P1.31. THERAPEUTIC POTENTIAL OF PAPE-1 AGAINST HYPOXIC/ISCHEMIC BRAIN INJURY: A DUAL NEURON - GLIA TARGETED APPROACH
Andrzej Łach1, Karolina Przepiórska-Drońska2, Bernadeta A. Pietrzak-Wawrzyńska2, Wiktoria Płonka1, Agnieszka Wnuk1
1 Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Team I, Smetna Street 12, 31–343 Krakow, Poland; lach@if-pan.krakow.pl, wnuk@if-pan.krakow.pl
2 Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Laboratory of Neuropharmacology and Epigenetics, Smetna Street 12, 31–343 Krakow, Poland
INTRODUCTION: Hypoxic-ischemic brain injuries are among the leading causes of mortality and long-term disability worldwide. Despite ongoing advances in neuroscience and clinical medicine, the development of effective therapeutic interventions for these conditions remains a major challenge.
AIM(S): In this context, we propose the application of Pathway Preferential Estrogen-1 (PaPE-1), a novel synthetic compound that selectively activates non-nuclear estrogen receptors. This mechanism enables rapid, non-genomic cellular responses while reducing the risk of side effects commonly linked to classical estrogen receptor activation.
METHOD(S): Our research integrates in vitro models employing primary mouse cortical neurons and human microglial cells subjected to hypoxic/ischemic conditions, followed by post-treatment with PaPE-1 to reflect clinically relevant therapeutic paradigms. Simultaneously, we are developing the photothrombotic stroke model as a preliminary in vivo tool to study focal cerebral ischemia and assess PaPE-1’s therapeutic potential.
RESULTS: Our original findings indicate that PaPE-1 exhibited pronounced neuroprotective efficacy in hypoxic/ischemic models through the modulation of key pathological pathways, including apoptosis, autophagy, and oxidative stress. Treatment with PaPE-1 restored the expression of neuronal injury biomarkers, indicative of preserved cellular integrity and functionality. Furthermore, PaPE-1 regulated neuroimmune signaling in both primary neuronal and human microglial cultures, underscoring its comprehensive mechanism of action and potential as a therapeutic agent for ischemic brain injury.
CONCLUSIONS: Based on these findings, we postulate that post-treatment with PaPE-1 exerts a multifaceted modulatory effect on diverse cellular pathways involved in hypoxic/ischemic injury. This cumulative influence underscores the potential of PaPE-1 as a promising therapeutic agent for neuroprotection, capable of mitigating neuronal damage and promoting recovery following hypoxic/ischemic insults.
FINANCIAL SUPPORT: The National Science Centre, Poland: grant no. 2021/43/D/NZ7/00633.