The principal molecular mechanisms behind the activation of Keap1/Nrf2/ARE pathway leading to neuroprotective action in Parkinson's disease

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder. PD is associated with the loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain. Present therapies for PD provide only symptomatic relief by restoring the dopamine (DA) level. However, they are not disease modifying agents and so they do not delay the disease progression. Alpha-synuclein aggregation, oxidative stress, mitochondrial dysfunction and chronic inflammation are considered to be the major pathological mechanisms mediating neurodegeneration in PD. To resist oxidative stress, the human body has an antioxidant defence mechanism consisting of many antioxidants and cytoprotective genes. The expression of those genes are largely controlled by the Kelch-like ECH-associated protein 1/Nuclear factor - erythroid - 2 - related factor 2/Antioxidant response element (Keap1/Nrf2/ARE) signalling pathway. The transcription factor Nrf2 is activated in response to oxidative or electrophilic stress and protects the cells from oxidative stress and inflammation. Nrf2 has been widely considered as a therapeutic target for neurodegeneration and several drugs are now being tested in clinical trials. Regulation of the Keap1/Nrf2/ARE pathway by small molecules which can act as Nrf2 activators could be effective for treating oxidative stress and neuroinflammation in PD. In this review, we had discussed the principal molecular mechanisms behind the neuroprotective effects of Keap1/Nrf2/ARE pathway in PD. Additionally, we also discussed the small molecules and phytochemicals that could activate the Nrf2 mediated anti-oxidant pathway for neuroprotection in PD.

Keywords: Alpha synuclein; Nrf2 activators; Nrf2/Keap1; Oxidative stress; Parkinson's disease; ROS.