The Therapeutic Effect of Curcumin in Quinolinic Acid-Induced Neurotoxicity in Rats is Associated with BDNF, ERK1/2, Nrf2, and Antioxidant Enzymes.

Ricardo A Santana-Martínez,Perla D Maldonado,Rogelio Hernández-Pando,Yessica Y Fernández-Orihuela,José Pedraza-Chaverri,Diana Barrera-Oviedo,Carlos A Silva-Islas

doi:10.3390/antiox8090388

Abstract

In the present study we investigated the participation of brain-derived neurotropic factor (BDNF) on the activation of the mitogen activated protein kinase (MAPK) protein extracellular signal-regulated kinase-1/2 (ERK1/2) as a mechanism of curcumin (CUR) to provide an antioxidant defense system mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2) in the neurotoxic model induced by quinolinic acid (QUIN). Wistar rats received CUR (400 mg/kg, intragastrically) for 6 days after intrastriatal injection with QUIN (240 nmol). CUR improved the motor deficit and morphological alterations induced by QUIN and restored BDNF, ERK1/2, and Nrf2 levels. CUR treatment avoided the decrease in the protein levels of glutathione peroxidase (GPx), glutathione reductase (GR), γ-glutamylcysteine ligase (γ-GCL), and glutathione (GSH) levels. Only, the QUIN-induced decrease in the GR activity was prevented by CUR treatment. Finally, QUIN increased superoxide dismutase 2 (SOD2) and catalase (CAT) levels, and the γGCL and CAT activities; however, this increase was major in the QUIN+CUR group for γ-GCL, CAT, and SOD activities. These data suggest that the therapeutic effect of CUR could involve BDNF action on the activation of ERK1/2 to induce increased levels of protein and enzyme activity of antioxidant proteins regulated by Nrf2 and GSH levels.

Highlights

Quinolinic acid (QUIN) is a neuroactive metabolite of the kynurenine pathway in the brain, which is the main route of catabolism of tryptophan to produce nicotinamide adenine dinucleotide (NAD+ ).quinolinic acid (QUIN) is present in human and rat brains at nanomolar concentrations [1]; an increase in QUIN levels is observed in several neurodegenerative diseases [2]
There are reports indicating that the intrastriatal administration of QUIN can be used as a biochemical model to study the excitotoxicity and oxidative stress, two mechanisms involved in the pathophysiology of neurodegenerative diseases
Cells have an adaptive response system to endure oxidative stress; these include a battery of cytoprotective genes involved in (1) the detoxification of xenobiotics; (2) the regulation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) levels; (3) the homeostasis of glutathione (GSH) levels (γ-glutamylcysteine ligase, γ-GCL; glutathione peroxidase, GPx; and glutathione reductase, GR); (4) the decrease of oxidative stress, and other processes [10]

Summary

Introduction

QUIN is present in human and rat brains at nanomolar concentrations [1]; an increase in QUIN levels is observed in several neurodegenerative diseases [2]. There are reports indicating that the intrastriatal administration of QUIN can be used as a biochemical model to study the excitotoxicity and oxidative stress, two mechanisms involved in the pathophysiology of neurodegenerative diseases. Cells have an adaptive response system to endure oxidative stress; these include a battery of cytoprotective genes involved in (1) the detoxification of xenobiotics (glutathione S-transferase, GST); (2) the regulation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) levels (glucose 6-phosphate dehydrogenase; G6PDH); (3) the homeostasis of glutathione (GSH) levels (γ-glutamylcysteine ligase, γ-GCL; glutathione peroxidase, GPx; and glutathione reductase, GR);

Methods

Results

Conclusion