1,4-dihydropyridine-benzylidenhydrazon derived AChE inhibitor induces H2S formation


Sevin G. , Alancay E., Parlar Çoşkun S. , Özbek E. N. , Kaya O., Alptüzün V. , et al.

MuTaLig COST ACTION CA15135 3rd WG meeting 2019, Paris, Fransa, 23 - 24 Şubat 2019, ss.59

  • Basıldığı Şehir: Paris
  • Basıldığı Ülke: Fransa
  • Sayfa Sayısı: ss.59

Özet

H2S-signaling pathways have been described to offer protection against Alzheimer's amyloid vasculopathy and neurodegeneration. H2S can work in the central nervous system as a neuromodulator to promote long-term potentiation and protect the nervous system from oxidative stress, apoptosis, or degeneration (1). Dysregulation of H2S homeostasis is implicated in the pathological processes of AD. Both in vivo and in vitro studies shows that H2S prevents neuronal impairment and attenuates cognitive dysfunction in the experimental model of AD (1). Previously we have shown that 1,4-dihydropiridine-benzylidenhidrazon derived C1 coded chemical that we synthesized inhibits AChE, Aβ fibril formation and causes destruction of already formed fibrils (IC50: 0.27 µМ) (2). Thus we now would like to study whether C1 causes H2S formation and have potential to be effective in alzheimer treatment by polypharmacological effects of H2S. We investigated the effect of C1 (10uM) on basal or L-cysteine (L-cyst;10 mM) induced H2S formation in the presence and absence of Cystathionine-gamma-lyase (CSE) inhibitor PAG (2 mM) in mouse aorta and lung homogenates by methylene blue assay. C1 induced basal H2S formation both in lung (1.302±0.05 vs 1.522±0.07, n=6) and aorta homogenates (0.695± 0.03 vs 0.782±0.02, n=8-4, P<0.05 Unpaired t-test,). C1-induced basal H2S formations were inhibited by PAG significantly in both lung and aorta (0.854±0.05 and 0.622±0.06, P<0.001 and P<0.05, Unpaired t-test n=6 and 4, respectively,). C1 significantly increased L-cyst induced H2S formation both in aorta (6.173±0.15 vs 8.046±0.28, P<0.001 Unpaired t-test, n=9) and lung homogenates (1.784±0.06 vs 2.286±0.12, P<0.001 Unpaired t-test, n=8). Augmentation of L-cyst induced H2S formation by C1 was inhibited by PAG significantly in both aorta (5.999±0.29, P<0.001 One way ANOVA, n=4) and lung (1.279±0.03, P<0.001 One way ANOVA, n=3), confirmed that C1 causes endogenous H2S synthesis. We conclude that C1 can augment L-cysteine-induced H2S formation in vascular tissues and thereby have a potential to be effective in Alzheimer. Because H2S level is decreased in Alzheimer and H2S production have protective effects in Alzheimer through inhibition of oxidation and inflammation as well as increasing neuronal dysfunction.