NeuralCipher Research overview
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Parkinson's disease (PD) remains a major neurodegenerative disorder with limited therapeutic options. Several in vivo animal studies using different experimental PD models have shown that progesterone (P4) may exert neuroprotective effects; however, the exact cellular and molecular mechanisms, including the receptors mediating these actions of P4, have not been investigated. A recent study from the laboratory of Peter Thomas demonstrated that the selective membrane progesterone receptor α (mPRα/PAQR7) agonist Org OD 02-0 (10-ethenyl-19-norprogesterone) exhibits neuroprotective effects in a human PD cell model, identifying mPRα as a promising target for the development of therapeutic strategies for PD prevention and management. However, the blood-brain barrier (BBB) penetration and in vivo pharmacokinetics of Org OD 02-0 have not yet been examined. Therefore, the aim of the present pilot study was to investigate the BBB penetration and tissue distribution of Org OD 02-0 following systemic administration in rats. To achieve this, we first developed a sensitive high-performance liquid chromatography-coupled mass spectrometry method for the detection and quantification of Org OD 02-0 in rat tissues. Using this method, we investigated the distribution of Org OD 02-0 in male Wistar rats following subcutaneous administration (2.6 mg/kg). Org OD 02-0 was detectable in all examined tissues, showing higher concentrations in the brain (frontal lobe) and kidney and lower levels in plasma and liver at 1, 3, 6, and 12 h post-injection. The concentration data suggested differential tissue distribution and potential preferential accumulation in the kidneys. Importantly, our results demonstrate, for the first time, that Org OD 02-0 crosses the BBB and reaches pharmacologically relevant concentrations in the central nervous system following systemic administration, supporting its potential as a candidate for PD therapy. Based on these data, in vivo studies in rat PD models are warranted to further evaluate the therapeutic efficacy of Org OD 02-0.
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