Perinatal Brain Injury and Inflammation: Lessons from Experimental Murine Models

Abstract

Perinatal brain injury or neonatal encephalopathy (NE) is a state of disturbed neurological function in neonates, caused by a number of different aetiologies. The most prominent cause of NE is hypoxic ischaemic encephalopathy, which can often induce seizures. NE and neonatal seizures are both associated with poor neurological outcomes, resulting in conditions such as cerebral palsy, epilepsy, autism, schizophrenia and intellectual disability. The current treatment strategies for NE and neonatal seizures have suboptimal success in effectively treating neonates. Therapeutic hypothermia is currently used to treat NE and has been shown to reduce morbidity and has neuroprotective effects. However, its success varies between developed and developing countries, most likely as a result of lack of sufficient resources. The first-line pharmacological treatment for NE is phenobarbital, followed by phenytoin, fosphenytoin and lidocaine as second-line treatments. While these drugs are mostly effective at halting seizure activity, they are associated with long-lasting adverse neurological effects on development. Over the last years, inflammation has been recognized as a trigger of NE and seizures, and evidence has indicated that this inflammation plays a role in the long-term neuronal damage experienced by survivors. Researchers are therefore investigating the possible neuroprotective effects that could be achieved by using anti-inflammatory drugs in the treatment of NE. In this review we will highlight the current knowledge of the inflammatory response after perinatal brain injury and what we can learn from animal models.

Keywords: hypoxia; hypoxia–ischemia; inflammation; neonatal encephalopathy; perinatal brain injury.

Figure 1

Intracellular pathways activated by DAMPS and PAMPS. DAMPS and PAMPS will bind to the membrane receptors, e.g., TLR and P2X7. This activation will trigger a series of intracellular events resulting in an increase of inflammation. Note: the red arrows represent experiments which have blocked the actions of the elements they are pointed at.

Figure 2

Summary of the inflammatory processes that occur following neonatal encephalopathy (NE), highlighting the cell types involved from both the CNS and peripheral immune response along with the ramifications of NE that persist long after this inflammatory response abates.