Carboxypeptidase E/NFα1: A New Neurotrophic Factor against Oxidative Stress-Induced Apoptotic Cell Death Mediated by ERK and PI3-K/AKT Pathways

Abstract

Mice lacking Carboxypeptidase E (CPE) exhibit degeneration of hippocampal neurons caused by stress at weaning while over-expression of CPE in hippocampal neurons protect them against hydrogen peroxide-induced cell death. Here we demonstrate that CPE acts as an extracellular trophic factor to protect neurons. Rat hippocampal neurons pretreated with purified CPE protected the cells against hydrogen peroxide-, staurosporine- and glutamate-induced cell death. This protection was observed even when hippocampal neurons were treated with an enzymatically inactive mutant CPE or with CPE in the presence of its inhibitor, GEMSA. Purified CPE added to the culture medium rescued CPE knock-out hippocampal neurons from cell death. Both ERK and AKT were phosphorylated within 15 min after CPE treatment of hippocampal neurons and, using specific inhibitors, both signaling pathways were shown to be required for the neuroprotective effect. The expression of the anti-apoptotic protein, B-cell lymphoma 2 (BCL-2), was up-regulated after hippocampal neurons were treated with CPE. Furthermore, hydrogen peroxide induced down-regulation of BCL-2 protein and subsequent activation of caspase-3 were inhibited by CPE treatment. Thus, this study has identified CPE as a new neurotrophic factor that can protect neurons against degeneration through the activation of ERK and AKT signaling pathways to up-regulate expression of BCL-2.

Quercetin attenuates high fructose feeding-induced atherosclerosis by suppressing inflammation and apoptosis via ROS-regulated PI3K/AKT signaling pathway

“…Study before reported that PI3K/AKT-regulated NF-kB pathway was included in the myocardial injury after chronic stress [45]. Given that the possible causal relationship between vascular inflammation and atherogenesis, we supposed that PI3K/AKTregulated NF-kB pathway might be also involved in high fructose feeding-induced atherosclerosis.…”

Effects of Neurotrophin-3 Plasmids on Myocyte Apoptosis and Ca2+-ATPase Content in the Muscle After Nerve Injury in Rats

“…NT-3 may inhibit transcription of the caspase-3 gene, reduce pro-apoptotic factors, and inhibit in such a way neuronal apoptosis [19,20]. However, many other apoptosis-related proteins, such as the Bcl-2 family and P53 protein, were found [21,22]. Our experiments showed that caspase-3 gene transcription and the respective protein expression level began to increase 2 h after nerve injury.…”

Carboxypeptidase E (NF-α1): a new trophic factor in neuroprotection

“…For example, primary cultured hippocampal neurons from CPE KO mice are more prone to die in culture than those from wild-type littermates [20] . Also, low-potassium-induced apoptosis is significantly increased in CPE +/ cerebellar granule neurons (CGNs) in comparison to CPE +/+ CGNs, indicating that CPE plays a neuroprotective role in this type of neuron as well as hippocampal neurons [21] .…”

“…However, a recent study suggests that CPE acts extracellularly as a neuroprotective trophic factor, independent of its enzymatic activity. Extracellular CPE functions by signaling through the ERK and Akt pathways to up-regulate the expression of the pro-survival protein Bcl-2 and inhibit caspase-3 activation, indicating that it confers neuroprotection against cell death by modulating mitochondrial energetics [20] . CPE also protects hippocampal neurons against cell death induced by oxidative stress and glutamate neurotoxicity.…”

“…CPE also protects hippocampal neurons against cell death induced by oxidative stress and glutamate neurotoxicity. In addition, it promotes the long-term survival of embryonic hippocampal neurons from CPE KO mice in culture [20] . Since the pattern of the CPE-induced activation of the ERK and Akt signaling pathways is similar to classic trophic factors such as BDNF and NGF, an alternative name was given to CPE, “Neurotrophic Factor-α1” (NF-α1), indicating its functions as a trophic factor.…”