Research Institute in Chemical Sciences, Faculty of Chemical and Technological Sciences, Catholic Cuyo University, San Juan, Argentina.
Laboratory of Basic and Translational Experimental Pharmacology, Department of Pathology, Faculty of Medical Sciences, National University of Cuyo (IMBECU-CONICET), Mendoza, Argentina.
Adv Med Sci. 2021 Mar;66(1):72-80. doi: 10.1016/j.advms.2020.12.003. Epub 2020 Dec 31.
Hypertensive lesions induce alterations at hemodynamic, peripheral, and central levels. Anandamide (N-arachidonoylethanolamine; AEA) protects neurons from inflammatory damage, but its free administration may cause central adverse effects. AEA controlled release by nanoformulations could reduce/eliminate its side effects. The present study aimed to evaluate the effects of nanoformulated AEA (nf-AEA) on systolic blood pressure (SBP), behavior, and central/peripheral inflammatory, oxidative, and apoptotic state in spontaneously hypertensive rats (SHR).
MATERIALS/METHODS: Male rats were used, both Wistar Kyoto (WKY) and SHR (n = 10 per group), with/without treatment with nf-AEA (obtained by electrospraying) at a weekly dose of 5 mg/kg IP for 4 weeks. SBP was measured and behavioral tests were performed. Inflammatory/oxidative markers were quantified at the central (brain cortex) and peripheral (serum) level.
SHR showed hyperactivity, low anxiety, and high concentrations of central/peripheral inflammatory/oxidative markers, also higher apoptosis of brain cortical cells compared to WKY. As opposed to this group, treatment with nf-AEA in SHR significantly reduced SBP, peripheral/central inflammatory/oxidative makers, and central apoptosis. Nf-AEA also increased neuroprotective mechanisms mediated by intracellular heat shock protein 70 (Hsp70), which were attenuated in untreated SHR. Additionally, nf-AEA reversed the abnormal behaviors observed in SHR without producing central adverse effects.
Our results suggest protective properties of nf-AEA, both peripherally and centrally, through a signaling pathway that would involve the type I angiotensin II receptor, Wilms tumor transcription factor 1, Hsp70, and iNOS. Considering non-nf-AEA limitations, this nanoformulation could contribute to the development of new antihypertensive and behavioral disorder treatments associated with neuroinflammation.
高血压病变可引起血液动力学、外周和中枢水平的改变。花生四烯酸乙醇胺（N-花生四烯酸乙醇胺；AEA）可保护神经元免受炎症损伤，但直接给予 AEA 可能会引起中枢不良反应。通过纳米制剂控制 AEA 的释放可以减少/消除其副作用。本研究旨在评估纳米制剂 AEA（nf-AEA）对自发性高血压大鼠（SHR）的收缩压（SBP）、行为以及中枢/外周炎症、氧化和凋亡状态的影响。
材料/方法：使用雄性大鼠，包括 Wistar Kyoto（WKY）和 SHR（每组 n=10），用每周腹腔注射 5mg/kg 的 nf-AEA（通过电喷雾获得）进行治疗，持续 4 周。测量 SBP 并进行行为测试。在中枢（大脑皮层）和外周（血清）水平定量炎症/氧化标志物。
与 WKY 相比，SHR 表现出多动、焦虑程度低以及中枢/外周炎症/氧化标志物浓度高，大脑皮质细胞凋亡也更高。与该组相反，nf-AEA 治疗可显著降低 SHR 的 SBP、外周/中枢炎症/氧化标志物和中枢细胞凋亡。nf-AEA 还增加了由细胞内热休克蛋白 70（Hsp70）介导的神经保护机制，而未治疗的 SHR 中的这些机制会减弱。此外，nf-AEA 逆转了 SHR 异常行为，而没有产生中枢不良反应。
我们的结果表明，nf-AEA 具有外周和中枢保护作用，通过涉及 I 型血管紧张素 II 受体、Wilms 肿瘤转录因子 1、Hsp70 和 iNOS 的信号通路发挥作用。考虑到非 nf-AEA 的局限性，这种纳米制剂可能有助于开发与神经炎症相关的新型抗高血压和行为障碍治疗方法。
