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.

Revisiting the effect of cholesteryl sulfate on clotting and fibrinolysis: Inhibition of human thrombin and other human blood proteases

“…4 ). Given the results of this study, we strongly recommend further in vitro (for example, thrombo-elastography) and in vivo (for example, animal models of venous and arterial thrombosis) investigation of CS to better understand its (patho-)physiological roles in coagulation and hemostasis which may intersect with the other reported biological effects of CS [ [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] ].…”

Molecular mechanisms and therapeutic potential of lithium in Alzheimer’s disease: repurposing an old class of drugs

“…Lithium ascorbate, which has low acute and chronic toxicity, has been found to mitigate ischemia-induced brain damage and play a significant neuroprotective role ( Torshin et al, 2022 ). In studies on AD, lithium benzoate and lithium cholesterol sulfate have been shown to improve cognitive and memory functions in animal models through multiple pathways ( Hu et al, 2022 ; Lu et al, 2022 ). Nanolithium, which utilizes Medesis Pharma’s innovative drug delivery technology (Aonys ® ) to enhance the bioavailability of lithium and reduce its toxicity, has demonstrated potential in preclinical studies with the microdose lithium formulation (NP03) for the treatment of AD ( Wilson et al, 2020 ).…”

Current and future therapeutic strategies for Alzheimer’s disease: an overview of drug development bottlenecks

“…However, clinically available Lithium has serious side effects (SAE) with long-term use. It requires constant monitoring of Lithium concentrations in the blood; safer and more effective Lithium is needed for clinical use (Haussmann et al, 2021;Hu et al, 2022;Muronaga et al, 2022;Luca and Luca, 2023).…”