Progesterone for Neuroprotection in Pediatric Traumatic Brain Injury

Courtney L. Robertson, MD, FCCM; Emin Fidan, MD; Rachel M. Stanley, MD, MHSA; Corina Noje, MD; Hülya Bayir, MD

Disclosures

Pediatr Crit Care Med. 2015;16(3):236-244. 

In This Article

Abstract and Introduction

Abstract

Objective To provide an overview of the preclinical literature on progesterone for neuroprotection after traumatic brain injury and to describe unique features of developmental brain injury that should be considered when evaluating the therapeutic potential for progesterone treatment after pediatric traumatic brain injury.

Data Sources National Library of Medicine PubMed literature review.

Study Selection The mechanisms of neuroprotection by progesterone are reviewed, and the preclinical literature using progesterone treatment in adult animal models of traumatic brain injury is summarized. Unique features of the developing brain that could either enhance or limit the efficacy of neuroprotection by progesterone are discussed, and the limited preclinical literature using progesterone after acute injury to the developing brain is described. Finally, the current status of clinical trials of progesterone for adult traumatic brain injury is reviewed.

Data Extraction and Data Synthesis Progesterone is a pleiotropic agent with beneficial effects on secondary injury cascades that occur after traumatic brain injury, including cerebral edema, neuroinflammation, oxidative stress, and excitotoxicity. More than 40 studies have used progesterone for treatment after traumatic brain injury in adult animal models, with results summarized in tabular form. However, very few studies have evaluated progesterone in pediatric animal models of brain injury. To date, two human phase II trials of progesterone for adult traumatic brain injury have been published, and two multicenter phase III trials are underway.

Conclusions The unique features of the developing brain from that of a mature adult brain make it necessary to independently study progesterone in clinically relevant, immature animal models of traumatic brain injury. Additional preclinical studies could lead to the development of a novel neuroprotective therapy that could reduce the long-term disability in head-injured children and could potentially provide benefit in other forms of pediatric brain injury (global ischemia, stroke, and statue epilepticus).

Introduction

Every year in the United States alone, nearly a half million children sustain traumatic brain injury (TBI), and ~3,000 children per year die of these injuries (Centers for Disease Control and Prevention). Despite recent advances in neurointensive care and reduction in the overall mortality rate,[1] the long-term morbidity of severe TBI in childhood remains high. Survivors of pediatric TBI suffer from many long-term physical, cognitive, psychological, and emotional impairments.[2,3] After TBI, a cascade of secondary insults leads to cell death. The developing brain may be uniquely vulnerable to some of these secondary insults, due to maturational features. The steroid hormone progesterone has been studied extensively in preclinical models of adult TBI. It provides multiple mechanisms of neuroprotection that could be very important after pediatric TBI, such as reducing cerebral edema, as well as anti-inflammatory, antioxidant, antiapoptotic, and antiexcitatory properties. This review will highlight progress to date in using progesterone for neuroprotection after TBI and will discuss unique features of developmental brain injury that should be considered when evaluating the therapeutic potential for progesterone treatment after pediatric TBI.

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