Unique Features of the Developing Brain
Many of the pathologic cascades that are activated following TBI are developmentally regulated. Some developmental features could confer improved benefits compared to the adult brain, while other developmental features could limit progesterone's effectiveness after pediatric TBI. For example, progesterone influences neurotransmission by inhibiting NMDA receptors and potentiating GABAA receptors. The balance of excitatory and inhibitory neurotransmission is different in the young brain. There is a heightened sensitivity of the very young brain to excitotoxicity after hypoxic-ischemic injury,[61,62] and regional expression of glutamate receptors (NMDA, AMPA, and kainate) changes throughout brain development.[63,64] Furthermore, the GABAA receptor, which is responsible for inhibitory neurotransmission in the adult brain, can be excitatory in early development.[65,66] Taken together, these developmental differences in glutamate receptors could results in increased sensitivity of the young brain to excitotoxicity after injury, making progesterone treatment even more effective than in the adult brain. However, in the very young brain, the excitatory nature of the GABAA receptor could make progesterone treatment result in neurotoxicity.
A second important consideration is that the baseline and postinjury antioxidant capacity of the immature brain is significantly reduced compared with a mature brain (reviewed in[67,68]). For example, the activity of key antioxidant enzymes, such as Cu, Zn superoxide dismutase, manganese superoxide dismutase, and glutathione peroxidase, is 20–40% lower in the young brain compared with the adult brain. An in-depth discussion of these developmental vulnerabilities and their influence after TBI in the immature brain is found in a review by Bayir et al. Overall, this would suggest that the antioxidant capacity of progesterone would be especially beneficial in pediatric TBI.
Posttraumatic inflammation is a significant contributor to neuropathology after TBI. Progesterone has anti-inflammatory effects by suppressing microglial activation and generation of proinflammatory cytokines. In early development, microglia are predominantly present in the white-matter tracts and play a crucial role in remodeling and restructuring, moving to the cortex by about 2 years of age in humans. Microglial activation after brain injury could damage surrounding oligodendrocytes, worsening the normal myelination process occurring during brain development.[71,72] Progesterone's ability to limit inflammation could therefore have age- and brain region-specific neuroprotection.
A fourth key aspect of the immature brain is the dominant role that apoptotic cell death cascades play after injury. With normal programmed cell death that occurs in the postnatal period, proapoptotic proteins are expressed at higher levels in the immature brain. This could increase vulnerability to molecular cell death cascades after developmental brain injury. Accordingly, progesterone's ability to increase antiapoptotic Bcl-2 protein levels while decreasing proapoptotic protein levels could be beneficial. There are many other aspects of developmental neurobiology that could influence efficacy of progesterone in the young brain, such as protection against mitochondrial dysfunction and improvement in neurogenesis. In summary, studies evaluating the neuroprotective features of progesterone must take into account the age-specific mechanisms of secondary injury and recovery after pediatric TBI.
Pediatr Crit Care Med. 2015;16(3):236-244. © 2015 Lippincott Williams & Wilkins