Pyrithiamine (hydrobromide)

Pyrithiamine (hydrobromide) is a thiamine analogue that inhibits the metabolism of thiamine (vitamin B1)^[1]. Pyrithiamine (hydrobromide) has high affinity to thiamine transporters in neurons, with a K_d of approximately 60 nM^[2]. Pyrithiamine (hydrobromide) is also a substrate of thiamine pyrophosphate kinase (TPK) and can be converted into pyrithiamine pyrophosphate (PPP)^[3]. Pyrithiamine (hydrobromide) can be used in microbial culture to inhibit the growth of microorganisms that require thiamine^[4].

In vitro, Pyrithiamine (hydrobromide) (10μM) treated the HeLa cell line for 4 days, significantly reducing cellular nucleotide levels, and intracellular dATP, dCTP, dGTP and dTTP were all reduced^[5]. Pyrithiamine (hydrobromide) (0.25mM) treated Neuro 2a cells, resulting in a strong reduction in intracellular ThDP levels, and the cells began to die after 48 hours ^[6].

In vivo, Pyrithiamine (hydrobromide) (250 or 500 μg/kg/day) treated mice by intraperitoneal injection for 4 weeks, causing thiamine deficiency, leading to cognitive dysfunction and neuropathological changes in wild-type mice, but it had no effect on existing mice. There is no corresponding effect on AD model mice with obvious cognitive impairment ^[7]. Pyrithiamine (hydrobromide) (0.5g/kg) was administered intraperitoneally to rats for 11 days, causing thiamine deficiency, leading to enlargement of the lateral ventricles and reduced levels of choline-containing compounds in the body ^[8].

References:

[1] Chauhan A, Srivastva N, Bubber P. Thiamine deficiency induced dietary disparity promotes oxidative stress and neurodegeneration[J]. Indian Journal of Clinical Biochemistry, 2018, 33: 422-428.

[2] Mulholland P J, Self R L, Stepanyan T D, et al. Thiamine deficiency in the pathogenesis of chronic ethanol-associated cerebellar damage in vitro[J]. Neuroscience, 2005, 135(4): 1129-1139.

[3] Liu J Y, Timm D E, Hurley T D. Pyrithiamine as a substrate for thiamine pyrophosphokinase[J]. Journal of biological chemistry, 2006, 281(10): 6601-6607.

[4]Brandenburger E, Gressler M, Leonhardt R, et al. A highly conserved basidiomycete peptide synthetase produces a trimeric hydroxamate siderophore[J]. Applied and Environmental Microbiology, 2017, 83(21): e01478-17.

[5]Tiwana G S, Prevo R, Buffa F M, et al. Identification of vitamin B1 metabolism as a tumor-specific radiosensitizing pathway using a high-throughput colony formation screen[J]. Oncotarget, 2015, 6(8): 5978.  

[6]Sambon M, Napp A, Demelenne A, et al. Thiamine and benfotiamine protect neuroblastoma cells against paraquat and β-amyloid toxicity by a coenzyme-independent mechanism[J]. Heliyon, 2019, 5(5).

[7]Zhao J, Sun X, Yu Z, et al. Exposure to pyrithiamine increases β-amyloid accumulation, Tau hyperphosphorylation, and glycogen synthase kinase-3 activity in the brain[J]. Neurotoxicity research, 2011, 19: 575-583.

[8]Zahr N M, Sullivan E V, Rohlfing T, et al. Concomitants of alcoholism: differential effects of thiamine deficiency, liver damage, and food deprivation on the rat brain in vivo[J]. Psychopharmacology, 2016, 233: 2675-2686.

Pyrithiamine (hydrobromide)是一种硫胺素类似物，可抑制硫胺素（维生素B1）的代谢^[1]。Pyrithiamine (hydrobromide)与神经元中的硫胺素转运蛋白具有高亲和力，K_d约为60 nM^[2]。Pyrithiamine (hydrobromide)也是硫胺素焦磷酸激酶（TPK）的底物，可以转化为吡啶硫胺焦磷酸盐（PPP）^[3]。Pyrithiamine (hydrobromide)可用于微生物培养，抑制需要硫胺素的微生物生长^[4]。

在体外，Pyrithiamine (hydrobromide)（10μM）处理HeLa细胞系4天，显著降低了细胞核苷酸水平，细胞内dATP、dCTP、dGTP和dTTP都被还原^[5]。Pyrithiamine (hydrobromide)（0.25mM）处理Neuro 2a细胞，导致细胞内ThDP水平强烈降低，48h后细胞开始死亡^[6]。

在体内，Pyrithiamine (hydrobromide)（250 or 500μg/kg/day）通过腹腔注射处理小鼠4周，引起硫胺素缺乏，导致野生型小鼠的认知功能障碍和神经病理变化，但对已有明显认知障碍的AD模型小鼠无相应影响^[7]。Pyrithiamine (hydrobromide)（0.5g/kg）通过腹腔注射处理大鼠11天，引起硫胺素缺乏，导致侧脑室扩大，体内含胆碱化合物水平降低^[8]。