Abstract
Oxidative stress (OS) plays a critical role in the pathophysiology of several brain-related 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.
Highlights
Oxidative stress (OS) is a pathological condition resulting from an imbalance between reactive oxygen species (ROS) generation and cellular antioxidant capacity
Howsoever caused, when encountered, cells compensate for the damaging effect of OS by activating the intracellular antioxidant defense system, which is compromised in a background of neurodegenerative diseases (NDDs)
Oxidative stress has been implicated in the pathogeneses of degenerative brain disorders, and its targeting offers a means of developing a viable strategy to treat these chronic brain diseases
Summary
Oxidative stress (OS) is a pathological condition resulting from an imbalance between ROS generation and cellular antioxidant capacity. The excitotoxic stimulation of cultured rat hippocampal neurons results in the downregulation of TrkB.FL, while upregulation of TrkB.T1 expression caused a significant alternation in the ratio of the two receptors (Gomes et al, 2012), which allows BDNF to induce Nrf activation in the presence of p75NTR (Ishii and Mann, 2018) This mechanism protects neurons from oxidative damage during excitotoxic stimulation with glutamate, an event that frequently encountered in neural injury, stroke, and NDDs (Ishii and Mann, 2018). Neuroprotection (antioxidation, anti-apoptosis, attenuates mitochondrial dysfunction); amelioration of memory impairment
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