Benefits of an Effective Pharmacological Treatment to Improve TBI Outcomes

Despite the enormity of the problem, scientists have yet to identify an effective pharmacological treatment for TBI. Current TBI therapy is supportive, with primary treatment goals being maintenance of blood pressure and oxygenation, and reduction of secondary brain injury through control of increased intracranial pressure.1 No drug or any interventions or treatments, of the many evaluated, have been shown to consistently improve survival or neurological outcome, and to date nearly all rigorously conducted clinical trials in neuroprotection have failed to show any consistent improvement in outcome for TBI patients.2,3,4

The development of a therapeutic agent for the successful treatment of TBI will provide significant benefits to patients and society. Potential benefits include:

  1. Efficacious treatment for TBI patients, where there is currently an unmet medical need
  2. Decreased mortality from brain injury
  3. Reduction of short-term and long-term disability
  4. Reduction of direct and indirect health care costs

Intravenous progesterone may prove to be such an agent.

Introduction

Progesterone – also known as P4 (pregn-4-ene-3,20-dione) – is a 21-carbon steroid hormone known principally for its involvement in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans. Progesterone belongs to the progestin class of hormones, and is the major naturally occurring human progestogen. Its biological fate within the body is well known.

Discovery of progesterone's neuroprotective properties began with the observation of a gender difference in response to experimentally induced traumatic brain injury (TBI). After noting anecdotal reports that female rats recover better than male rats following TBI, researcher Donald Stein and his co-workers conducted studies which showed that the hormone might account for this discrepancy in outcomes.

While progesterone initially may seem like an unusual choice as a neuroprotective therapeutic agent, there is abundant evidence suggesting that, in fact, this is a normal role of this steroid hormone. In addition to its well-known effects on the reproductive system, progesterone is a potent neurosteroid and progesterone receptors are abundant and widely distributed in the central nervous system (CNS). Moreover, unlike other sex steroids, such as estrogen, progesterone is not only synthesized in the gonads and adrenal glands, but also produced by glial cells in the brain and by Schwann cells in the peripheral nervous system. In addition, allopregnanolone, a metabolite of progesterone preferentially produced in the CNS, has been shown to be an active neuroprotectant molecule.6

  1. Park, E. et al., (2008). CMAJ., 178(9), 1163-1170.
  2. Beauchamp, K., Mutlak, H., Smith, W.R., Shohami, E., and Stahel, P.F. (2008). Mol. Med. 14(11-12), 731-740.
  3. Kazanis, I. (2005). Brain Res. Rev., 50, 377-386.
  4. Tolias, C.M., and Bullock, M.R. (2004). NeuroRx., 1(1), 71-79.
  5. Goldfien, A. (1989) The gonadal hormones & inhibitors. In: Katzung BG, ed. Basic and Clinical Pharmacology (pp 493-516). 4 ed. Appleton & Lange: Norwalk.
  6. Stein, D.G. (2008). Brain Res. Rev., 57, 386-397.