User:Iian007/sandbox

Research using metal Chelators and ionophores

A: Clioquinol (CQ) promotes less aggregation of mutant huntingtin protein decreasing symptoms of Huntington's. Clioquinol is a compound that binds copper ions and improves excretion from the body. This results in there being a lower concentration of copper ions in the body. Huntington’s disease patients have increased levels of copper and the CQ would be able to eliminate these excess copper ions. A number of  tests were done to determine if CQ would have any effect on the concentration of mutant huntingtin (Htt) proteins in the body and if it would increase the pathology of mice.


 * 1) The first test showed that the presence of CQ reduced the mutant Htt protein concentrations. The first test also found that in relation with the decrease in mutant huntingtin protein the cell survival rate increased depending on the dose of CQ given.
 * 2) The second test found that the addition of CQ did not influence the levels of mRNA present. To test if CQ affected protein degradation rates the CQ was added to the Htt protein along with a protease inhibitor to see if CQ would still work. The result was the same as with no inhibitor so CQ does not work to increase proteasome degradation.
 * 3) The third test was done to determine of CQ could lessen the clumping of the Aggregated Mutant Htt protein. This test was done on mice which were given CQ pills for an 8-week period and mice that were not given the CQ compound. After the 8-week period, there was a reduction in the quantity of aggregated mutant Htt compared to the control.
 * 4) The final test was conducted on mice to determine if CQ could increase the pathology, motor function and lifespan of the mice. When the mice were exposed to CQ the size of the lateral ventricle was reduced by 55%. The second thing looked at was foot clasping, which is when the feet of the mice twist up while they are hung by their tail due to late stage huntington's. When these mice were exposed to CQ there was a 48 % reduction in clasping. The mice treated with CQ also scored far better on a test of agility and coordination. Weight loss in the mice was also reversed with the addition of CQ. The lifespan of the mice treated with the CQ was  increased by 20% compared to the non-treated mice

B: Research into Clioquinol has found that it has trouble penetrating the blood brain barrier for treatment in humans. The blood brain barrier is a series of capillaries that controls the blood flow into the brain. These capillaries stop toxins and pathogens from entering the brain and causing harm. A new drug,PBT2, has been found to penetrate the blood brain barrier easier and to aid in the removal of copper more effectively than CQ. due to this benefits PBT2 has become the new drug of choice for research into lessen Htt aggregation. PBT2 prevents protein accumulation while also transferring copper ions into the cell. Having PBT2 transfer copper and zinc into the cells reduces their extracellular levels and in turn reducing protein aggregation. There is still more research being done to further study the effects of PBT2.