Hu Weiqiang, Zhao Menghua, Lian Junrong, Li Dandan, Wen Jinhua, Tan Jun
Department of GCP/Psychosomatic Medicine, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
College of Pharmacy, Nanchang University, Nanchang 330006, China.
CNS Neurol Disord Drug Targets. 2023;22(8):1250-1258. doi: 10.2174/1871527321666220825114236.
Recent studies have shown that lithium treatment can reduce symptoms of Alzheimer's disease (AD) and Autism Spectrum Disorder (ASD). However, the present lithium salts clinically available have serious short-term and long-term side effects, requiring frequent monitoring of blood chemistry and plasma lithium levels to avoid toxicity. Consequently, there is a demand for a safer and more effective lithium formulation to treat these diseases.
Hence, we firstly synthesized lithium cholesterol sulfate (LiCS) and compared its pharmacological effects with that of lithium chloride (LiCl) and sodium cholesterol sulfate (NaCS) on markers of neurodegenerative disease in cell cultures.
LiCS was more potent than LiCl in increasing inhibitory GSK3β (Ser9) phosphorylation (pGSK3β) in both CHO and SH-SY5Y cells. These agents dose-dependently increased pGSK3β, starting at 10 μM for LiCS and 60 μM for LiCl and maximally by approximately 100% at 60 μM for LiCS and 1.25 mM for LiCl, without altering total GSK3β levels. In HEK293/tau cells, LiCS reduced tau (Thr231) phosphorylation (ptau) starting at 10 μM and maximally by 63% at 40 μM without altering total tau levels, but ptau levels were not altered by LiCl at any dose between 60 μM and 1.25 mM. In BV2 cells, LiCS and LiCl decreased LPS-induced TNFα levels, starting at 20 μM for LiCS and 5 mM for LiCl, and maximally by approximately 30% at 80 μM for LiCS and 20 mM for LiCl. NaCS at any dose between 5 and 90 μM did not alter pGSK3β, ptau or LPS-induced TNFα.
LiCS may become a new drug with good pharmacological potential for the treatment of neurodegenerative disorders, such as AD and ASD, by allowing lithium to more readily access intracellular pathological processes.
近期研究表明，锂盐治疗可减轻阿尔茨海默病（AD）和自闭症谱系障碍（ASD）的症状。然而，目前临床上可用的锂盐具有严重的短期和长期副作用，需要频繁监测血液化学成分和血浆锂水平以避免毒性。因此，需要一种更安全、更有效的锂制剂来治疗这些疾病。
因此，我们首先合成了硫酸锂胆固醇（LiCS），并在细胞培养中比较了其与氯化锂（LiCl）和硫酸锂钠（NaCS）对神经退行性疾病标志物的药理作用。
在CHO和SH-SY5Y细胞中，LiCS在增加抑制性GSK3β（Ser9）磷酸化（pGSK3β）方面比LiCl更有效。这些药物剂量依赖性地增加pGSK3β，LiCS从10μM开始，LiCl从60μM开始，LiCS在60μM时最大增加约100%，LiCl在1.25 mM时最大增加约100%，且不改变总GSK3β水平。在HEK293/tau细胞中，LiCS从10μM开始降低tau（Thr231）磷酸化（ptau），在40μM时最大降低63%，且不改变总tau水平，但在60μM至1.25 mM之间的任何剂量下，LiCl均未改变ptau水平。在BV2细胞中，LiCS和LiCl降低LPS诱导的TNFα水平，LiCS从20μM开始，LiCl从5 mM开始，LiCS在80μM时最大降低约30%，LiCl在20 mM时最大降低约30%。在5至90μM之间的任何剂量下，NaCS均未改变pGSK3β、ptau或LPS诱导的TNFα。
LiCS可能通过使锂更容易进入细胞内病理过程，成为一种具有良好药理潜力的治疗神经退行性疾病（如AD和ASD）的新药。
