CO exposure, as observed during low-flow anesthesia, may be one reason why animal models of neuroapoptosis aren’t quite the same as are found in humans. (Image source: Thinkstock)

CO exposure, as observed during low-flow anesthesia, may be one reason why animal models of neuroapoptosis aren’t quite the same as are found in humans. (Image source: Thinkstock)

Why are animal studies not easily translatable to humans?  Specifically for neuroapoptosis, why is the relationship between anesthesia exposure and neuroapoptosis so clear in animals, but the same is not true for humans?  It was recently shown in this journal that carbon monoxide (CO) is detected in the breathing circuit of infants and children, particularly during low-flow anesthesia.  CO is antiapoptotic.  Could it be protective?

Ying Cheng and Dr. Richard J. Levy, Division of Anesthesiology and Pain Medicine, Children’s National Medical Center, The George Washington University School of Medicine and Health Sciences, Washington, DC sought to determine whether CO would limit neuroapoptosis after seven-day-old mouse pups were exposed to isoflurane.  The findings of their study, “Subclinical Carbon Monoxide Limits Apoptosis in the Developing Brain After Isoflurane Exposure,” appeared in the June 2014 issue of Anesthesia & Analgesia.

On postnatal day 7 (P7), 94 male CD-1 mouse pups were exposed to either 0 ppm CO (air), 5 ppm CO in air, or 100 ppm CO in air with and without isoflurane (2%) for 1 hour.  Carboxyhemoglobin (COHb) levels increased significantly in those exposed to 100 ppm CO without isoflurane and almost significantly in animals exposed to 100 ppm with isoflurane.  Of note was that COHb levels in the animals approximated the same levels in humans exposed to CO for a similar length of time (mean of 3.27% COHb in humans after 1-hour exposure to 100 ppm CO), were below levels that would result in tissue hypoxia (70% COHb), and were less than values known to generate signs and symptoms in humans (10% COHb).

Cytochrome c release and cytochrome c peroxidase activity initiate the mitochondrial apoptosis pathway. Both increased in a concentration-dependent manner with exposure to isoflurane. CO substantially reduced the isoflurane-induced increase in cytochrome c release and cytochrome c peroxidase activity in forebrain mitochondria, reducing the number of activated caspase-3 positive (apoptotic) cells. CO exposure was associated with a decrease in neuroapoptosis in every brain region compared to animals who received isoflurane but no CO. The antiapoptotic effect increased with increasing concentration of CO.

This study did not show that CO can treat neuroapoptosis, yet CO exposure may be one reason why animal work does not quite match what is happening in humans.  The neuroapoptosis story continues to unfold.