Progesterone to improve neurocognitive outcomes following cranial irradiation.

Abstract

128 Background: Neurocognitive functional decline is a common sequalae of cranial irradiation (CI) that significantly impacts quality of life. Preclinical studies and randomized clinical trials show that following traumatic brain injury and cerebrovascular accidents, premenopausal women demonstrate decreased mortality and improved neurocognitive function, with these benefits presumed to be derived from progesterone. We hypothesized that progesterone may serve similar role in neuroprotection following cranial irradiation. Methods: Adult non-tumor bearing wild type C57BL/6 male mice were treated with two separate fractionated radiation therapy regimen (9 Gy and 15 Gy) to the brain. Cohorts of these mice were administered progesterone (16mg/kg daily) as a pretreatment for 3 days and concurrent with the radiotherapy for a total of 14 days with tapering during the last two days. The animals were then tested using different behavioral measures for cognitive function including morris water maze (MWM) for assessing spatial and related forms of learning and memory, elevated plus maze (EPM), , and spontaneous locomotor activity (SLA) tests. Mice were tested for cognitive function on day 10 and after 30 days of treatment for short and long-term effects of (CI) on memory function. Results: All irradiated mice showed statistically significant decline in MWM, EPM, and SLA measures. There were no significant differences in the 9 Gy versus 15 Gy cohorts. Progesterone administration produced a statistically significant group effect (F (4, 25) = 8.553; P<0.001) in the improvement of long-term memory function over 5 days of learning process. Progesterone administration also demonstrated a significant group effect (F (4, 25) = 8.613; P<0.001) in the probe trial, and a significant beneficial effect (F (4, 25)= 7.993; P<0.001) in short-term memory functional latency to reach the platform. Conclusions: The preclinical data show that progesterone improves radiation-induced deficits in short-and long-term memory functions in adult mice. Further work is required to show if progesterone may show similar clinical benefit in neuroprotection for adults undergoing prophylactic CI or definitive CI for brain metastases or benign intracranial processes such as AVM.