Transdermal delivery of mitochondrial-targeted hydrogen sulphide donor, AP39 protects against 6-hydroxydopamine-induced mitochondrial dysfunction

Mandeep Kaur Marwah; Bahareh Manhoosh; Hala Shokr; Mohamad Anas Al Tahan; Roderick Stewart; Mohammed Iqbal; Lorena Diaz Sanchez; Sewa Abdullah; Shakil Ahmad; Keqing Wang; Karan Singh Rana; Lissette Sanchez-Aranguren

doi:10.1016/j.ejpb.2023.09.004

Transdermal delivery of mitochondrial-targeted hydrogen sulphide donor, AP39 protects against 6-hydroxydopamine-induced mitochondrial dysfunction

Eur J Pharm Biopharm. 2023 Oct:191:166-174. doi: 10.1016/j.ejpb.2023.09.004. Epub 2023 Sep 4.

Affiliations

¹ Aston Medical School, College of Health and Life Sciences, Aston University, UK. Electronic address: m.marwah1@aston.ac.uk.
² Aston Medical School, College of Health and Life Sciences, Aston University, UK.
³ Pharmacy Division, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK.
⁴ School of Pharmacy, College of Health and Life Sciences, Aston University, UK.
⁵ Quest Healthcare, Birmingham, UK; Aston Pharmacy School, College of Health and Life Sciences, Aston University, UK.
⁶ School of Biosciences, College of Health and Life Sciences, Aston University, UK.
⁷ Aston Medical School, College of Health and Life Sciences, Aston University, UK. Electronic address: l.sanchez-aranguren2@aston.ac.uk.

PMID: 37673316
DOI: 10.1016/j.ejpb.2023.09.004

Abstract

Hydrogen sulphide (H₂S) 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 H₂S 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 H₂S 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 H₂S 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 H₂S delivery whereas gels without PG have potential for therapy requiring sustained H₂S delivery.

Keywords: Hydrogen sulphide donors; Mitochondrial bioenergetics; Neurodegenerative conditions; Sustained release; Transdermal drug delivery.