CCAAT/enhancer binding protein β deficiency provides cerebral protection following excitotoxic injury

Abstract

The CCAAT/enhancer-binding protein β (C/EBPβ, also known as CEBPB) was first identified as a regulator of differentiation and inflammatory processes in adipose tissue and liver. Although C/EBPβ was initially implicated in synaptic plasticity, its function in the brain remains largely unknown. We have previously shown that C/EBPβ regulates the expression of genes involved in inflammatory processes and brain injury. Here, we have demonstrated that the expression of C/EBPβ is notably increased in the hippocampus in a murine model of excitotoxicity. Mice lacking C/EBPβ showed a reduced inflammatory response after kainic acid injection, and exhibited a dramatic reduction in pyramidal cell loss in the CA1 and CA3 subfields of the hippocampus. These data reveal an essential function for C/EBPβ in the pathways leading to excitotoxicity-mediated damage and suggest that inhibitors of this transcription factor should be evaluated as possible neuroprotective therapeutic agents.

Troxerutin Counteracts Domoic Acid–Induced Memory Deficits in Mice by Inhibiting CCAAT/Enhancer Binding Protein β–Mediated Inflammatory Response and Oxidative Stress

“…Despite considerable progress in excitotoxic research and antiexcitotoxic drug therapies, few studies have investigated the mechanisms and potential treatment strategies focused on excitotoxic-induced cognitive impairment. Previous work by our laboratory and others has demonstrated that inflammation and oxidative stress play important roles in the pathological process of excitotoxic-induced cognitive impairment (5,10,33). Consistent with a recent report, we have shown that DA treatment significantly stimulates the release of proinflammatory cytokines such as IL-1b, TNF-a, Cox-2, and iNOS, and induces astrocytic activation by upregulating C/EBP b expression in the hippocampus of mice (10).…”

“…Excitotoxic brain damage is considered to be one of the major mechanisms by which neurons of the CNS die and can result in memory decline. Excitotoxicity may also be involved in the pathogenesis of many brain disorders, including brain ischemia, epilepsy, traumatic brain injury, and neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease (5,10,33,45). Despite considerable progress in excitotoxic research and antiexcitotoxic drug therapies, few studies have investigated the mechanisms and potential treatment strategies focused on excitotoxic-induced cognitive impairment.…”

“…Several lines of evidence show that activation of KA receptors impairs mitochondrial function, provokes the release of inflammatory factors, and increases the generation of reactive oxygen species (ROS), which disrupt neural signaling pathways and cause structural cellular damage, ultimately leading to cognitive deficits and brain damage (2,(5)(6)(7)(8)(9)(10). Because the pathogenic process of cognitive deficits and brain damage induced by DA involves a complex cascade of events, the precise biological mechanisms underlying these effects still need to be explored.…”

“…Because the pathogenic process of cognitive deficits and brain damage induced by DA involves a complex cascade of events, the precise biological mechanisms underlying these effects still need to be explored. Growing evidence suggests that inflammatory response and oxidative stress play key roles in the pathogenesis of DA-induced brain damage (5)(6)(7)(8)(9)(10).…”

“…Recent findings show that C/EBP binduced inflammatory responses mediate KA-triggered excitotoxic brain injury (10). In response to excitotoxic insults, C/EBP b induces glial cell activation and stimulates the protein expression of inflammatory mediators and proinflammatory cytokines, which results in neuronal damage.…”