Marwah Mandeep Kaur, Manhoosh Bahareh, Shokr Hala, Al Tahan Mohamad Anas, Stewart Roderick, Iqbal Mohammed, Sanchez Lorena Diaz, Abdullah Sewa, Ahmad Shakil, Wang Keqing, Rana Karan Singh, Sanchez-Aranguren Lissette
Aston Medical School, College of Health and Life Sciences, Aston University, UK.
Aston Medical School, College of Health and Life Sciences, Aston University, UK.
Eur J Pharm Biopharm. 2023 Oct;191:166-174. doi: 10.1016/j.ejpb.2023.09.004. Epub 2023 Sep 4.
Hydrogen sulphide (HS) is an important gaseous signalling molecule with emerging roles as a neuroprotectant. The objective of this study was to investigate the feasibility of transdermal delivery of mitochondrial-targeted HS donor, AP39 whilst investigating the ability of permeated AP39 on abrogating 6-hydroxydopamine (6-OH-dop)-induced mitochondrial dysfunction, as a model of Parkinson's disease, established in human neuroblastoma cells, SHSY-5Y. Aqueous hypromellose gels (5% w/v) were prepared with up to 10% v/v propylene glycol (PG) with 0.002% w/w AP39. AP39 permeation from formulations across excised murine skin into PBS was quantified over 24 h using HPLC-UV detection. Media was collected and applied to a microvasculature blood-brain-barrier (BBB) model to evidence AP39 permeability. Following, the permeate was applied to neuroblastoma cells SHSY-5Y to evidence its therapeutic potential in modulating the mitochondrial bioenergetics and antioxidant in response to 6-OH-dop-induced mitochondrial dysfunction. The presence of PG in gel formulations significantly increased the cumulative amount of AP39 permeated across murine skin over 24 h from 24.40 ± 2.39 % to 48.59 ± 2.93 %. Conditioned media applied to a microvasculature BBB model observed AP39 permeation across the barrier and HS release. Finally, permeated AP39 enhanced parameters of mitochondrial bioenergetics in SHSY-5Y exposed to 6-OH-dop. Moreover, permeated AP39 abrogated mitochondrial-specific reactive oxygen species generation induced by 6-OH-dop. These findings demonstrate transdermal delivery of AP39 may provide a promising alternative to deliver this mitochondrial-targeted HS donor and this approach allows the potential to cross the BBB reaching CNS organs in the treatment of neurodegenerative conditions such as Parkinson's disease. Moreover, our observations show that gels prepared with 10% v/v PG have the potential for use in conditions requiring rapid HS delivery whereas gels without PG have potential for therapy requiring sustained HS delivery.
硫化氢（HS）是一种重要的气体信号分子，作为神经保护剂正发挥着新的作用。本研究的目的是研究线粒体靶向HS供体AP39经皮给药的可行性，同时研究渗透的AP39对消除6-羟基多巴胺（6-OH-dop）诱导的线粒体功能障碍的能力，6-OH-dop诱导的线粒体功能障碍是在人神经母细胞瘤细胞SHSY-5Y中建立的帕金森病模型。制备含高达10%（v/v）丙二醇（PG）和0.002%（w/w）AP39的羟丙甲纤维素水凝胶（5%，w/v）。使用HPLC-UV检测法定量制剂中AP39经切除的小鼠皮肤进入PBS的渗透情况，持续24小时。收集培养基并应用于微血管血脑屏障（BBB）模型，以证明AP39的通透性。随后，将渗透液应用于神经母细胞瘤细胞SHSY-5Y，以证明其在调节线粒体生物能量学和抗氧化方面对6-OH-dop诱导的线粒体功能障碍的治疗潜力。凝胶制剂中PG的存在显著增加了24小时内AP39经小鼠皮肤渗透的累积量，从24.40±2.39%增加到48.59±2.93%。应用于微血管BBB模型的条件培养基观察到AP39穿过屏障并释放HS。最后，渗透的AP39增强了暴露于6-OH-dop的SHSY-5Y中线粒体生物能量学的参数。此外，渗透的AP39消除了6-OH-dop诱导的线粒体特异性活性氧的产生。这些发现表明，AP39的经皮给药可能为递送这种线粒体靶向HS供体提供一种有前景的替代方法，并且这种方法有可能穿过血脑屏障到达中枢神经系统器官，用于治疗帕金森病等神经退行性疾病。此外，我们的观察结果表明，含10%（v/v）PG制备的凝胶有潜力用于需要快速递送HS的情况，而不含PG的凝胶有潜力用于需要持续递送HS的治疗。
