# A Highly Potent Apomorphine Derivative Enhancing Neurite Outgrowth via Nrf2 Activation

## TL;DR

A new apomorphine derivative, D55, was found to strongly promote nerve growth through Nrf2 activation, offering potential for treating neurodegenerative diseases.

## Contribution

The study introduces D55, a novel apomorphine derivative with high potency for Nrf2 activation and neurite outgrowth.

## Key findings

- D55 showed the highest potency (EC50 = 0.5661 nM) in promoting neurite outgrowth.
- Neuroplasticity effects of APO, D55, and Eda were Nrf2-dependent, as shown by siRNA knockdown.
- D30, with a methoxy substitution, had no effect on neurite outgrowth.

## Abstract

Apomorphine (APO), a dopamine agonist, activates nuclear factor erythroid 2-related factor 2 (Nrf2) and exerts antioxidant effects, making it a promising candidate for neuroprotection against oxidative stress. This study evaluated neuroplasticity-enhancing properties of newly synthesized APO derivatives, focusing on their ability to promote neurite outgrowth in PC12 cells under nerve growth factor (NGF) stimulation. D55, an APO derivative, retains the hydroxyl group at APO’s 11th position while substituting the 10th with an ethoxy group. D55 exhibited the highest potency (EC50 = 0.5661 nM), significantly enhancing neurite outgrowth. APO demonstrated the highest efficacy (Emax ~10-fold increase), while edaravone (Eda) required higher concentrations (EC50 = 22.5 nM) for moderate effects (Emax ~4-fold increase). D30, in which the 11th hydroxyl was replaced with a methoxy group, had no effect. Neurite outgrowth-promoting effects of APO, D55, and Eda were significantly attenuated by Nrf2 siRNA knockdown, confirming that their neuroplasticity effects are Nrf2-mediated. These findings confirm that D55 is a highly potent Nrf2-activating compound with strong neuroprotective potential, providing new insights into its therapeutic applications for neurodegenerative diseases associated with oxidative stress.