Modulation of CREB and its associated upstream signaling pathways in pesticide-induced neurotoxicity

Abstract

Human beings are exposed to various environmental xenobiotics throughout their life consisting of a broad range of physical and chemical agents that impart bodily harm. Among these, pesticide exposure that destroys insects mainly by damaging their central nervous system also exerts neurotoxic effects on humans and is implicated in the etiology of several degenerative disorders. The connectivity between CREB (cAMP Response Element Binding Protein) signaling activation and neuronal activity is of broad interest and has been thoroughly studied in various diseased states. Several genes, as well as protein kinases, are involved in the phosphorylation of CREB, including BDNF (Brain-derived neurotrophic factor), Pi3K (phosphoinositide 3-kinase), AKT (Protein kinase B), RAS (Rat Sarcoma), MEK (Mitogen-activated protein kinase), PLC (Phospholipase C), and PKC (Protein kinase C) that play an essential role in neuronal plasticity, long-term potentiation, neuronal survival, learning, and memory formation, cognitive function, synaptic transmission, and suppressing apoptosis. These elements, either singularly or in a cascade, can result in the modulation of CREB, making it a vulnerable target for various neurotoxic agents, including pesticides. This review provides insight into how these various intracellular signaling pathways converge to bring about CREB activation and how the activated or deactivated CREB levels can affect the gene expression of the upstream molecules. We also discuss the various target genes within the cascade vulnerable to different types of pesticides. Thus, this review will facilitate future investigations associated with pesticide neurotoxicity and identify valuable therapeutic targets.

Keywords: AKT; BDNF; CREB; Neurotoxicity; PI3K; Pesticides.

Fig. 1

Pesticides on entering the body through inhalation, ingestion, and skin absorption can reach the brain due to their lipophilic nature. Upon entering the brain, it can target the components within the various signaling pathways like BDNF/TrkB pathway, RAS/RAF/MEK pathway, Pi3K/AKT pathway, PLC/PKC pathway, or through the Calcium–Calmodulin pathway and cAMP pathway and ultimately affect CREB phosphorylation and gene expression. The changes in the phosphorylation or gene expression can, in turn, affect the various functions of CREB, including the regulation of neuronal plasticity and survival. [The scientific diagram was constructed using Servier Medical Art (SMART), licensed under a Creative Commons Attributio 3.0- https://smart.servier.com]

Fig. 2

Gross summary of cellular and molecular changes accompanying the modulation of CREB-related pathways and their outcomes in the pesticide-exposed individuals. Pesticide exposure can lead to cellular and molecular alterations within the neurons while also enhancing microglial activation, damaging the neuronal morphology, and sometimes leading to apoptosis. These changes most often present themselves in the form of immobility, cognitive damage, and impaired learning and memory in the exposed individual. (Created with BioRender.com.)