Novel Synthetic Coumarin-Chalcone Derivative (E)-3-(3-(4-(Dimethylamino)Phenyl)Acryloyl)-4-Hydroxy-2H-Chromen-2-One Activates CREB-Mediated Neuroprotection in Aβ and Tau Cell Models of Alzheimer's Disease.
Ya-Jen ChiuTe-Hsien LinChiung-Mei ChenChih-Hsin LinYu-Shan TengChung-Yin LinYing-Chieh SunHsiu Mei Hsieh-LiMing-Tsan SuGuey-Jen Lee-ChenWenwei LinKuo-Hsuan ChangPublished in: Oxidative medicine and cellular longevity (2021)
Abnormal accumulations of misfolded Aβ and tau proteins are major components of the hallmark plaques and neurofibrillary tangles in the brains of Alzheimer's disease (AD) patients. These abnormal protein deposits cause neurodegeneration through a number of proposed mechanisms, including downregulation of the cAMP-response-element (CRE) binding protein 1 (CREB) signaling pathway. Using CRE-GFP reporter cells, we investigated the effects of three coumarin-chalcone derivatives synthesized in our lab on CREB-mediated gene expression. Aβ-GFP- and ΔK280 tauRD-DsRed-expressing SH-SY5Y cells were used to evaluate these agents for possible antiaggregative, antioxidative, and neuroprotective effects. Blood-brain barrier (BBB) penetration was assessed by pharmacokinetic studies in mice. Of the three tested compounds, (E)-3-(3-(4-(dimethylamino)phenyl)acryloyl)-4-hydroxy-2H-chromen-2-one (LM-021) was observed to increase CREB-mediated gene expression through protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and extracellular signal-regulated kinase (ERK) in CRE-GFP reporter cells. LM-021 exhibited antiaggregative, antioxidative, and neuroprotective effects mediated by the upregulation of CREB phosphorylation and its downstream brain-derived neurotrophic factor and BCL2 apoptosis regulator genes in Aβ-GFP- and ΔK280 tauRD-DsRed-expressing SH-SY5Y cells. Blockage of the PKA, CaMKII, or ERK pathway counteracted the beneficial effects of LM-021. LM-021 also exhibited good BBB penetration ability, with brain to plasma ratio of 5.3%, in in vivo pharmacokinetic assessment. Our results indicate that LM-021 works as a CREB enhancer to reduce Aβ and tau aggregation and provide neuroprotection. These findings suggest the therapeutic potential of LM-021 in treating AD.
Keyphrases
- induced apoptosis
- protein kinase
- signaling pathway
- cell cycle arrest
- blood brain barrier
- gene expression
- pi k akt
- binding protein
- endoplasmic reticulum stress
- cell proliferation
- oxidative stress
- cell death
- dna methylation
- poor prognosis
- cognitive decline
- crispr cas
- genome wide
- multiple sclerosis
- end stage renal disease
- high resolution
- anti inflammatory
- metabolic syndrome
- patient reported outcomes
- chronic kidney disease
- cerebrospinal fluid
- skeletal muscle
- brain injury
- mild cognitive impairment
- long non coding rna
- cell therapy
- resting state
- bone marrow