Introduction: Aneurysmal subarachnoid hemorrhage(SAH) represents 5% of all strokes. Growing evidence suggests that progesterone(PRG) can improve behavioral and functional recovery by reducing inflammation and neuronal cell death after SAH-induced acute brain injury with a proven safety profile and predictable pharmacokinetics. In the proposed study, we investigated the effect of PRG treatment on arterial vasospasm and neurobehavioral outcomes in a rodent SAH model.
Methods: Adult wild-type C57BL/6 mice (n=59) were randomized to five groups for neurobehavioral analysis: Group-1 underwent sham surgery and treatment with vehicle (n=10). Group-2 underwent sham surgery with saline injection and vehicle treatment (n=11). Group-3 underwent SAH induction and vehicle treatment (n=13), Group-4 and 5 received SAH and PRG (8 mg/kg; n=13 and 16 mg/kg; n=12 respectively).For histopathological analysis, animals (n=41) were randomized into five groups: Group-1 underwent sham surgery(n=8),Group-2 SAH induction only(n=7),Group-3 SAH and vehicle treatment(n=8), Group-4 and 5 SAH and PRG treatment (8 mg/kg;n=10 and 16 mg/kg;n=8 respectively). SAH was induced with blood injection into cisterna magna. Treatment injections started 1-hour post-injury intraperitoneally, followed by subcutaneous injections at 6h and 24h for animals in the histopathological cohort and for 5 consecutive days animals in the behavioral cohort. Vasospasm was assessed by measuring basilar artery circumference. Behavioral outcomes were evaluated using rotarod latency, open field activity and grip strength tests.
Results: Basilar artery lumen patency was significantly increased in SAH animals treated with PRG when compared to controls (PRG-8mg/kg:512.1±9.4µm, PRG-16mg/kg: 514.0±14.0 µm, Vs. SAH+vehicle 425.5±34.7µm, P<0.05). PRG-8mg/kg improved rotarod performance at day 6 (PRG-8mg/kg:104.2±6.7%,Vs. SAH+vehicle 91.0±4.9%,P>0.05). Locomotor activity was decreased after SAH and improved with PRG at day 9 (PRG-8mg/kg 81.0±5.7%,Vs. SAH+vehicle 72.4±6.8%,P>0.05). PRG significantly improved grip strength at day-9 (PRG-8mg/kg 99.2±8.1%,Vs. SAH+vehicle 78.6±5.5%,P<0.05).
Conclusions: Conclusion: PRG ameliorates cerebral vasospasm and improves neurobehavioral scores in this model, further studies will clarify the translational potential of PRG therapy for clinical use.
Patient Care: Progesterone therapy has a proven safety profile in phase 3 trials of TBI, its mechanism of action targets multiple components of the acute and chronic brain injury that follows aneurysmal SAH, which make it an ideal candidate for human testing
Learning Objectives: By the conclusion of this session, participants should be able to:
1) Describe the anti-inflammatory effects of progesterone in the injured CNS
2) Understand the effects of induced SAH on arterial vasospasm and neurobehavioral tests in rodent models
3) Describe the translational profile of progesterone including its biosafety and pharmacokinetic properties