Lithium Cholesterol Sulfate: A Novel and Potential Drug for Treating Alzheimer’s Disease and Autism Spectrum Disorder

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 which requires frequent monitoring of blood chemistry and plasma lithium levels so as 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 60µM 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.