22.6 %, respectively), was comparable to that by ET-3 (0.5 pmol/paw) alone (65.4 ± 10.9 %), whereas neither ET-1 nor ET-3 in the presence of BQ-788 showed inhibitory activity. BQ-3020 (0.5 pmol/paw) inhibited the oedema by 50.9 ± 6.0 %, whereas IRL-1620 showed almost no activity. Additionally, L-NAME markedly attenuated the inhibitory effects of ET-3 on PAF-induced paw oedema. These results indicate that ETB2 may mediate NO production and attenuation of PAF-induced inflammatory responses. Moreover, ET-3 (0.5 pmol/paw) inhibited the oedema induced by ET-1 at higher dose and zymosan by 76.6 ± 11.0 and 85.4 ± 13.6 %, respectively, indicating that ET-3 at lower concentrations inhibits the paw oedema induced by various inflammatory substances.CONCLUSIONSET-3 at low concentrations may attenuate inflammatory responses via ETB2 activation and NO production.

2012-01-01·Cellular Physiology and Biochemistry

Pharmacological Differences of Endothelin Receptors-mediated Modulation in Cultured Interstitial Cells of Cajal from the Murine Small and Large Intestine

Article

作者: So, Insuk ; Kim, Byung Joo ; Chang, In Youb

Interstitial cells of Cajal (ICCs) are pacemaker cells that activate the periodic spontaneous depolarization (pacemaker potentials) responsible for the production of slow waves in gastrointestinal smooth muscle. Under current clamping, ICCs had a mean resting membrane potential of -58 ± 3 mV and externally applied ET produced membrane depolarization in a dosedependent manner. These effects were reduced by intracellular GDP beta S. A comparison of the concentration-dependent membrane depolarizations on pacemaker potentials to ET-1, ET-2 and ET-3 showed a rank order of potency ET-1≥ET-2≥ET-3 in cultured murine small intestinal ICCs. The pretreatment with Ca(2+)-free solution and thapsigargin, a Ca(2+)-ATPase inhibitor in endoplasmic reticulum, abolished the generation of pacemaker potentials and suppressed the ET-1 induced membrane depolarizations. Chelerythrine and calphostin C, protein kinase C inhibitors or naproxen, an inhibitor of cyclooxygenase, did not block the ET-1 induced effects on pacemaker potentials. Pretreatment with BQ-123 (ET(A )receptor antagonist) or BQ-788 (ET(B )receptor antagonist) blocked the ET-1 induced effects on pacemaker potentials in cultured murine small intestinal ICCs. However, pretreatment with BQ-788 selectively did not block the ET-1 induced effects on pacemaker potentials in cultured murine large intestinal ICCs. Also, only externally applied selective ET(B )receptor agonist, IRL 1620 did not show any influence on pacemaker potentials in cultured murine large intestine ICCs. RT-PCR results indicated the presence of the ET(A )and ET(B )receptor in ICCs. These results suggested that ET-1 modulates pacemaker potentials through ET(A )and ET(B )receptor activation in murine small intestinal ICCs and ET(A )receptor activation in murine large intestinal ICCs by external Ca(2+) influx and internal Ca(2+) release via protein kinase C or cyclooxygenase-independent mechanism. Therefore, the ICCs are targets for ET and their interaction can affect intestinal motility.

100 项与 ET-03 (Eirion Therapeutics) 相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
雄激素脱发	临床前	美国	Eirion Therapeutics, Inc.初创企业	2022-01-30
早熟性白发	临床前	美国	Eirion Therapeutics, Inc.初创企业	2022-01-30