Mechanism of CNS oxygen toxicity?

[kafkaland]

The recent discussion of hyperbaric oxygen and oxygen toxicity made me realize that I don't really understand how CNS oxygen toxicity works, and a quick search didn't yield any useful results. Perhaps someone can fill me in?

First, how does the oxygen get to the brain? The hemoglobin is already saturated at 0.2 PPO2, so is the excess dissolved in the blood like inert gases? Then, how does it trigger an excitory neural response? What channels and neurotransmitters are involved? Finally, what's know now about the interplay with CO2? Apparently retained CO2 potentiates the effect of the O2, but is anything known about the mechanism? I found on study that looked at the effect of CO2 on neuronal cell cultures, and it seemed inconclusive at best, reporting increased thresholds in some cells, and lowered ones in others. So I'm a bit at a loss of how all of this fits together.

 

[Duke Dive Medicine]

Hi kafkaland,

Re oxygen transport, yes, oxygen dissolves in blood plasma. At 60 feet on 100% O2 there is enough dissolved oxygen to support life without hemoglobin. It's been done in pigs (but not humans for obvious reasons). That's part of the therapeutic mechanism of hyperbaric oxygen.

The exact mechanism of CNS O2 toxicity is still under investigation. We know that excess oxygen in the body produces reactive oxygen species (ROS), aka free radicals. Excess ROS can overwhelm the body's defensive antioxidant mechanisms.

ROS can decrease the activity of Na+/K+ ATPase, which is an enzyme in the plasma membranes of neurons that helps regulate ion concentrations. ROS also decrease GABA (an inhibitory neurotransmitter) activity, but the exact role that GABA plays in O2 toxicity isn't clear.

ROS will also scavenge endogenous nitric oxide, which is a vasodilator that is produced and stored in different parts of the body. Reducing the amount of circulating nitric oxide produces net vasoconstriction.

The enzyme that catalyzes the formation of nitric oxide is called nitric oxide synthase (NOS). There are several variations of NOS, among them endothelial NOS (ENOS), which is produced by the vascular endothelium (i.e. the lining of the blood vessels) and neuronal NOS (NNOS). Under hyperoxic conditions, ENOS production is not upregulated, which means that the peripheral blood vessels remain constricted due to the reduced amount of NO. NNOS production, however, is upregulated, which produces net vasodilation and concomitant increased blood flow to the brain.

CO2 retention increases the risk of O2 toxicity because CO2 is a vasodilator. Excess CO2 can lead to increased cerebral blood flow.

Hope this helps!

Best regards,
DDM

 

[kafkaland]

Hi kafkaland,

Re oxygen transport, yes, oxygen dissolves in blood plasma. At 60 feet on 100% O2 there is enough dissolved oxygen to support life without hemoglobin. It's been done in pigs (but not humans for obvious reasons). That's part of the therapeutic mechanism of hyperbaric oxygen.

The exact mechanism of CNS O2 toxicity is still under investigation. We know that excess oxygen in the body produces reactive oxygen species (ROS), aka free radicals. Excess ROS can overwhelm the body's defensive antioxidant mechanisms.

ROS can decrease the activity of Na+/K+ ATPase, which is an enzyme in the plasma membranes of neurons that helps regulate ion concentrations. ROS also decrease GABA (an inhibitory neurotransmitter) activity, but the exact role that GABA plays in O2 toxicity isn't clear.

ROS will also scavenge endogenous nitric oxide, which is a vasodilator that is produced and stored in different parts of the body. Reducing the amount of circulating nitric oxide produces net vasoconstriction.

The enzyme that catalyzes the formation of nitric oxide is called nitric oxide synthase (NOS). There are several variations of NOS, among them endothelial NOS (ENOS), which is produced by the vascular endothelium (i.e. the lining of the blood vessels) and neuronal NOS (NNOS). Under hyperoxic conditions, ENOS production is not upregulated, which means that the peripheral blood vessels remain constricted due to the reduced amount of NO. NNOS production, however, is upregulated, which produces net vasodilation and concomitant increased blood flow to the brain.

CO2 retention increases the risk of O2 toxicity because CO2 is a vasodilator. Excess CO2 can lead to increased cerebral blood flow.

Hope this helps!

Best regards,
DDM

Thank you very much! That gives me a much better idea of what's going on, and what we know that we still don't know. I really appreciate it.

 

[northernone]

Thank you for a succinct answer without excessively dumbing down the details.

Best regards,
Cameron

 

[Kevrumbo]

. . .
Finally, what's know now about the interplay with CO2? Apparently retained CO2 potentiates the effect of the O2, but is anything known about the mechanism? I found on study that looked at the effect of CO2 on neuronal cell cultures, and it seemed inconclusive at best, reporting increased thresholds in some cells, and lowered ones in others. So I'm a bit at a loss of how all of this fits together.

Interesting practical article from an anecdotal physiological perspective by @Dr Simon Mitchell on high ppO2 exposure, CNS Oxygen Toxicity and PetCO2 on nominal decompression stops.

Advanced Knowledge Series: Carbon Dioxide Retention