主催: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
会議名: WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
開催地: Kyoto
開催日: 2018/07/01 - 2018/07/06
Introduction: Intracellular α-synuclein (α-syn)-rich protein aggregates called Lewy bodies (LB) and neuronal death are present in nearly all cases of sporadic Parkinson disease (PD). It is widely believed that LB appears early in the disease and spreads in synaptically coupled brain networks, driving neuronal dysfunction and death.
Objective: This study examined the effects of telmisartan (angiotensin II receptor type 1 (AT1R) blocker), CGP42112 (AT2R agonist) and Y-27632 (Rho-associated protein kinase inhibitor) in a genetic in vitro PD model produced by α-synuclein in H4 human neuroglioma cell line.
Methods: H4 neuroglioma cells (HTB-148, ATCC) maintained in OPTI-MEM media supplemented with10% fetal bovine serum, transfected with equimolar ratio of wild-type α-synuclein expression constructs (WTSyn) and synphilin-1 (SNCAIP-) or empty vector control, with simultaneous treatment with telmisartan, CGP42112 or Y-27632 (1, 5 or 10μM) or telmisartan (5μM) + Y-27632 (5μM) in a 24 well plate.
Results: telmisartan, CGP42112 and Y27632 up to 100μM did not affect H4 cell viability (MTT assay). WTSyn-EGFP-Synphilin-1 induced marked cell toxicity compared with empty vector control. However, telmisartan or Y-27632 (1, 5 or 10 μM) produced concentration dependent decrease in toxicity with peak effect (66.92±8.96 or 46.89%, respectively). CGP42112 (1, 5 or 10 μM) produced (2.03±0.95, 8.52±2.54 and 15.87±4.12%, respectively). Interestingly, synergism was observed in telmisartan (5μM) +Y-27632 (5μM) treated cells producing 86.72±14.58% reduction.
Conclusion: Findings from this study showed that telmisartan and Y-27632 attenuates α-synuclein pathology. This underscores the translational potential of telmisartan and Y-27632 as disease-modifying drugs for the treatment of PD.
