Combination Therapy of Estrogen and Progesterone Attenuates Behavioral Impairments and Autophagy via circLrp1b/miR-27a-3p/Dram2 Pathway After Traumatic Brain Injury.

In the present investigation, the influences of progesterone (P4) and 17β-estradiol (estradiol or E2), alone and in combination, on spatial and non-spatial cognition and anxiety-like behaviors were assessed following traumatic brain injury (TBI). We also evaluated the impacts of these sex hormones on the miR-27a-3p and CircLrp1b gene expression and proteins involved in the autophagy pathway in the hippocampus of rats. Male rats were randomly divided into 12 groups (six groups to measure brain water content and six groups for molecular and behavioral studies): sham, TBI, TBI/vehicle, TBI/P4, TBI/E2, and TBI/P4 + E2 (P4 1.7 mg/kg and E2 33.3 μg/kg via intraperitoneally for 30 min after TBI induction). Diffuse concussion induced by the Marmaro method in all groups of animals except the sham group. E2, P4, and their combination administration could improve behavioral impairments due to TBI. E2, P4, and their combination therapy reduced the Microtubule-associated protein light chain 3 I/II (LC3II/I) ratio, which indicates autophagy impairment following TBI. CircLrp1b expression was significantly reduced in E2, P4, and E2 + P4 groups. The decreased level of circLrp1b was accompanied by an increase in miR-27a-3p and the reduction of Dram2 (damage-regulated autophagy modulator 2). These treatments could improve cognitive impairments and inhibit autophagy following TBI through modulation of the circLrp1b/miR-27a-3p/Dram2 pathway.