Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected Targets

Area of Science:

• Neuroscience
• Pharmacology
• Medicinal Chemistry

Background:

• Neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, are driven by oxidative stress and neuroinflammation.
• Current treatments for these conditions remain inadequate, highlighting the need for novel therapeutic strategies.
• Pioglitazone, an antidiabetic drug, shows promise as a neuroprotective agent due to its MAO-B inhibitory activity.

Purpose of the Study:

• To enhance the neuroprotective profile of pioglitazone by incorporating antioxidant functionalities.
• To develop novel compounds with direct and indirect antioxidant properties, targeting Nrf2 pathway activation and radical scavenging.
• To identify potent and selective MAO-B inhibitors for potential therapeutic applications in neurodegenerative diseases.

Main Methods:

• Synthesized and screened pioglitazone derivatives for MAO-B inhibitory properties.
• Evaluated compounds for selectivity against MAO-A.
• Assessed the ability of lead compounds to activate the Nrf2 pathway and reduce reactive oxygen species (ROS) levels.

Main Results:

• A caffeic acid derivative (compound 2) demonstrated potent and selective MAO-B inhibition with a reversible mechanism.
• Compound 2 effectively activated the Nrf2 pathway, evidenced by increased Nrf2 nuclear translocation.
• The derivative significantly reduced ROS content under both physiological and stressed conditions, indicating strong antioxidant capacity.

Conclusions:

• The modified pioglitazone scaffold exhibits significant antioxidant properties, making it a promising starting point for developing new therapeutics.
• The developed compound shows potential for treating neurodegenerative disorders by mitigating oxidative stress and neuroinflammation.
• Further research is warranted to fully elucidate the neuroprotective mechanisms and therapeutic efficacy of this novel agent.