Acute expression of the transcription factor Nrf2 after treatment with quinolinic acid is not induced by oxidative stress in the rat striatum.

Quinolinic acid (QUIN) is an excitotoxic and pro-oxidant molecule used in the study of neurodegenerative disorders because it reproduces certain biochemical characteristics present in these diseases. The use of antioxidant molecules in the QUIN model reduces cellular damage through the nuclear factor erythroid 2-related to factor 2 (Nrf2) pathway. The Nrf2 transcription factor is considered the master regulator of antioxidant genes expression, and its activation occurs by an increase in the reactive oxygen species (ROS) levels or in the presence of electrophilic compounds. However, Nrf2 activation also occurs in an oxidative stress-independent process caused by the disruption of the Keap1-Nrf2 complex by the direct interaction of Keap1 with certain proteins, such as DPP3 and p62. The aim of this study was to evaluate the effect of QUIN on Nrf2 activation over short periods of time. QUIN administration increased Nrf2 activation at 30 min in the striatum without increasing ROS production or modifying the redox cellular state. Moreover, QUIN increased Keap1 and Nrf2 nuclear levels and increased the protein-protein interaction between Keap1 and DPP3 and Keap1 and p62 30 min after QUIN administration. Finally, we found that Nrf2 activation primarily occurs in striatal neurons. Our results show that QUIN administration in vivo stimulates Nrf2 expression and activation in the absence of oxidative stress primarily in neurons and increases the interaction of p62 and DPP3 with Keap1, which could participate in Nrf2 activation.