TPPB (α-Amyloid Precursor Protein Modulator)는 벤졸락탐 유도체인 세포 투과성 단백질 키나제 C (PKC) 활성제 (Ki = 11.9nM)이다. TPPB는 α-시크릿타제 활성을 증가시켜 sAPPα 분비를 증가시키고 동시에 β-secretase (BACE1) 발현과 Aβ40 조각의 방출을 줄인다 [2-3]. TPPB는 주로 알츠하이머병 치료에 사용된다 [4].
SH-SY5Y 세포에서 TPPB(0.1-100nM; 3h)는 세포 분비물 sAPPα를 유도한다 [5]. PC12 세포에서 TPPB(0-10μM; 3h)는 전신 APP의 표현을 영향주지 않고 sAPPα의 분비를 촉진하였다 [6].
실험성 자가면역성 뇌척수염(EAE) 쥐 모델에서 TPPB(50nmol/kg; ip; 21d; 주 3일)은 신경학적 손상을 완화할 수 있다 [7].
References:
[1]. Kozikowski A P, Nowak I, Petukhov P A, et al. New amide-bearing benzolactam-based protein kinase C modulators induce enhanced secretion of the amyloid precursor protein metabolite sAPPα[J]. Journal of medicinal chemistry, 2003, 46(3): 364-373.
[2]. Yang H Q, Pan J, Ba M W, et al. New protein kinase C activator regulates amyloid precursor protein processing in vitro by increasing α‐secretase activity[J]. European Journal of Neuroscience, 2007, 26(2): 381-391.
[3]. Hong-Qi Y, Zhi-Kun S, Sheng-Di C. Current advances in the treatment of Alzheimer's disease: focused on considerations targeting Aβ and tau[J]. Translational neurodegeneration, 2012, 1(1): 21.
[4]. Yang H Q, Li X, Yang W M, et al. Neuroprotective Effects of New Protein Kinase C Activator TPPB Against Aβ25–35 Induced Neurotoxicity in PC12 Cells[J]. Neurochemical research, 2012, 37(10): 2213-2221.
[5]. Yi P, Schrott L, Castor T P, et al. Bryostatin-1 vs. TPPB: dose-dependent APP processing and PKC-α,-δ, and-ε isoform activation in SH-SY5Y neuronal cells[J]. Journal of Molecular Neuroscience, 2012, 48(1): 234-244.
[6]. Yang H Q, Pan J, Ba M W, et al. New protein kinase C activator regulates amyloid precursor protein processing in vitro by increasing α‐secretase activity[J]. European Journal of Neuroscience, 2007, 26(2): 381-391.
[7]. Shanmukha S, Godfrey W H, Gharibani P, et al. TPPB modulates PKC activity to attenuate neuroinflammation and ameliorate experimental multiple sclerosis[J]. Frontiers in Cellular Neuroscience, 2024, 18: 1373557.