Progesterone for Traumatic Brain Injury: Neurodegenerative, Focal and Diffuse Pathways

Abstract

Progesterone is a gonadal steroid hormone synthesized in the adult central nervous system. Synthesis in the adrenal glands, gonads, and central nervous system produces neuroactive progesterone since the molecule crosses the blood-brain barrier. It has been shown to be neuroprotective when administered shortly before or shortly following injury, with efficacy up to four hours after injury. The interactions of progesterone with severe traumatic brain injury, particularly its interactions with the blood-brain barrier, corporeal immune system and the secondary injury cascade initiated by the lysis of neurons, neural processes and glia will be examined. One of its major pathways, shared with its metabolite, allopregnanolone (3α-hydroxy-5α-pregnan-20-one), is an agonistic modulation of the GABAA receptor, a common target for social anxiety disorder pharmacology. Recent findings include the role of membrane progesterone receptor alpha in response to injury, which might account for fast-acting effects of the molecule. A discussion regarding the current literature on repeated mild traumatic brain injury and chronic traumatic encephalopathy is included. Refined preclinical studies include treatment with allopregnanolone and combinatorial treatment with Vitamin D, and progesterone for brain injury is currently in phase III clinical trials. Progesterone is effective in reducing lesion size, improving cell counts and rescuing functional deficits following TBI in a variety of preclinical paradigms.