Neuroprotection Is in the Air-Inhaled Gases on Their Way to the Neurons

Abstract

Cerebral injury is a leading cause of long-term disability and mortality. Common causes include major cardiovascular events, such as cardiac arrest, ischemic stroke, and subarachnoid hemorrhage, traumatic brain injury, and neurodegenerative as well as neuroinflammatory disorders. Despite improvements in pharmacological and interventional treatment options, due to the brain's limited regeneration potential, survival is often associated with the impairment of crucial functions that lead to occupational inability and enormous economic burden. For decades, researchers have therefore been investigating adjuvant therapeutic options to alleviate neuronal cell death. Although promising in preclinical studies, a huge variety of drugs thought to provide neuroprotective effects failed in clinical trials. However, utilizing medical gases, noble gases, and gaseous molecules as supportive treatment options may offer new perspectives for patients suffering neuronal damage. This review provides an overview of current research, potentials and mechanisms of these substances as a promising therapeutic alternative for the treatment of cerebral injury.

Keywords: argon; carbon monoxide; desflurane; helium; hydrogen sulfide; ischemia/reperfusion injury; isoflurane; neon; neuronal cell death; noble gases; sevoflurane; volatile anesthetics; xenon.

Figure 1

Schematic overview of neuroprotection by the volatile anesthetics sevoflurane and isoflurane. (a) Isoflurane promotes cell survival by activating the DNA binding complex HIF-1α, resulting in increased levels of Erk1/2 and iNOS. Isoflurane also attenuates apoptosis via activation of TREK1- and K_ATP-channels. Activation of the TGF- β /JNK signaling pathway facilitates part of the neuroprotective effect of isoflurane. In addition, isoflurane leads to increased expression of SP1 and activation of the PI3K/Akt signaling pathway. Isoflurane, but not sevoflurane promotes part of its detrimental action with the p75-NTR receptor, located solely in neurons. (b) Sevoflurane reduces the expression of pro-inflammatory cytokines by regulating the TLR-4/NF-κB signaling pathway. Furthermore, sevoflurane improves neuronal survival and decreases apoptosis and cellular atrophy via the PI3K/Akt and JAK/STAT pathways. Sevoflurane also acts as an anti-oxidant and helps maintain vascular endothelial integrity.

Figure 2

Schematic overview of neuroprotection by the gaseous molecules H₂S and CO. (a) H₂S suppresses apoptosis of neuronal cells by reducing the expression of the pro-apoptotic Bax protein and increasing the expression of the anti-apoptotic protein BCL-2. Regulation of the p38/Erk1/2 signaling pathway and the heat-shock response are key elements in facilitating the neuroprotective effect of H₂S. Furthermore, H₂S decreases the expression of apoptotic and pro-inflammatory markers, such as caspase-3, ICAM-1, VEGF, and iNOS. (b) CO reduces neuroinflammation by downregulation of the expression of pro-inflammatory cytokines. CO also differentially regulates the activation of MAP kinases ERK1/2 and p38, resulting in anti-apoptotic signaling. Moreover, CO promotes neuronal cell survival and modulates the heat-shock response.

Figure 3

Schematic overview of noble gas-induced neuroprotection. (a) Xenon’s neuroprotective effect is mediated by the inhibition of NMDA receptors. In addition, Xenon can activate potassium channels (TREK-1) and functions as a potassium channel opener leading to increased K_ATP currents. Targeting Bax, Bcl-2 and HIF-1α, Xenon also provides anti-apoptotic and anti-inflammatory effects. (b) TLR2 and 4 are responsible for argon-mediated neuroprotective effects. The downstream signaling pathways PI3K/Akt and ERK1/2 impact transcription factors promoting cell survival and reducing pro-inflammatory cytokines and apoptosis signaling. (c): Helium promotes neuroprotection mainly via nitric oxide (NO) and increases the expression of antioxidases such as SOD-1 and HO-1.