In models of
acute brain injury,
progesterone improves recovery through several mechanisms including modulation of
neuroinflammation. Secondary injury from
neuroinflammation is a potential therapeutic target after
intracerebral hemorrhage (ICH). For potential translation of
progesterone as a clinical acute ICH therapeutic, the present study sought to define efficacy of exogenous
progesterone administration in ICH-relevant experimental paradigms. Young and aged C57BL/6 male, female, and ovariectomized (OVX) mice underwent left intrastriatal
collagenase (0.05-0.075 U) or autologous whole blood (35 μl) injection.
Progesterone at varying doses (4-16 mg/kg) was administered at 2, 5, 24, 48, and 72 h after injury. Rotarod and Morris water maze latencies were measured on days 1-7 and days 28-31 after injury, respectively.
Hematoma volume, brain water content (
cerebral edema), complementary immunohistochemistry, multiplex
cytokine arrays, and inflammatory
proteins were assessed at prespecified time points after injury.
Progesterone (4 mg/kg) administration improved rotarod and water maze latencies (p < 0.01), and decreased
cerebral edema (p < 0.05), microglial proliferation, and neuronal loss (p < 0.01) in young and aged male, young OVX, and aged female mice. Brain concentration of proinflammatory
cytokines and
Toll-like receptor-associated
proteins were also decreased after
progesterone (4 mg/kg) treatment (p < 0.01).
Progesterone-treated young female mice showed no detectable effects. Exogenous
progesterone improved short- and long-term neurobehavioral recovery and modulated
neuroinflammation in male and OVX mice after ICH. Future studies should validate these findings, and address timing and length of administration before translation to clinical trial.