SPINE Volume 24, Number 20, pp 2134 –2138 ©1999, Lippincott Williams & Wilkins, Inc. Progesterone is Neuroprotective After Acute Experimental Spinal Cord Trauma in Rats Ajith J. Thomas, MD,* Russ P. Nockels, MD,* Hiu Q. Pan, MD,* Christopher I. Shaffrey, MD,* and Michael Chopp, PhD† Study Design. A standardized rat contusion model was used to test the hypothesis that progesterone signif- icantly improves neurologic recovery after a spinal cord injury that results in incomplete paraplegia. Objectives. To compare the effect of progesterone ver- sus a variety of control agents to determine its effective- ness in promoting neurologic recovery after an incom- plete rat spinal cord injury. Summary of Background Data. Progesterone is a neu- rosteroid, possessing a variety of functions in the central nervous system. Exogenous progesterone has been shown to improve neurologic function after focal cerebral ischemia and facilitates cognitive recovery after cortical contusion in rats. Methods. A standardized contusion model of spinal cord injury using the New York University impactor that resulted in rats with incomplete paraplegia was used. Forty mature male Sprague–Dawley rats were randomly assigned to four groups: laminectomy with sham contu- sion, laminectomy with contusion without pharmacologic treatment, laminectomy with contusion treated with di- methylsulfoxide and dissolved progesterone, and lami- nectomy with contusion treated with dimethylsulfoxide. Functional status was assessed weekly using the Basso– Beattie–Bresnehan (BBB) locomotor rating scale for 6 weeks, after which the animals were killed for histo- logic studies. Results. Rats treated with progesterone had better outcomes (P = 0.0017; P = 0.0172) with a BBB score of 15.5, compared with 10.0 in the dimethylsulfoxide control group and 12.0 in the spinal cord contusion without phar- macologic intervention group. This was corroborated in histologic analysis by relative sparing of white matter tissue at the epicenter of the injury in the progesterone- treated group (P  0.05). Conclusions. Rats treated with progesterone had a better clinical and histologic outcome compared with the various control groups. These results indicate potential therapeutic properties of progesterone in the manage- ment of acute spinal cord injury. [Key words: Basso–Be- attie–Bresnehan score, progesterone, spinal cord contu- sion, spinal cord injury, white matter] Spine 1999;24: 2134 –2138 The optimal management of acute spinal cord injury continues to evolve. Current pharmacologic treatment involves the use of intravenous methylprednisolone within 8 hours of the injury. Results of several random- ized clinical trials indicate that methylprednisolone has a real but limited role in providing clinical improve- ment. 4,5 The preclinical search for better pharmacologic treatments has centered on the inhibition of detrimental posttraumatic pathochemical events, such as generation of free radicals, mediators of the inflammatory response, and local neurotransmitter toxicity. 18,33 Increasing attention has been focused on the actions of progesterone on the central nervous system. Proges- terone receptors are widely distributed in the central ner- vous system, including the hypothalamus, preoptic area, midbrain, cortex, amygdala, hippocampus, caudate, pu- tamen, and cerebellum. 17 Progesterone is considered a neurosteroid because of de novo synthesis and accumu- lation within the nervous system that is independent of steroidogenic gland secretion rates. 24 Classically, the ac- tions of progesterone in nerve cells have been thought to occur through cytosolic–nuclear receptors specific to the steroid. 22 More recently, progesterone has been shown to modify the function of traditional neurotransmitter systems in the central nervous system such as the inhib- itory -aminobutyric acid 15,16 and excitatory amino ac- ids. 30 The presence of receptors and sources of proges- terone within the nervous system as well as its modulation of inhibitory and excitatory amino acids in- dicate a possible broader role for progesterone than sim- ply as a gestational hormone. It has been shown that the administration of progesterone is neuroprotective in a transient focal ischemia model in the rat, either when administered before the onset of ischemia or 2 hours after the onset of ischemia. 12 Progesterone also facilitates cognitive recovery and reduces secondary neuron loss caused by cortical contusion injury in an ani- mal model. 25,28 Methods Mature male Sprague–Dawley rats (weight range, 295–305 g) were used for the study. Male rats were preferred because their endogenous progesterone levels do not fluctuate. Rats were anesthetized with 50 mg/kg intraperitoneal pentobarbital. Ce- fazolin (50 mg/kg) was injected subcutaneously before surgery. The surgical site was shaved and swabbed with alcohol and then with povidone alcohol. Rats were placed on a heated sur- gical table. Rectal temperature was maintained at 37 C throughout the surgical procedure using a feedback-regulated water heating system. A midline skin incision was made to expose the T6 –T10 spinal column. The muscles attached to the spinous process of T6 –T10 were cut and cleared away from the column. The T8 spinous process and the caudal half of the T7 spinous process and lamina were removed with microrongeurs, starting at the caudal edge of the T8 lamina. An opening was From the Departments of *Neurosurgery and †Neurology, Henry Ford Health Sciences Center, Detroit, Michigan. Acknowledgment date: December 2, 1998. Acceptance date: March 24, 1999. Device status category: 1. 2134