Title:Lithium Cholesterol Sulfate: A Novel and Potential Drug for Treating
Alzheimer’s Disease and Autism Spectrum Disorder
Volume: 22
Issue: 8
Author(s): Weiqiang Hu, Menghua Zhao, Junrong Lian, Dandan Li, Jinhua Wen*Jun Tan*
Affiliation:
- Department of GCP/Psychosomatic Medicine, The First Affiliated Hospital of Nanchang University, Nanchang
330006, China
- Key Laboratory of Endemic and Ethnic Diseases, the Ministry of Education,
Guizhou Medical University, Guiyang 550004, China
Keywords:
Lithium cholesterol sulfate, lithium chloride, Alzheimer’s disease, Autism spectrum disorder, phosphorylated GSK3β, phosphorylated tau, TNFα.
Abstract:
Background and Objective: 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.
Methods: 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.
Results: 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.
Conclusion: 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.