Neuroprotection by nitrous oxide: Facts and evidence*

Abstract

These data provide experimental evidence that nitrous oxide, which is a cost-efficient and easily available gas, has potentially neuroprotective properties in rodents when given alone at nonanesthetic concentrations. Therefore, because there is a lot at stake for the affected patients and society--in terms of easy access to treatment, profound impact of brain damage, cost of treatment, and subsequent financial cost on society--we believe that further studies should investigate thoroughly the possible potential clinical interest of nitrous oxide for the treatment of ischemic stroke in terms of optimal indications, type of ischemic injury, duration and time points for treatment, and the optimal concentration of gas to be used in clinical circumstances.

Interactions between Nitrous Oxide and Tissue Plasminogen Activator in a Rat Model of Thromboembolic Stroke

“…Next, in contrast to the adverse effect of intraischemic nitrous oxide and in agreement with previous reports in rats subjected to mechanical ischemia, 21,23 we found that nitrous oxide given after ischemia reduces ischemic brain damage at the cortical but not the subcortical level. Such a dichotomic effect of postischemic nitrous oxide has been attributed to the striatum (which constitutes the main part of the subcortical areas that are damaged in the MCAO ischemic model) being difficult to protect against stroke because it experiences complete blood flow cessation during ischemia because of its lack of collateral vasculature compared with the cortex.…”

“…Brain damage was assessed 24 h after injection of NMDA or NMDA plus tPA or after the onset of ischemia for intraischemic experiments and 48 h after the onset of brain ischemia for postischemic experiments to allow "better" comparison with previous mechanical and thromboembolic studies. 23,24,29 Comparative studies using multiple staining techniques 32,33 have shown that assessment of infarct size at 24 h is a time condition sufficient to obtain consolidated infarct volumes (i.e., whose assessment would be similar if performed one or several days later), thereby allowing reliable comparison between the data obtained at 24 h or 48 h after the onset of brain ischemia. The brain was removed and frozen in isopentane.…”

“…Nitrous oxide was used at 75 vol%, a concentration shown in a recent dose-effect study to provide maximal neuroprotection in rats subjected to MCAOinduced ischemia. 23 At 45 min after the onset of brain ischemia, rats were administered tPA in the form of Actilyse. In line with the findings of clinical studies of tPA-treated patients, 37,38 we found that rats injected with tPA exhibited full cerebral reperfusion 40 min after tPA injection.…”

“…Nitrous oxide was used at 75 vol%, a concentration shown in a recent dose-effect study to provide maximal neuroprotection in rats subjected to MCAO-induced ischemia. 23 Rats were subjected to MCAO-induced ischemia by administration of an autologous blood clot by the intraluminal method. Twenty-four hours before the animals were subjected to MCAO-induced ischemia, a whole caudal blood sample of 200 l was withdrawn and allowed to clot at 37°C for 2 h. The clot was extruded from the catheter into a saline-filled petri dish and stored at 4°C for 22 h before being used the day after to induce thromboembolic ischemia.…”

“…However, a recent study performed in a rat model of thromboembolic stroke has shown that xenon inhibits tPA by binding directly within its catalytic site, thereby producing adverse effects by reducing tPA-induced thrombolysis and, as a consequence, thrombolysis-induced reduction of brain damage when administered during the intraischemic period and beneficial effects by suppressing both ischemic brain damage and recombinant tPA-induced brain hemorrhages and disruption of the blood-brain barrier when given after reperfusion. 29 Because nitrous oxide shares pharmacologic and neuroprotective properties similar to that of xenon in excitotoxic-ischemic models, 14,[21][22][23] we hypothesized that nitrous oxide may modulate the catalytic efficiency of tPA and thereby alter the beneficial and/or adverse effects of recombinant tPA therapy in a rat model of thromboembolic ischemia.…”