Table 2.

Limitations and advantages of different Nrf2 activators.

Nrf2 Activators	Limitations	Advantages
Natural exogenous	Poor drug solubility Low oral bioavailability Increased first-pass metabolism Quick biotransformation and elimination Low plasma concentrations Non-specific effects (can act on other signaling pathways, especially at high doses)	Ingestion with food Available as dietary supplements Affordable due to fair price Increasing clinical trial experience for the treatment of neurodegenerative and neuro-inflammatory CNS disorders (including MS)
Synthetic exogenous	Lymphocytopenia, leukoencephalopathy	Clinically approved in MS treatment
Endogenous	Experimental preclinical evidence Preliminary investigational clinical evidence Less affordable due to high price of TPE	No need for pharmacokinetic (drug delivery) optimization Antioxidant, anti-inflammatory, and immunomodulatory rapid clinical improvement in MS patients