id_1047. EVALUATION OF NEUROPROTECTIVE POTENTIAL OF HISTAMINE H3 RECEPTOR (H3R) ANTAGONISTS IN CELLULAR MODELS OF APOPTOSIS
Aleksandra Mąsior1, Katarzyna Szczepańska2, Danuta Jantas1
1 Department of Brain Biochemistry, Maj Institute of Pharmacology of the Polish Academy of Sciences, Krakow, Poland
2 Department of Medicinal Chemistry, Maj Institute of Pharmacology of the Polish Academy of Sciences, Krakow, Poland
INTRODUCTION: Growing evidence suggests that histamine H3 receptor (H3R) antagonists exert neuroprotective effects, particularly under excitotoxic and oxidative stress conditions. As apoptosis drives neuronal loss in Parkinson’s disease (PD), targeting these pathways is a promising therapeutic strategy.
AIM(S): Here, we examined selected H3R antagonists in cellular models of PD-relevant apoptosis to assess their potential to preserve neuronal survival.
METHOD(S): Four H3R antagonists: ciproxifan (CPX), JNJ-5207852 (JNJ), clobenpropit (CB) and pitolisant (Pit) at concentrations 0.01-10 uM were tested in human neuroblastoma SH-SY5Y cells exposed to pro-apoptotic agents: the dopaminergic neurotoxin MPP⁺ and inducer of extracellular apoptosis, doxorubicin (DOX). Experiments were performed in undifferentiated (UN-) and retinoic acid (RA-) differentiated cells. Cytotoxicity (LDH release) assay was used for assessment of neuroprotection whereas caspase-3 activity was measured as a marker of apoptosis.
RESULTS: In the MPP⁺ model only CPX (1–10 uM) exerted modest protective effects in UN-SH-SY5Y cells, whereas JNJ, CB, and Pit were ineffective. In RA-SH-SY5Y cells, none of the tested compounds attenuated the MPP⁺-induced cytotoxicity. In both cell phenotypes, MPP⁺-evoked increase in caspase-3 activity which was attenuated by Pit (10 uM) in UN-SH-SY5Y cells, and by CPX (10 uM), JNJ (1 uM) and Pit (10 uM) in RA-SH-SY5Y cells. In the DOX model of apoptosis neuroprotection demonstrated JNJ (0.1-10 uM), CB (0.01 and 1 uM) and Pit (0.01 and 1 uM) and this effect was observed only in UN-SH-SY5Y cells. Moreover, the Dox-evoked caspase-3 activity in UN-SH-SY5Y cells was significantly attenuated by CB (10 uM) and Pit (1 uM).
CONCLUSIONS: The H3R antagonists exhibit some neuroprotective potential in cellular models of apoptosis, however this effect is dependent on the type of pro-apoptotic inducer, type of H3R antagonist and cell differentiation status.
FINANCIAL SUPPORT: The study was supported by the statutory funds of Maj Institute of Pharmacology Polish Academy of Sciences.