Hematoma Volume Alters Efficacy of Progesterone Treatment for Preclinical Intracerebral Hemorrhage

Beilei Lei, Ramona Rodriguiz M, Talagnair Venkatraman, Haichen Wang, Christopher Lascola D, Jay Lusk B, Anna Covington, Daniel Laskowitz T, David Warner S, William Wetsel C, Michael James L

Hematoma volume after intracerebral hemorrhage (ICH) affects recovery in humans but has been inadequately examined in preclinical models. Recovery after preclinical ICH improves with progesterone treatment, but the effects of hematoma volumes are unknown. Thus, mice were subjected to 0.03U or 0.1U intrastriatal collagenase injections followed by concealed vehicle or progesterone treatment and assessed using neurobehavioral tests over 28 days. 24 hours after injury, hematoma volume by MRI increased with collagenase dose; perfusion and diffusion were unaffected. Open field testing did not distinguish ICH condition from sham injury. Both collagenase doses increased foot-fault errors, decreased latencies on rotarod, and perturbed prepulse inhibition relative to sham controls. Notably, mice injured with 0.1U collagenase were deficient in short- and long-term memory on novel object recognition tasks compared to sham and 0.03U collagenase injured animals. Progesterone treatment did not affect these assessments. Morris water maze performance was similar among ICH groups. However, vehicle-treated mice injured with 0.1U collagenase failed to distinguish target quadrants on probe trials. Progesterone treatment resulted in partial recovery for this group to identify the target quadrant. Findings that hematoma volume and progesterone treatment variably affect neurobehavioral tests after intrastriatal collagenase injection in mice could have implications for the translation of progesterone into acute ICH therapeutics.