Lamptey Richard Nii Lante, Sun Chengwen, Singh Jagdish
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58102, United States.
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58102, United States.
Biomed Pharmacother. 2025 Jan;182:117790. doi: 10.1016/j.biopha.2024.117790. Epub 2024 Dec 24.
Neurogenic hypertension (NH) is characterized by heightened sympathetic activity mediated by angiotensin II in specific brain areas including the paraventricular nucleus and circumventricular organs. While strategies targeting sympathetic activity have shown effectiveness in managing NH, their invasive nature hinders their widespread clinical adoption. Conversely, nose-to-brain drug delivery is emerging as a promising approach to access the brain with reduced invasiveness. We hypothesize that the intranasal delivery of plasmid DNA encoding angiotensin receptor shRNA (PEAS) can effectively lower blood pressure (BP). PEAS was administered encapsulated within transferrin and Tetanus Toxin Fragment C-functionalized liposomes. Equal number of both male and female spontaneously hypertensive rats (SHR) were used to determine the effect of PEAS delivery to brain. Blood pressure was measured by the tail cuff measurement. Synthesized liposomes were found to be cationic, < 200 nm, entrapped over 88 % of the plasmid and protected PEAS from DNase degradation. In vitro, formulations caused a significant (p < 0.05) decrease (>70 %) in angiotensin receptor expression in brain endothelial cell lines, primary astrocytes and primary neurons. Intranasal administration of PEAS to SHR resulted in a significant (p < 0.05) reduction of angiotensin receptor gene expression in the brain. In the hypothalamus of SHR, intranasal administration resulted in > 70 % reduction in gene expression, ∼15 % greater than intravenous administration. Both routes were associated with an over 25 mmHg significant (p < 0.05) reduction in BP following administration of PEAS. Intranasal administration of PEAS effectively lowered BP in SHR, offering a promising non-invasive approach for managing NH.
神经源性高血压（NH）的特征是在包括室旁核和室周器官在内的特定脑区，由血管紧张素II介导的交感神经活动增强。虽然针对交感神经活动的策略在管理NH方面已显示出有效性，但其侵入性阻碍了它们在临床上的广泛应用。相反，鼻内给药正成为一种有前景的、侵入性较小的进入大脑的方法。我们假设，鼻内递送编码血管紧张素受体短发夹RNA的质粒DNA（PEAS）可以有效降低血压（BP）。PEAS被包裹在转铁蛋白和破伤风毒素片段C功能化的脂质体中给药。使用数量相等的雄性和雌性自发性高血压大鼠（SHR）来确定向大脑递送PEAS的效果。通过尾袖法测量血压。发现合成的脂质体是阳离子性的，直径小于200nm，包封了超过88%的质粒，并保护PEAS免受DNase降解。在体外，制剂导致脑内皮细胞系、原代星形胶质细胞和原代神经元中的血管紧张素受体表达显著（p<0.05）降低（>70%）。对SHR鼻内给药PEAS导致大脑中血管紧张素受体基因表达显著（p<0.05）降低。在SHR的下丘脑，鼻内给药导致基因表达降低>70%，比静脉给药高约15%。在给予PEAS后，两种给药途径均与血压显著（p<0.05）降低超过25mmHg相关。鼻内给药PEAS可有效降低SHR的血压，为管理NH提供了一种有前景的非侵入性方法。
