Table 4.

NSAIDS

Paper	Animal model and injury model	Intervention and timing	Experimental groups	Reported outcomes: • Histologic/biochemical/physiological • Behavioral
Wang J Neurotrauma2009	Model: Female SD Rats, 250-270 g Injury: T7 MASCIS Impactor 10 g × 25 mm	Ibuprofen SC • 70mg/kg/d (osmotic minipump) @ 3d PI, continuously for 28 days Naproxen • 25mg/kg/d (osmotic minipump) @ 3d PI, then daily × 28d	SCI + • Ibuprofen (n = 25) • Naproxen (n = 6) • Saline (n = 22)	Histologic/Biochemical/Physiological: Ibuprofen suppressed twofold RhoA activation induced by injury to the level below than that in the uninjured animals. Behavioral: After 3w of treatment and up to 7w of observation, ibuprofen (but not naproxen) showed a significant improvement in BBB scores (9.4 ± 0.5 vs. 7.7 ± 0.7 for saline vs. 6.8 ± 0.5 for naproxen at 7w). At 7w, 13 of 25 animals in the ibuprofen group had hindlimb weight support vs. 7 of 28 animals in the two other groups.
Fu J Neurosci2007	Model: Female SD Rats, 180-250 g Injury: • T6-T7 Dorsal Over-Hemisection, 1.9 mm deep (CST lesion) • T8/T9 NYU Moderate Contusion	Ibuprofen SC • 60 mg/kg/d (osmotic pump) @ 0 h PI for CST lesion or @ 7d PI, then daily × 28d for contusion Naproxen SC • 50 mg/kg/d (osmotic pump) @ 0 h PI for CST or 7d PI, then daily × 28d for contusion	SCI (CST lesion) + • Ibuprofen (n = 12) • Naproxen (n = 7) • Vehicle (n = 7) SCI (Contusion) + • Ibuprofen (n = 6) • Vehicle (n = 6)	Histologic/Biochemical/Physiological: Ibuprofen (but not naproxen) enhanced corticospinal and serotonergic sprouting caudal to the injury in both injury models. Ibuprofen reduces RhoA activation at the injury site, 5-7 days after SCI. (Supported with in vitro neurite outgrowth and neuronal RhoA expression assays) Behavioral: 42d PI, Ibuprofen (but not naproxen) significantly improved locomotor recovery (BBB, Grid walk, and footprint) in both injury models, even in the contusion model where the drug delivery was delayed for 7 days. BBB scores were ∼15.5 vs. ∼13.5 for Ibuprofen and control respectively.
Harada J Neurotrauma2006	Model: Male Wistar Rats, 300-350 g Injury: T12 Compression 20 g × 20 min	Indomethacin SC • 5, 10, and 20 mg/kg @ 1sh PRIOR to SCI NS-398 oral gavage • 30 mg/kg @ 1 h PRIOR to SCI Iloprost IP infusion • 100 ng/kg/min @ 30 min PRIOR to SCI, continued for 3 h PI.	SCI + • Indomethacin • NS-398 • Iloprost • Vehicle Locomotor: n = 10/group Biochemistry: n = 6/group	Histologic/Biochemical/Physiological: Indomethacin, not NS-398, attenuated increases in prostacyclin thromboxane metabolites. Furthermore, COX inhibition after SCI with indomethacin increased MPO activity and TNF expression in the spinal cord. These outcomes were reversed with iloprost, a prostacyclin analogue (prostacyclin is a product of COX). Behavioral: 56d PI, indomethacin treatment at 5, 10, and 20 mg/kg resulted in decreased performance on inclined plane test and footprint analysis. No effect was seen with NS-398. Lastly, iloprost, a prostacyclin analogue, increased motor recovery.
Pantovic Spinal Cord2005	Model: Adult Rabbits, 2.5-3.5 kg Injury: L2 Weight Drop Contusion 12.5 g × 120 mm/150 g-cm	Indomethacin IV • 0.1, 0.3, 1.0, or 3.0 mg/kg @ 0 h PI	SCI + • Indomethacin • Vehicle Sham n = 6/group	Histologic/Biochemical/Physiological: The measurement of free fatty acids in the cord was used as a measure of overall tissue damage and/or protection. The elevation of free fatty acids after SCI was significantly reduced with indomethacin treatment in a dose dependent manner. Behavioral: Indomethacin had a positive effect on locomotor recovery measured on the Tarlov scale. Significant improvements were observed in a dose dependent manner, with 3.0mg/kg having the greatest effect (2.7 vs. 1.3).
Schwab Glia2004	Model: Male Lewis rats, 250 - 300 g Injury: T8 Dorsal spinal cord Symmetrical four-fifth Overhemisection	Indomethacin IP • 2 mg/kg/day × 3d (no description of start time)	SCI + • Indomethacin (n = 5) • Vehicle (n = 5) • Sham operated (n = 3)	Histologic/Biochemical/Physiological: Indomethacin significantly decreases the number of RhoA+ cells, and these mainly include granulocytes, ED1 + macrophages/microglia, and GFAP + astrocytes. Lastly, GAP-43 + neurites at the injury site are also increased with indomethacin treatment. Behavioral: Not reported.
Sharma Muscle and Nerve2002	Model: Male SD Rats, 350-420 g Injury: T10-T11 Longitudinal incision into the Right Dorsal Horn	Indomethacin IP • 10 mg/kg @ 30 min PRIOR to SCI Ibuprofen IP: • 10 mg/kg @ 30 min PRIOR to SCI	SCI + • Indomethacin (n = 6) • Ibuprofen (n = 7) • Vehicle (n = 6)	Histologic/Biochemical/Physiological: Both indomethacin and ibuprofen significantly reduced edema, BSCB permeability, and changes in spinal cord blood flow 5 h after injury. Both attenuated reductions in somatosensory evoked potentials 5h after SCI Behavioral: Not reported.
Hains J Neurotrauma2001	Model: Male SD Rats, 200-225 g Injury: T13 NYU Weight Drop Contusion 10 g × 12.5 mm	NS-398 IP (selective COX2 inhibitor) • 5 mg/kg @ 15 min PRIOR to injury	SCI + • NS-398 • Vehicle n = 20/group	Histologic/Biochemical/Physiological: From day 14 – 28 post injury, NS-398 promoted significantly greater tissue sparing as compared to the control treatment, and also decreased PGE2 in the caudal spinal cord. Behavioral: From day 14 – 28 post injury, NS-398 promoted significantly higher BBB locomotor score (∼17.4) than control animals (∼14.7). NS-398 treatment also attenuated the development of mechanical allodynia.
Resnick Spine J 2001	Model: Long Evans Rats, 2.5 months old Injury: T9, NYU Impactor 25 g × cm	Celebocid oral gavage (selective COX2 inhibitor) • 3 mg/kg @ 20 min PI, sacrificed at 2, 4, 6, 12, 24, 48, and 72 h (no perfusion) or 4, 24 h (with perfusion)	SCI + • Celebocid Sham operated n = 4/group/timepoint	Histologic/Biochemical/Physiological: 5-mm segment centered at the region of injury was harvested. In saline perfused animals, celebocid resulted in statistically significant reduction in spinal cord PGE2 and TxB2 levels 4 and 24 h post injury Behavioral: Not reported.
Guven Pediatr Neurosurg1999	Model: Female Wistar Rats 160-200 g Injury: T7-T8 Aneurysm Clip 150 g × 1 min	Indomethacin IP • 3 mg/kg @ 0 h PI	SCI + • Indomethacin • Vehicle n = 8/group	Histologic/Biochemical/Physiological: The absorption of thiobarbituric acid reactive substances was measured as an indicator of lipid peroxidation at 1, 15, 30, 60, and 90 min after SCI. Indomethacin significantly increased lipid peroxidation after SCI, suggesting a harmful role for this drug. Behavioral: Not reported.
Resnick J Neurotrauma1998	Model: Male Long Evens Rats, 275-340 g Injury: T8-T9 NYU Impactor 12.5 or 25 g × cm	SC58125 oral gavage (selective COX2 inhibitor) • 3 mg/kg @ 15 min PI	SCI + • SC58125 • Vehicle n = 8/group	Histologic/Biochemical/Physiological: There was an increased expression of COX2 up to at least 48 hours after SCI (Western Blot). Furthermore, this COX2 expression occurs in neurons and blood vessels. Behavioral: BBB locomotor scores were significantly improved by SC58125 treatment only in the 12.5 g-cm injury model.
Guth PNAS1994 & Guth Exp Neurol1994	Model: Female SD rats, 170-200 g Injury: T8 Compression with jewelers forceps 2 sec	Indomethacin (IM) IP • 0.2 mg @ 0 h PI, then q24 h × 21d. Pregnenolone (PREG) Lipopolysaccharide (LPS)	SCI + • IM (n = 6) • IM + LPS (n = 4) • IM + PREG + LPS (n = 6) • PREG (n = 6) • LPS (n = 4) • Vehicle (n = 6)	Histologic/Biochemical/Physiological: Indomethacin alone did not reduce lesion area 21 days post injury. However, the cavity area was reduced when Indomethacin was combined with pregnenolone and lipopolysaccharide Behavioral: A modified Tarlov's motor scale was used to assess animals (day 21 PI). Indomethacin treatment alone did not improve locomotor recovery. However, it did improve locomotor recovery markedly when combined with pregneolone and lipopolysaccharide.
Sharma Acta Neuropath1993	Model: Male SD Rats, 200 – 300 g Injury: T10-T11 2mm Longitudinal incision into the Right Dorsal Horn	Indomethacin IP • 1,5, and 10 mg/kg @ 30 min PRIOR to SCI	SCI + • Indomethacin • Vehicle n = 5/group	Histologic/Biochemical/Physiological: Only pretreatment with 10 mg/kg significantly reduced spinal cord edema. Indomethacin reduced the sponginess of tissue and the number of neurons exhibiting cytological changes, and immuno-staining for MBP was improved. Behavioral: Not reported.
Sharma Neuroscience1993	Model: Adult Wistar Rats Injury: T10-T11 2mm Longitudinal incision into the Right Dorsal Horn	Indomethacin IP • 5 and 10 mg/kg @ 30 min PRIOR to SCI	SCI + • Indomethacin • Vehicle	Histologic/Biochemical/Physiological: Pretreatment with 10 mg/kg indomethacin but not 5mg/kg significantly reduced edema (water content), microvascular permeability (Evens blue extravasation), and attenuates increases in serotonin levels. Behavioral: Not reported.
Winkler Neuroscience1993	Model: Male SD Rats, 350-400 g Injury: T10-T11 2mm Longitudinal incision into the Right Dorsal Horn.	Indomethacin IP • 5 and 10 mg/kg @ 30 min PRIOR to SCI	SCI + • Indomethacin (n = 11) • Vehicle (n = 6)	Histologic/Biochemical/Physiological: Edema formation was significantly decreased by indomethacin treatment. Electrophysiologically, 5h after injury, indomethacin pretreated animals showed significant decreases in trauma-induced changes of spinal cord evoked potentials. Behavioral: Not reported.
Simpson J Spinal Disord1991	Model: SD Rats, 250-350 g Injury: Midthoracic Weight Drop Contusion 50 g × cm	Indomethacin IP • 2 mg/kg @ 0h PI, then q24 h, subcutaneously, ×7d	SCI + • Indomethacin (n = 10) • Vehicle (n = 12)	Histologic/Biochemical/Physiological: Indomethacin treatment resulted in less histopathological changes in the spinal cord 6 weeks after injury (tissue loss). No improvements in somatosensory evoked and corticomotor evoked potentials were observed with the treatment compared to vehicle control. Behavioral: Indomethacin significantly improved locomotor recovery 6 weeks after SCI (inclined plane test). No improvements in sensory recovery.
Fadenl Brain Res1988	Model: SD Rats, 275-325g Injury: T9 Weight Drop 50 g × cm	BW755C IV (dual lipoxygenase/COX inhibitor) • 10 mg/kg @ 15 min PI	SCI + • BW755C • Vehicle n = 15/group for behavior n = 8/group for biochemistry	Histologic/Biochemical/Physiological: BW755C did not lower water (edema) or cation content in the spinal cord after injury. However, this treatment did significantly lower tissue levels of thromboxane B2 after SCI. Behavioral: Groups were analyzed with the incline plane test and for locomotor recovery. BW755C treated animals had significantly better neurological recovery than saline controls on both tests.
Fujita Paraplegia1985	Model: Rats (no details) Injury: T2-T3 Aneurysm Clip	Aspirin IV or IP • 5, 15, or 50 mg/kg @ 30 min PRIOR to injury	SCI + • Aspirin • Saline	Histologic/Biochemical/Physiological: 30 minutes PI, Na +/K +-ATPase activity and the levels of 6-keto-PGF1 and thromboxane B2 in the cord were determined. Aspirin, starting at 5mg/kg, significantly prevented decreases in the activity of Na+/K+-ATPase, and decreased total 6-keto-PGF1 and thromboxane B2 levels in the spinal cord in a dose dependent manner. Behavioral: Motor performance was assessed using the incline plane test. 7 days after injury, aspirin delivered at 50mg/kg enhanced motor recovery.

SCI: spinal cord injury; d: day, days; h: hour, hours; w: week, weeks; PI: post-injury; q24h: interval 24 hours;

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

BBB: Basso, Beattie and Bresnahan locomotor test; COX: - cyclooxygenase; GAP: growth-associated protein; GFAP: glial fibrillary acidic protein; MPO: Myeloperoxidase; PG: prostaglandin; SD rats: Sprague-Dawley rats; TNF: tumor necrosis factor; Tx - thromboxane.