Neuroprotection Against Oxidative Stress: Phytochemicals Targeting TrkB Signaling and the Nrf2-ARE Antioxidant System

Abstract

Oxidative stress (OS) plays a critical role in the pathophysiology of several brainrelated disorders, including neurodegenerative diseases and ischemic stroke, which are the major causes of dementia. The Nrf2-ARE (nuclear factor erythroid 2-related factor 2/antioxidant responsive element antioxidant) system, the primary cellular defense against OS, plays an essential role in neuroprotection by regulating the expressions of antioxidant molecules and enzymes. However, simultaneous events resulting in the overproduction of reactive oxygen species (ROS) and deregulation of the Nrf2-ARE system damage essential cell components and cause loss of neuron structural and functional integrity. On the other hand, TrkB (tropomyosin-related kinase B) signaling, a classical neurotrophin signaling pathway, regulates neuronal survival and synaptic plasticity, which play pivotal roles in memory and cognition. Also, TrkB signaling, specifically the TrkB/PI3K/Akt (TrkB/phosphatidylinositol 3 kinase/protein kinase B) pathway promotes the activation and nuclear translocation of Nrf2, and thus, confers neuroprotection against OS. However, the TrkB signaling pathway is also known to be downregulated in brain disorders due to lack of neurotrophin support. Therefore, activations of TrkB and the Nrf2-ARE signaling system offer a potential approach to the design of novel therapeutic agents for brain disorders. Here, we briefly overview the development of OS and the association between OS and the pathogenesis of neurodegenerative diseases and brain injury. We propose the cellular antioxidant defense and TrkB signaling-mediated cell survival systems be considered pharmacological targets for the treatment of neurodegenerative diseases, and review the literature on the neuroprotective effects of phytochemicals that can co-activate these neuronal defense systems.

Neuroprotective Potentials of Marine Algae and Their Bioactive Metabolites: Pharmacological Insights and Therapeutic Advances

“…Oxidative stress (OS) is a pathological condition that develops when the production of reactive oxygen species (ROS) reaches an excessive level with lower efficiency of the cellular antioxidant defense system [ 40 ]. Factors contributing to OS in the brain include excitotoxicity, depletion of the cellular antioxidant system, high susceptibility to lipid peroxidation, and high oxygen demand [ 41 ].…”

7β-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z Notonipetranone Attenuates Neuropathic Pain by Suppressing Oxidative Stress, Inflammatory and Pro-Apoptotic Protein Expressions

“…Nrf2 binding with the antioxidant responsive element (ARE) leads to the transcriptional activation of downstream genes such as NAD(P)H: quinone oxidoreductase (NQO1), glutathione-S-transferase (GST), and hemeoxygenase-1 (HO-1) [ 27 , 30 , 31 , 32 ]. Moreover, several studies have shown that overexpression of Nrf2 produces a protective effect against oxidative stress [ 18 , 33 , 34 , 35 ]. Recently, the activation of inflammatory markers and apoptotic pathways in the pathogenesis of neuropathic pain has been demonstrated [ 36 , 37 , 38 ].…”

Anti-Amnesic Effect of Walnut via the Regulation of BBB Function and Neuro-Inflammation in Aβ1-42-Induced Mice

“…The decrease in p-Akt also affects the reduction of the antioxidant system’s ability to eliminate ROS and oxidative stress [ 72 ]. p-Akt increases the expression of Nrf2 from Kelch-like, ECH-associated protein 1 (keap1), and the generated Nrf2 increases the expression of HO-1, NAD(P)H quinone oxidoreductase (NQO1), and SOD protecting the antioxidant system [ 76 ]. However, a decrease in p-Akt inhibits the normal function of the neuronal survival pathway, and accumulated oxidative stress leads to neuronal cell death [ 72 ].…”