Promising Outcomes of Original Grant:
A newly developed glyoxylate series of metalloporphyrin compounds designed to penetrate the blood brain barrier have shown high potencies as antioxidants. A recent NADD award from the MJFF enabled optimization of the structures of promising novel metalloporphyrins and subsequent evaluation of their bioavailability and efficacy in pre-clinical models. Our results identified several compounds in this series with promising oral bioavailability and pre-clinical efficacy in the MPTP pre-clinical model of PD.
Objectives for Supplemental Investigation:
Oxidative stress is a well-defined therapeutic target for Parkinson’s disease (PD) and antioxidant therapy is one of the most promising neuroprotective strategies for its treatment. Metalloporphyrins are synthetic catalytic antioxidants that mimic the body’s own antioxidant defensive enzymes i.e. superoxide dismutases and catalase. The goal of this proposal is to determine if a newly developed glyoxylate (AEOL112) series of metalloporphyrins designed to penetrate the blood brain barrier shows promise for treatment of PD. To expedite clinical development of this class of compounds, the proposed studies will determine if two lead lipophilic metalloporphyrins show favorable pharmacokinetic profiles in pre-clinical models and efficacy in the 6-hyroxydopamine (6OHDA) model of parkinsonism. The studies will determine 1) the plasma and brain pharmacokinetic profiles of lead compounds in models and 2) their ability to protect dopaminergic neurons in the 6OHDA model.
Importance of This Research for the Development of a New PD Therapy:
Current therapeutic approaches to treat PD are associated with serious adverse effects and fail to provide long-term control this inexorably progressive disease. Therefore, there is an urgent need for novel classes of therapeutic agents for the treatment of PD. This project can rapidly identify an orally active compound for the treatment of PD.
To expedite clinical development of a promising class of lipid soluble catalytic antioxidants, it was essential to test their efficacy in an additional species and model of parkinsonism. Furthermore, it was also important to determine whether the compounds cross the blood-brain barrier (BBB) and are neurorestorative in a post-treatment paradigm. Therefore, the goal of this proposal is to determine if two lead AEOL 112 compounds (AEOL11207 and AEOL11114B) cross the BBB and whether they are efficacious in the 6OHDA model in a neurorestorative paradigm. The rationale for choice of AEOL11207 and AEOL11114B as leads is that these compounds were found in our previous NADD-funded study to be 1) orally active, 2) efficacious in the MPTP model and 3) negative in brain manganese bioaccumulation. We established MTDs, pharmacokinetics, dosing paradigm, drug stability, drug protein binding and efficacy in the 6OHDA model of AEOL11207 and AEOL11114. Our data suggest that every-other-day dosing with both compounds one day after 6OHDA lesion is protective against behavioral test and dopamine depletion. These results validate our MPTP efficacy data and suggest that the drugs can be started in a post-lesion manner to achieve neuroprotection.