Patients with Parkinson’s disease (PD) do not produce enough of a compound called ATP. If a person does not make enough ATP, the cells in the body can die. This is very important for cells, like those in the brain, that use a lot of energy. We found a medication, terazosin, that can raise ATP levels in the body. This medication has been around for many years to treat high blood pressure and enlarged prostate. We gave terazosin to pre-clinical models with Parkinson’s to see if their ATP levels would increase. We also wanted to see if their PD symptoms got better. We found that the models treated with terazosin had better motor scores and more ATP in their brains. As a result, we looked at databases of humans and found that patients who were taking terazosin were less likely to get Parkinson’s. Their motor symptoms also did not worsen as quickly as people who were not using terazosin. These findings provide significant rationale for a clinical trial of terazosin in patients with Parkinson’s. However, we first need to assess markers of target engagement of terazosin (a key indicator of the drug’s effectiveness) before beginning a clinical trial. The experiments outlined in this proposal will provide data from pre-clinical models and humans that will provide invaluable guidance for future clinical trials of terazosin and other medications aimed at increasing ATP and glycolysis (the process of breaking down glucose) in patients with Parkinson’s.
We hypothesize that the administration of terazosin to pre-clinical models and humans will result in increases in brain ATP levels and an enhanced rate of glycolysis in the brain.
This study will include experiments in pre-clinical models and humans. The pre-clinical experiments will allow us to directly test the concentration of terazosin in the brain, as well as ATP levels in the brain. We will first test the effect of terazosin by measuring serial concentrations from the blood and cerebrospinal fluid over time in pre-clinical models. We will also assess ATP and glucose changes after administering terazosin. Lastly, six healthy human control volunteers will be given terazosin up to a daily dose of five milligrams. We will assess if changes in brain ATP concentration can be measured and also if changes in glycolysis can be measured in the brain. Based on this information, we may recruit an additional six participants at differing doses of terazosin.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
We believe that terazosin has the potential to be the first medication to slow the progression of Parkinson’s. The proposed experiments will significantly increase our understanding of how the medication reaches the brain and how it exerts its effects once it reaches the brain. This information is vital to design more efficient and effective clinical trials in the future.
Next Steps for Development:
If we are able to measure target engagement of terazosin in these experiments, our next step will be to design a Phase II clinical trial of terazosin in Parkinson’s.