Table 7.

Progesterone

Paper	Animal model and injury model	Intervention and timing	Experimental groups	Reported outcomes: • Histologic/biochemical/physiological • Behavioral
Gonzalez, Cell Mol Neurobiol2009	Model: Male SD Rats, 250–300 g Injury: T10 Complete Transection	Progesterone (PROG) SC • 4 mg/kg in vegetable oil @ 1, 24, 48 and 72 h PI Vehicle (oil) SC • @ 1, 24, 48 and 72 h PI * 1h doses given IP	SCI + • Progesterone • Vehicle Sham + • Progesterone • Vehicle n = 5/group	Histologic/Biochemical/Physiological: Spinal cords at L1 were examined by immunoelectron microscopy at 75 h PI. After SCI nuclear changes include dispersion of the nucleoplasm and eccentric location within the cell. Cytoplasm became chromatolytic. These changes were not present or reduced by PROG treatment. SCI also caused reduced MAP2 staining in dendrites, reflecting cytoskeletal disruption. PROG treatment reduced these changes. Behavioral: Not reported.
Labombarda Glia2009	Model: Male SD Rats, 250–300 g Injury: T10 Complete Transection	Progesterone (PROG) SC • 16 mg/kg/day in vegetable oil started @ 3 h PI, for 3 or 21d Vehicle (oil) SC • @ 3 h PI, for 3 or 21d	SCI + • Progesterone (n = 6) • Vehicle (n = 6) Sham + • Progesterone (n = 5) • Vehicle (n = 5) Animals sacrificed at 3d or 21d PI, 4 sections per animal.	Histologic/Biochemical/Physiological: Short-term PROG treatment significantly increased the number of oligodendrocyte precursor cells (NG2+/Ox42-cells) in the injured spinal cord and induced their differentiation into mature oligodendrocytes by increasing the expression of Olig2 and Nkx2.2. • 21d of threatment increased the number of mature oligodendrocytes and favored remyelination by increasing proteolipid protein expression and Olig1m transcription factor involved in myelin repair. Behavioral: Not reported.
Fee, Brain Res2007	Model: Male or Female SD Rats, 192-300 g Injury: T10 IH Impactor 150 kdynes	Progesterone (PROG) IP • 4 mg/kg in DMSO @ 0.5, 6, 24, 48, 72, 96, and120h PI • 8mg/kg @ 0.5, 24, 48, 72, 96, and 120h PI • 8 mg/kg or 16mg/kg @ 0.5, 6 h, then q24h for 14d Vehicle DMSO IP • @ 0.5, 6, 24, 48, 72, 96, and 120 h PI or @ 0.5h, 6h, then q24 h for 14d	SCI + • Progesterone • DMSO n = 18male, 19female/group for 14d n = 19male/female/group for 5d	Histologic/Biochemical/Physiological: No effects of PROG treatment or gender were found in injury length or sparing of white or grey matter. Behavioral: BBB scores did not differ between groups with respect to PROG treatment or gender.
Labombarda, J Endocrinol2006	Model: Male SD Rats, 250–300g Injury: T10 Complete Transection	Progesterone (PROG) SC • 4 mg/kg in vegetable oil @ 1, 24, 48 and 72h PI * 1 h doses given IP	SCI + • Progesterone (n = 6) • No treatment (n = 11) Sham (n = 5)	Histologic/Biochemical/Physiological: Spinal cords at L1 were examined at 75h PI. Steroid levels were measured by GC/Mass Spec in the spinal cord and plasma. SCI caused increased PROG, 5αhydroprogesterone and 3α5α-tetrahydroprogesterone in the spinal cord without increases in plasma. PROG treatment mirrored these outcomes in plasma and spinal cord. 3β5α-tetrahydroprogesterone levels increased in the spinal cord but were barely detected in plasma. The ratio of reduced metabolites to PROG was 65-times higher in spinal cord than plasma, suggesting that the metabolites originated from local spinal cord biosynthesis. Behavioral: Not reported.
Labombarda, J Neurotrauma2006	Model: Male SD Rats, 250–300 g Injury: T10 Complete Transection	Progesterone (PROG) SC • 4 mg/kg in vegetable oil @ 1, 24, 48 and 72 h PI Vehicle (oil) SC • @ 1, 24, 48 and 72 h PI * 1h doses given IP	SCI + • Progesterone • No treatment Sham + • Progesterone • No treatment n = 4-6/group	Histologic/Biochemical/Physiological: L4 spinal cords examined at 75h PI. SCI decreased immunostaining for myelin basic protein (MBP) in the corticospinal tract and dorsal ascending tract but not in the ventral funiculus. PROG treatment after SCI reversed this response. MBP mRNA in these tracts increased with SCI + PROG but not in other groups. SCI increased the number of NG2 immunoreactive cells (oligodendrocyte precursors) in grey and white matter and PROG + SCI further increased this number. Immunostaining for mature oligos (RIP) revealed no changes after SCI or SCI + PROG. Behavioral: Not reported.
Gonzalez, Neuroscience2004	Model: Male SD Rats, 250–300 g Injury: T10 Complete Transection	Progesterone (PROG) SC or IP (1st dose) • 4 mg/kg SC @ 1, 24, 48 and 72 h PI	SCI + • Progesterone • No treatment Sham + • Progesterone • No treatment n = 4-5/group	Histologic/Biochemical/Physiological: L1 spinal cords examined at 75h PI. SCI produced severe chromatolysis of L1 motoneurons (Nissl staining). PROG reversed this response. SCI decreased BDNF mRNA (in situ hybridization) and protein (immunocytochemistry) expression. PROG reversed this response. In sham operated spinal cords, PROG increased BDNF protein expression without changing mRNA. Behavioral: Not reported.
Labombarda, J Neurochem2003	Model: Male SD Rats, 250–300 g Injury: T10 Complete Transection	Progesterone (PROG) SC • 4 mg/kg in vegetable oil @ 1, 24, 48 and 72 h PI * 1 h doses given IP	SCI + • Progesterone (n = 4) • No treatment (n = 10) Sham (n = 6)	Histologic/Biochemical/Physiological: Spinal cords at L1 were examined at 72h PI. SCI reduced the mRNA expression of the classical intracellular progesterone receptor (PR) but did not change that of 25-Dx, a membrane binding site (RT-PCR). PROG treatment after SCI had no effect on the low levels of PR but increased 25-Dx. Immunostaining of PR showed it inside neurons and glia whereas 25-Dx was on cell membranes of dorsal horn and central canal neurons. Numbers of PR-immunoreactive neurons was unchanged by SCI or SCI + PROG. In contrast, numbers of 25-Dx-immunoreactive neurons decreased after SCI and this number was restored after PROG treatment. Behavioral: Not reported.
Labombarda, J Neurotrauma2002	Model: Male SD Rats, 250–300 g Injury: T10 Complete Transection	Progesterone (PROG) SC • 4 mg/kg in vegetable oil @ 1, 24, 48 and 72h PI Vehicle (oil) SC • @ 1, 24, 48 and 72h PI * 1h doses given IP	SCI + • Progesterone • No treatment Sham + • Progesterone • No treatment n = 6/group	Histologic/Biochemical/Physiological: Spinal cords at L1 were examined at 75h PI. SCI reduced the expression of choline acetyl transferase (ChAT) in L1 segment motorneurons and PROG restore this immunoreactivity. SCI also reduced the expression of mRNA (in situ hybridization) for the α3 and β1 regulatory subunits of neuronal Na-K-Atpase and PROG restored both subunit mRNA to normal levels. Upregulation of GAP-43 in motorneurons of SCI rats was further enhanced by PROG. None of these effects were observed in sham-operated rats. Behavioral: Not reported.
Labombarda, J Steroid Biochem Mol Biol2000	Model: Male SD Rats, 250-300 g Injury: T10 Complete Transection	Progesterone (PROG) SC • 4 mg/kg in vegetable oil @ 1, 24, 48 and 72h PI * 1h dose given IP	SCI + • Progesterone • No treatment Sham + • Progesterone • No treatment n = 4-6/group	Histologic/Biochemical/Physiological: Spinal cords immediately above, immediately below and caudal to the SCI were examined at 75h PI. In SCI rats PROG increased the number of NADPH-diaphorase active (NOS) astrocytes in grey and white matter above and below the injury but not far caudal to it. In contrast, the number of GFAP-expressing astrocytes (activated cells) was increased by PROG in sham-injured but not SCI rats. GFAP was increased significantly in all areas measured by SCI alone. Behavioral: Not reported
Thomas, Spine1999	Model: Male SD Rats, 295-305 g Injury: T8 NYU Impactor 10g × 25 mm	Progesterone (PROG) IP • 4mg/kg in DMSO @ 0.5, 6, 24, 48, 72, 96, and120h PI Vehicle DMSO IP • @ 0.5, 6, 24, 48, 72, 96, and 120h PI	SCI + • Progesterone • Vehicle • No treatment Sham n = 10/group	Histologic/Biochemical/Physiological: At 6w PI, SCI + PROG had significantly more intact white matter (H&E + Luxol, 53%) than SCI only (24%) or SCI + vehicle (31%). Behavioral: BBB: SCI + PROG (15.5 pt) different from SCI only (12) and SCI + vehicle (10.3) only at 6w PI.

SCI: spinal cord injury; d: day, days; h: hour, hours; w: week, weeks; PI: post-injury

T8: thoracic vertebra 8; C5: cervical vertebra 5; IP: intraperitoneal; SC: subcutaneous

BBB: Basso, Beattie and Bresnahan locomotor test; BDNF: brain-derived neurotrophic factor; DMSO: dimethyl sulfoxide; GAP: growth-associated protein; GFAP: glial fibrillary acidic protein; MAP-2: Microtubule-associated protein 2; SD rats: Sprague-Dawley rats.