Hypoxia-ischemia is a serious complication in which restricted blood flow deprives the brain of oxygen. The lack of oxygen levels results into brain injury and its consequences gradually affects the entire lifespan and sternness ranges from mild to severe. A maternal/placental problem, such as placental abruption or cord prolapse, can cause complications during or before birth. Fetal/newborn issues, such as asphyxia due to labor difficulties, infection, and fetal-maternal bleeding or twin-to-twin transfusion can also cause complications.
Researchers evaluated new born experimental models that were exposed to hypoxia-ischemia in a study. Standard cooling therapy (therapeutic hypothermia) alone and in combination with a selective Src kinase inhibitor, PP2 (blocks a regulatory enzyme of apoptosis) were given to experimental models.
The Food and Drug Administration (FDA) has approved Src kinase inhibitor as an oncology treatment. Blocking this regulatory enzyme in the neurological damage caused by brain hypoxia-ischemia is the first study to test the benefits.
Panagiotis Kratimenos, the study lead author, explained, "In hypoxia-ischemia, CaM kinase is over-activated, but hypothermia has been shown to decrease this enzyme's activation. Researchers theorized 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." He added, "From this study, we were pleased that this seems to be the case."
Neuropathology, adenosine triphosphate and phosphocreatine concentrations as well as CaM kinase IV activity were assessed by the research team. The CaM kinase IV activity in cerebral tissue was 2,002 (plus or minus 729), 4,104 (plus or minus 542), and 2,165 (plus or minus 415) in normal oxygen levels with normal temperatures, in hypoxia with hypothermia treatment and hypoxia with hypothermia treatment combined with PP2 administration respectively.
The researchers concluded that the over-activation of CaM kinase IV was reduced by hypothermia alone and improved neuropathology after hypoxia. However, when compared to the hypothermia alone, hypothermia combination with Src kinase inhibition following hypoxia further attenuated the increased activation of CaM kinase IV, in the newborn experimental brain model.
Therapeutic hypothermia was the only treatment for hypoxia-ischemia. The doctors in the neonatal intensive care unit lower a baby's temperature (about 30 C for three days), starting in the first six hours of life. This therapy proved to reduce neural defects by up to 30 percent, however, even after the therapeutic cooling treatment many infants still showed poor outcomes.
To target the apoptotic cascade, Dr. Kratimenos envisions studying the effect of other types of small molecule inhibitors possibly in multiple doses, eliminating the potential side effects, and determining the best dose and duration of treatment.
Dr. Kratimenos mentioned, "If confirmed by further studies, this approach in combination with cooling may help to further attenuate neurological damage that babies suffer after experiencing hypoxia-ischemia."