A Novel Small Molecule Enhances Stable Dopamine Delivery to the Brain in Models of Parkinson’s Disease

TL;DR

A new small molecule called Pegasus shows promise in delivering stable dopamine to the brain and reducing Parkinson’s disease symptoms in animal models.

Contribution

Pegasus is a novel small molecule that delivers stable dopamine and reduces alpha-synuclein pathology in Parkinson’s disease models.

Findings

Pegasus reduces soluble and insoluble alpha-synuclein levels and protects dopamine neurons in A53T mice.

Pegasus improves motor function and reduces anxiety-like behavior in Parkinson’s disease models.

Pegasus metabolizes into dopamine and tetracycline derivatives with abundant brain and plasma levels.

Abstract

Levodopa is the gold standard symptomatic treatment for Parkinson’s disease. Disease progression due to alpha-synuclein accumulation, brain inflammation, and the loss of dopamine neurons, as well as motor fluctuations, due to variations in levodopa plasma levels, remain a significant problem for Parkinson’s patients. Developing a therapeutic option that can simultaneously reduce the neuropathology associated with alpha-synuclein aggregation, attenuate oxidative stress and inflammation, and overcome variations in levodopa plasma levels is an unmet need to treat Parkinson’s disease. We determined the pharmacokinetics and pharmacodynamics of a small molecule, dubbed Pegasus, that conjugates dopamine with a nonantibiotic doxycycline derivative via a molecular linker. Mice harboring the human A53T mutation of alpha-synuclein or treated with MPTP were injected once daily with 50 mg/kg Pegasus for 2 weeks and assessed for motor, behavioral, and cognitive effects, followed by biochemical and histochemical analysis. Pegasus is a poor brain penetrant but it was metabolized to stable dopamine and tetracycline derivatives, and abundant plasma and brain levels of these metabolites were detected. Pegasus reduced soluble and insoluble alpha-synuclein levels, protected dopamine-producing neurons, and reduced astrocytic activation in A53T mice. Mice treated with Pegasus exhibited motor improvement (6.5 h) and reduction in anxiety-like behavior. Rotarod and grip strength improved in MPTP-treated mice when mice were treated with Pegasus or levodopa. Pegasus may be a multi-modal therapeutic option that can deliver stable dopamine into the CNS and reduce misfolded alpha-synuclein, activate dopamine receptors, and attenuate variations in dopamine levels.

Figures