Clioquinol: Review of its Mechanisms of Action and Clinical Uses in Neurodegenerative Disorders

Abstract

SUMMARYClioquinol was produced as a topical antiseptic and marketed as an oral intestinal amebicide in 1934, being used to treat a wide range of intestinal diseases. In the early 1970s, it was withdrawn from the market as an oral agent because of its association with subacute myelooptic neuropathy (SMON), a syndrome that involves sensory and motor disturbances in the lower limbs and visual changes. The first methods for determining plasma and tissue clioquinol (5-chloro-7-iodo-8-quinolinol) levels were set up in the 1970s and involved HPLC separation with UV detection, these were followed by a more sensitive GC method with electron capture detection and a gaschromatographic-massspectrometric (GC-MS) method. Finally, an HPLC method using electrochemical detection has proved to be as highly sensitive and specific as the GC-MS. In rats, mice, rabbits, and hamsters, clioquinol is rapidily absorbed and undergoes first-pass metabolization to glucuronate and sulfate conjugates; the concentrations of the metabolites are higher than those of free clioquinol. Bioavailabilty versus intraperitoneal dosingis about 12%. Dogs and monkeys form fewer conjugates. In man, single-dose concentrations are dose related, and the drug's half-life is 11-14 h. There is no accumulation, and the drug is much less metabolized to conjugates. Clioquinol acts as a zinc and copper chelator. Metal chelation is a potential therapeutic strategy for Alzheimer's disease (AD) because zinc and copper are involved in the deposition and stabilization of amyloid plaques, and chelating agents can dissolve amyloid deposits in vitro and in vivo. In general, the ability of clioquinol to chelate and redistribute metals plays an important role in diseases characterised by Zn, Cu, Fe dyshomeostasis, such as AD and Parkinson's disease, as it reduces oxidation and the amyloid burden. Zinc chelators may also act as anticancer agents. Animal toxicity studies have revealed species-specific differences in neurotoxic responses that are related to the serum levels of clioquinol and metabolites. This is also true in humans, who form fewer conjugates. The results of studies of Alzheimer patients are conflicting and need further confirmation. The potential therapeutic role of the two main effects of MPACs (the regulation of the distribution of metals and antioxidants) has not yet been fully explored.

The Antiparasitic Clioquinol Induces Apoptosis in Leukemia and Myeloma Cells by Inhibiting Histone Deacetylase Activity

“…the transportation of these ions (41). In Alzheimer and Parkinson disease treatment, CQ binds to copper, thus decreasing copper concentration accumulated in brain tissues (21). CQ is also able to inhibit RNA-dependent DNA polymerase and inactivates Rous sarcoma virus and Herpes simplex virus by forming a complex with copper (42).…”

“…CQ is the most studied one. In the treatment of Alzheimer's disease, CQ acts as a chelator to bind to zinc and copper highly accumulated in the brain tissue (21). In the presence of zinc and copper, CQ displays great activity to inhibit proteasome activity and induces cancer cell death.…”

Zinc and the aging brain

“…One of these drugs, clioquinol, was originally taken as an intestinal amebecide and then more generally to treat intestinal infections until being withdrawn for oral use after many patients using it developed subacute myelo-optic neuropathy (Bareggi and Cornelli 2012). Clioquinol is able to cross the blood brain barrier and binds to zinc and copper removing these metals from senile plaques.…”

Induction of cell cycle arrest via the p21, p27–cyclin E,A/Cdk2 pathway in SMMC-7721 hepatoma cells by clioquinol

“…In recent years, toxicology studies of clioquinol performed in both animals and humans show it has low side effects (4,5). Owing to its ability to bind copper/zinc and dissolve beta-amyloid plaques by activating autophagy in the brain, clioquinol has re-emerged as a potential therapy for Alzheimer's disease (6,7). Clioquinol was also reported to have anticancer activity in several carcinoma cells (8)(9)(10)(11).…”