The Effect of Progesterone Withdrawal on Molecular and Behavioral Indices after Traumatic Brain Injury

Abstract

Systemic injections of the neurosteroid progesterone (P) have been shown to improve cognitive, sensory and motor recovery after traumatic brain injury (TBI). Progesterone withdrawal (PW), however, increases the risk of ischemia, anxiety, seizure, and excitotoxicity. Given these side effects, it is possible that acute PW during recovery from TBI may retard the healing process. In this project, we investigated the effect of acute PW for short and long-term intervals, and optimized post-TBI P treatment through tapered P injections and slow-release implanted capsules. Male Sprague-Dawley rats received either frontal-bilateral cortical contusion injury or sham surgery. P-treated animals displayed increased anxiety in the elevated plus maze at the peak of acute withdrawal compared to tapered P doses or vehicle. Inflammation and apoptosis, as measured by TNF and #61537;, NF and #61547;B, and active caspase-3, among others, were decreased for all P-treated animals; these effects were further reduced with tapered treatment. Three weeks after injury, animals that received tapered P administration displayed fewer sensory deficiencies and increased motor activity. In addition, reducing the effects of acute PW increased the activity of HSP70 and BDNF while decreasing necrotic lesion size and reactive astrocyte staining, indicating increased neuroprotection. Finally, the beneficial effects of P administration after TBI were further enhanced through a steady-state release of P from a subcutaneously implanted silastic capsule. Compared to animals receiving a daily bolus through subcutaneous injections, capsule animals demonstrated decreased anxiety and edema. All P-treated animals, regardless of delivery method, had reduced inflammation and apoptosis compared to vehicle-treated animals. This system also serves as a model of steady-state intravenous P administration used in human clinical trials. In conclusion, all P treatment enhances both short and long term recovery after TBI. Acute PW, however, has a negative effect on both behavior and tissue recovery. At the peak of withdrawal, animals undergoing acute PW exhibit an increase in anxiety, sensory deficits, inflammation and apoptosis, and a decrease in locomotor activity, all of which are further exacerbated by injury. Tapered withdrawal enhances neuroprotection and plasticity, while a steady-steady application of P further decreases edema and the anxiogenic effects of withdrawal.