Creatine enhances survival of glutamate‐treated neuronal/glial cells, modulates Ras/NF‐κB signaling, and increases the generation of reactive oxygen species

Abstract

The protective effects of creatine against glutamate cytotoxicity have been demonstrated in neuronal cells and animal models of neurodegenerative diseases. The mechanisms underlying creatine neuroprotection against glutamate-induced cell death are understood poorly. For the first time, we demonstrate a correlation between the protective effect of creatine and the modulation of Ras-mediated redox-dependent signaling pathways, which involve nuclear factor kappaB (NF-kappaB) and reactive oxygen species (ROS). In primary cerebrocortical cultures of mixed neurons and glia, creatine significantly reduced glutamate-induced cell death. The increase in cell survival was accompanied by increased generation of oxygen radicals and decreased levels of farnesylated Ras and IkappaB, an inhibitor of NF-kappaB. Non-farnesylated Ras and ROS-dependent activation of NF-kappaB have been shown to promote neuronal survival. Our data suggest that creatine may enhance survival signaling via activation of the Ras/NF-kappaB system. Possible mechanisms underlying the protective effect of creatine are discussed, including normalization of cellular GTP levels.

The modulation of NMDA receptors and l-arginine/nitric oxide pathway is implicated in the anti-immobility effect of creatine in the tail suspension test

“…However, creatine incubated in vitro (0.1-10 mM) was reported to protect against glutamateinduced toxicity in cell cultures (Brewer and Wallimann 2000;Genius et al 2012;Juravleva et al 2003Juravleva et al , 2005. Considering that hippocampal slices offer certain advantages over cell cultures, as the pattern of synaptic connections within the slice is minimally altered and neuron-astrocyte-microglia interactions are preserved (Somjen et al 1987), in a next set of experiments the in vitro effect of creatine incubation in hippocampal slices was evaluated.…”

NF-κB 在中枢神经系统损伤和修复中的作用

“…Pretreatment of cultures with aspirin, which inhibits NF-B activation, or with specific p53 antisense oligonucleotide, which inhibits p53 transcription, completely prevents glutamate-induced p53 induction and apoptosis [16] . The glutamate-induced cell death in primary cerebrocortical cultures of mixed neuron and glia could be reduced by creatine, possibly via activation of the Ras/NF-B system [17] . The neuroprotective effect of stem cell factors (SCFs) against glutamate excitotoxicity also could be blocked by pharmacological inhibition of NF-B or dominant negative I B (I B-N).…”

Minocycline reduces astrocytic reactivation and neuroinflammation in the hippocampus of a vascular cognitive impairment rat model

“…These molecules include cyclooxygenase-2 (COX-2) [8,9] , nuclear factor-kappaB (NF-κB) [10][11][12] , tumor necrosis factor alphfa (TNF-α), and interleukin 1beta (IL-1β), a pro-inflammatory cytokine released by reactive astrocytes [13,14] . Various mechanisms of neuronal injury in CCH have been proposed, including formation of free radicals, oxidative stress, mitochondrial dysfunction, inflammatory processes, genetic factors, environmental impact factors, apoptosis [15][16][17][18][19][20] , etc.…”