The Molecular Pathway of Argon-Mediated Neuroprotection

Abstract

The noble gas argon has attracted increasing attention in recent years, especially because of its neuroprotective properties. In a variety of models, ranging from oxygen-glucose deprivation in cell culture to complex models of mid-cerebral artery occlusion, subarachnoid hemorrhage or retinal ischemia-reperfusion injury in animals, argon administration after individual injury demonstrated favorable effects, particularly increased cell survival and even improved neuronal function. As an inert molecule, argon did not show signs of adverse effects in the in vitro and in vivo model used, while being comparably cheap and easy to apply. However, the molecular mechanism by which argon is able to exert its protective and beneficial characteristics remains unclear. Although there are many pieces missing to complete the signaling pathway throughout the cell, it is the aim of this review to summarize the known parts of the molecular pathways and to combine them to provide a clear insight into the cellular pathway, starting with the receptors that may be involved in mediating argons effects and ending with the translational response.

Keywords: argon; cytokines; cytoprotection; heat shock proteins; mitogen-activated protein kinases; molecular pathway; neuroprotection; toll-like receptors; transcription factor.

Figure 1

Argon’s molecular mechanism. Argon is able to specifically activated toll-like receptors 2 and 4, mediating intracellular signaling via IRAK4 and ERK1/2 (and to some amount p38) and inhibiting the heat shock response (HSP-70, -90 and HO-1) or activating the PI3K/mTOR pathway. Mitochrondrial signaling includes Bcl-2, Bcl-X and BAX expression, while ROS is reduced and mitochondrial membrane potential remains constant. These intracellular proteins lead to a differential activation or suppression of transcription factors, thus inducing or inhibiting effector genes and proteins (e.g., IL-8). OGD = oxygen-glucose deprivation, LPS = lipopolysaccharide, tMCAO = transient mid cerebral artery occlusion, IRI = ischemia and reperfusion injury, SAH = subarachnoid hemorrhage, NMDA-R = N-methyl d-aspartate receptor, TLR = toll-like receptor, TRIF = TIR-domain-containing adapter-inducing interferon-β, MyD88 = myeloid differentiation primary response gene 88, IRAK4 = interleukin-1 receptor-associated kinase 4, PI3K = phosphoinositide 3-kinase, AKT = protein kinase B, m-TOR = mechanistic Target of Rapamycin, MKK = mitogen-activated protein kinases, ERK = extracellular signal regulated kinase, JNK = c-Jun N-terminal kinase, BAX/BCL-2/BCL-X = apoptotic genes, ROS = reactive oxygen species, ΔΨm = mitochondrial membrane potential, HSP = heat shock protein, HO-1 = heme-oxygenase-1, Nrf2 = Nuclear factor (erythroid-derived 2)-like 2, STAT = signal transducer and activator of transcription, HIF-1α = hypoxia inducible factor 1α, NF-κB = nuclear factor κB.