Evaluating the neurotherapeutic potential of a water-soluble progesterone analog after traumatic brain injury in rats. (October 2016)

• Record Type: Journal Article
• Authors: Wali, Bushra; Sayeed, Iqbal; Guthrie, David B.; Natchus, Michael G.; Turan, Nefize; Liotta, Dennis C.; Stein, Donald G.
• Is Part Of: Neuropharmacology. Volume 109(2016)
• Page Start: 148
• Page End: 158
• Publication Date: 2016-10
• Subjects: Traumatic brain injury -- Neurosteroid -- Progesterone -- Progesterone analogs -- Edema; ANOVA analysis of variance -- BWC brain water content -- CCI controlled cortical impact -- CNS central nervous system -- ent-PROG enantiomer of progesterone -- GABA gamma-aminobutyric acid -- GCS Glasgow Coma Score -- GFAP glial fibrillary acidic protein -- HBC 2-hydroxypropyl-β-cyclodextrin -- HDL high-density lipoprotein -- i.m. instramuscular -- i.v. intravenous -- JVC jugular vein catheter -- LDL low-density lipoprotein -- MFC medial frontal cortex -- MWM Morris water maze -- nAChR nicotinic acetylcholine receptor -- NMDA N-methyl-d-aspartate -- PBS phosphate buffered saline -- PK Pharmacokinetics -- p.o. per oral -- PR progesterone receptor -- PROG progesterone -- PXR pregnane X receptor -- RT room temperature -- SD Sprague Dawley -- TBI traumatic brain injury; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2016.05.017
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: 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. Highlights: Novel water-soluble analog of progesterone, EIDD-1723, was evaluated for neuroprotection. EIDD-1723 reduced cerebral edema and lesion size and improved functional recovery. It demonstrated first-order elimination kinetics and crossed the blood-brain barrier. EIDD-1723 decreased glial fibrillary acidic protein expression immunoreactivity.