Evaluating the neurotherapeutic potential of a water-soluble progesterone analog after traumatic brain injury in rats.
The poor aqueous solubility of progesterone (PROG) limits its potential use as a therapeutic agent. We designed and tested EIDD-1723, a novel water-soluble analog of PROG with >100-fold higher solubility than that of native PROG, as candidate for development as a field-ready treatment for traumatic brain injury (TBI). The pharmacokinetic effects of EIDD-1723 on morphological and functional outcomes in rats with bilateral cortical impact injury were evaluated. Following TBI, 10-mg/kg doses of EIDD-1723 or PROG were given intramuscularly (i.m.) at 1, 6 and 24 h post-injury, then daily for the next 6 days, with tapering of the last 2 treatments. Rats were tested pre-injury to establish baseline performance on grip strength and sensory neglect, and then retested at 4, 9 and 21 days post-TBI. Spatial learning was evaluated from days 11-17 post-TBI. At 22 days post-injury, rats were perfused and brains extracted and processed for lesion size. For the edema assay the animals were killed and brains removed at 24 h post-injury. EIDD-1723 significantly reduced cerebral edema and improved recovery from motor, sensory and spatial learning deficits as well as, or better than, native PROG. Pharmacokinetic investigation after a single i.m. injection in rats revealed that EIDD-1723 was rapidly converted to the active metabolite EIDD-036, demonstrating first-order elimination kinetics and ability to cross the blood-brain barrier. Our results suggest that EIDD-1723 represents a substantial advantage over current PROG formulations because it overcomes storage, formulation and delivery limitations of PROG and can thereby reduce the time between injury and treatment.
Department of Emergency Medicine, Brain Research Laboratory, Emory University, Atlanta, GA 30322, USA. Electronic address: bwali@emory.edu.
Bushra
B
Wali
Department of Emergency Medicine, Brain Research Laboratory, Emory University, Atlanta, GA 30322, USA.
Iqbal
I
Sayeed
Emory Institute for Drug Development/Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
David B
DB
Guthrie
Emory Institute for Drug Development/Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
Michael G
MG
Natchus
Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA 30322, USA.
Nefize
N
Turan
Emory Institute for Drug Development/Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
Dennis C
DC
Liotta
Department of Emergency Medicine, Brain Research Laboratory, Emory University, Atlanta, GA 30322, USA.
Donald G
DG
Stein
D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008297:Male; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000627:therapeutic use*; D011374:Progesterone / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014867:Water
D018696:Neuroprotective Agents; D014867:Water; D011374:Progesterone
Edema; Neurosteroid; Progesterone; Progesterone analogs; Traumatic brain injury