Promising new experimental combination therapy in Hypoxic Ischemic Injury

In a study published in Neonatology on Oct. 13, 2017, researchers from George Washington University, Washington, DC using newborn piglet models exposed to hypoxia-ischemia studied the ffect of standard cooling therapy (therapeutic hypothermia) alone and in combination with a selective Src kinase inhibitor, PP2, that blocks a regulatory enzyme of apoptosis (cell death). PP2 is a substance that has frequently been used in cancer research as a "selective" inhibitor for Src-family kinases.

In hypoxia-ischemia, CaM kinase is over-activated, but hypothermia has been shown to decrease this enzyme's activation. They hypothesized that a Src kinase inhibitor, in addition to hypothermia, would further attenuate the activation of CaM kinase IV and that the result might be less brain damage.

The research team assessed neuropathology, adenosine triphosphate and phosphocreatine concentrations as well as CaM kinase IV activity. The CaM kinase IV activity in cerebral tissue was 2,002 (+/- 729) with normal oxygen levels and in normal temperatures, 4,104 (+/- 542) in hypoxia with hypothermia treatment, and 2,165 (+/- 415) in hypoxia with hypothermia treatment combined with PP2 administration.

The authors conclude that hypothermia alone attenuated the over-activation of CaM kinase IV and improved neuropathology after hypoxia. However, the combination of hypothermia with Src kinase inhibition following hypoxia further attenuated the increased activation of CaM kinase IV, compared with hypothermia alone in the newborn swine brain.

At present therapeutic hypothermia remains the mainstay of treatment for hypoxia-ischemia is .This therapy is proven to reduce neural defects by up to 30 percent, yet many infants still have poor outcomes even after the therapeutic cooling treatment.

If confirmed by further studies, this approach in combination with cooling may help to further attenuate neurological damage following hypoxic ischemic injuries.

The group intends to study the effect of other types of small molecule inhibitors to target the apoptotic cascade. 

Effect of Concurrent Src Kinase Inhibition with Short-Duration Hypothermia on Ca2+/Calmodulin Kinase IV Activity and Neuropathology after Hypoxia-Ischemia in the Newborn Swine Brain

Kratimenos P et al. Neonatology 2018;113:37-43
https://doi.org/10.1159/000480067