Effect of Mas Receptor agonist angiotensin 1-7 on thoracic aorta response and rage (Receptor for Advanced Glycation End Products) in rat adjuvant arthritis model

Romatoid Artritte (RA)'da inflamasyonla birlikte oluşan erken vasküler hasar sonrası endotelyal fonksiyonlarda azalma görülmektedir. Deneysel artrit modellerinde de artritin şiddetine bağlı olarak vasküler reaktivitede değişiklikler söz konusudur. Angiotensin 1-7 (Ang 1-7) Mas Reseptör (MasR) agonistidir ve kardiyovasküler homeostazda merkezi bir role sahiptir. Vasodilatör, hipotansif, anti aritmik ve kalbi koruyucu etkilerinin yanı sıra vasküler, antiinflamatuar etkilere de sahiptir. Çalışmamızda, Freund's Complete Adjuvant (FCA) ile indüklenen sıçan artrit modeli kullanılarak, Ang 1-7'nin artrit bulguları, izole torasik aorta damar yanıtları, kan sRAGE, TNF-α, IL-1β seviyelerini inceledik. Bu çalışmada 30 adet erkek Wistar Albino sıçan kullanıldı. FCA 0.1mL sağ arka pençe plantar yüzeye intradermal verilerek artrit oluşturuldu. Artrit bulguları 1., 3., 7., 10. ve 15. günlerde değerlendirildi. Ang 1-7, FCA verildikten 7 gün sonra, 3mg/kg i.p. olarak 8 gün boyunca verildi. Pençe ödemi vernier kaliper, indirekt kan basıncı ölçümü tail-cuff yöntemi ile ölçüldü. Endotelli ve endotelsiz aort yanıtları 8 kanallı izole organ banyosunda incelendi. Kasıcı yanıtlar fenilefrin ve KCl, gevşeme yanıtları ise asetilkolin ve sodyum nitroprusid ile değerlendirildi. ELISA kitlerle serum sRAGE, TNF-α ve IL-1β seviyelerine ve immünohistokimyasal olarak aorta preparatları değerlendirildi. Artritli sıçanlarda FCA verilmesini takiben 3. günden itibaren artrit bulguları olan ağırlıkta azalma, arterial basınçta ve pençe ödeminde artış görülmüştür. FCA uygulanması, TNF-α ve IL-1β'yı arttırırken sRAGE'yi azaltmıştır. Endotel zedelenmesinin ACh gevşemesini ve Ang1-7'nin gevşetici etkisini azalttığı görüldü. Ang 1-7'nin, artritli sıçanlarda artan pençe ödemini, kan basıncını, aortada kasılma yanıtlarını ve TNF-α seviyelerini azaltırken, sRAGE'yi arttırdığı saptanmıştır. Sonuç olarak Ang 1-7 tedavisi, artrit bulguları ve endotel fonksiyonları üzerine olumlu etkileri nedeniyle artritli hastalarda önemli bir tedavi seçeneği olabilir.A decrease in endothelial function consequent to the vascular damage associated with the inflammation is observed in the rheumatoid arthritis (RA). Changes in the vascular reactivity, related to the severity of arthritis, are also observed in experimental arthritis models. Angiotensin 1-7 (Ang 1-7) is MasR agonist and plays a central role in the cardiovascular homeostasis. It has vasodilator, hypotensive, antiarhythmic and cardioprotective effects besides vascular antiinflammatory activities. In our study, we used Freund's Complete Adjuvant (FCA)-induced rat arthritis model, investigated the effect of Ang 1-7 on thoracic aortic responses, and blood levels of sRAGE, TNF-α, and IL-1β. In this study, 30 male Wistar rats were used. Arthritis was induced by intradermal injection of 0,1 mL FCA into the plantar surface of right hind limb. Arthritis parameters were evaluated on day 1, 3, 7, 10 and 15. Ang 1-7 (3 mg/kg i.p) was administered 7 days after FCA. Paw edema and indirect blood pressure were measured using vernier caliper and tail-cuff methods respectively. The aortic (with and without endothelium) responses were investigated using isolated organ bath. The contractile responses were induced by phenylephrine and KCl, whereas the relaxation was induced by acetylcholine and sodium nitroprussid. Serum sRAGE, TNF-α and IL-1β were analyzed by ELISA and aortic preparations were evaluated immunohistochemically. Body weight was decreased, whereas paw edema and blood pressure were increased in the arthritic rats 3 days after FCA administration. Moreover, FCA increased TNF-α and IL-1β, but decreased sRAGE. Damaging the endotheliumreduced ACh-relaxation and the relaxing effect of Ang 1-7. Ang 1-7 decreased paw edema, blood pressure, aortic contractile responses and TNF-α levels, but increased sRAGE in the arthritic rats. In conclusion: Ang1-7 could be a significant choice in the treatment of patients with arthritis due to its positive effects on arthritic complications and endothelial functions

Effect of varenicline on behavioral deficits in a rat model of Parkinson's disease induced by unilateral 6-hydroxydopamine lesion of substantia nigra

Nicotinic acetylcholine receptors (nAChRs) are implicated in the pathogenesis of Parkinson's disease (PD). Varenicline tartrate is a partial agonist at α4β2 and full agonist at α7 neuronal nAChR subunits. A unilateral lesion of the substantia nigra (SN) has been used as a reliable model of PD. This study aimed to investigate the effect of varenicline on locomotor and nonlocomotor behavioral deficits induced by a unilateral lesion of the SN induced by 6-hydroxydopamine (6-OHDA) (8 g/4 l). Varenicline (1 mg/kg) was administered to the lesioned rats daily for 2 weeks, which commenced 3 weeks after 6-OHDA administration. The results showed that varenicline improved motor deficits induced by 6-OHDA. It improved locomotor and nonlocomotor activities such as forelimb use, rotarod performance, and forelimb asymmetry. Varenicline did not change rearing or vibrissae-elicited forelimb placing but did increase apomorphine-induced rotation. In conclusion, the present results suggest that drugs with specific partial/full agonistic activity on nAChR subunits could be of value in the treatment of neurodegenerative disorders such as PD. © 2018 Wolters Kluwer Health, Inc. All rights reserved