Neuroprotective therapies after perinatal hypoxic-ischemic brain injury

Abstract

Hypoxic-ischemic (HI) brain injury is one of the main causes of disabilities in term-born infants. It is the result of a deprivation of oxygen and glucose in the neural tissue. As one of the most important causes of brain damage in the newborn period, the neonatal HI event is a devastating condition that can lead to long-term neurological deficits or even death. The pattern of this injury occurs in two phases, the first one is a primary energy failure related to the HI event and the second phase is an energy failure that takes place some hours later. Injuries that occur in response to these events are often manifested as severe cognitive and motor disturbances over time. Due to difficulties regarding the early diagnosis and treatment of HI injury, there is an increasing need to find effective therapies as new opportunities for the reduction of brain damage and its long term effects. Some of these therapies are focused on prevention of the production of reactive oxygen species, anti-inflammatory effects, anti-apoptotic interventions and in a later stage, the stimulation of neurotrophic properties in the neonatal brain which could be targeted to promote neuronal and oligodendrocyte regeneration.

Figure 1

Cascade of biochemical mechanism after hypoxic-ischemic (HI) brain injury. A schematic diagram that summarizes the cellular and molecular events triggered after HI injury in the developing brain. Mitochondrial damage, the cytotoxic levels of intracellular calcium and the release of inflammatory mediators cause metabolic failure, oxidative stress and ultimately the cell death.

Figure 2

Neuroprotective therapies and their optimal moment of administration, according to their mechanisms of action. In this sense, pharmacological antioxidant therapies such as melatonin, allopurinol, hypothermia or magnesium sulfate could be useful just after the HI event. After the reperfusion, when the secondary energy failure takes place, other therapeutic options like cannabinoids, erythropoietin or iminobiotin, which have anti-inflammation and anti-apoptotic effects, could be promising therapies.