The CREB/CRE transcriptional pathway: protection against oxidative stress‐mediated neuronal cell death

Abstract

Formation of reactive oxygen and nitrogen species is a precipitating event in an array of neuropathological conditions. In response to excessive reactive oxygen species (ROS) levels, transcriptionally dependent mechanisms drive the up‐regulation of ROS scavenging proteins which, in turn, limit the extent of brain damage. Here, we employed a transgenic approach in which cAMP‐response element binding protein (CREB)‐mediated transcription is repressed (via A‐CREB) to examine the contribution of the CREB/cAMP response element pathway to neuroprotection and its potential role in limiting ROS toxicity. Using the pilocarpine‐evoked repetitive seizure model, we detected a marked enhancement of cell death in A‐CREB transgenic mice. Paralleling this, there was a dramatic increase in tyrosine nitration (a marker of reactive species formation) in A‐CREB transgenic mice. In addition, inducible expression of peroxisome proliferator‐activated receptor gamma coactivator‐1α was diminished in A‐CREB transgenic mice, as was activity of complex I of the mitochondrial electron transport chain. Finally, the neuroprotective effect of brain‐derived neurotrophic factor (BDNF) against ROS‐mediated cell death was abrogated by disruption of CREB‐mediated transcription. Together, these data both extend our understanding of CREB functionality and provide in vivo validation for a model in which CREB functions as a pivotal upstream integrator of neuroprotective signaling against ROS‐mediated cell death.

Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach

“…Given that ERK activation of CREB induces the expression of a number of antioxidant genes, activation of this pathway may represent an adaptive mechanism to reduce oxidative damage (reviewed in [73]). This contention is supported by the observation that molecularly interfering with CREB increases seizure-induced cell death and production of reactive oxygen species, and blocked the neuroprotective effect of BDNF [74].…”

Cell Death and Autophagy under Oxidative Stress: Roles of Poly(ADP-Ribose) Polymerases and Ca2+

“…Stress response kinases are activated in a Ca 2ϩ -independent manner (2,17,22,37). Therefore, we analyzed the phosphorylation of p38, stress-activated protein kinase/Jun amino-terminal kinase (SAPK/JNK), and their related transcription factors cyclic AMP response element-binding protein (CREB) and its activating transcription factor (ATF-1) in WT and Parp1 Ϫ/Ϫ cells (Fig.…”

New hypothesis and treatment targets of depression: an integrated view of key findings

“…Additional studies showed that the increases of inflammatory cytokines and glucocorticoids caused by stress lead to a reduction of central astrocytes, causing a decreased capacity of the glutamate transporters in astrocytes to transport intracellular glutamate and thus increasing extrasynaptic glutamate [50,51] . Notably, the excitatory neurotoxicity caused by glutamate (mainly oxidative stress) can also lead to reduced BDNF expression, which is the core mechanism of the occurrence of depression [52,53] (Fig. 2).…”