Minocycline Reduces Cell Death and Improves Functional Recovery after Traumatic Spinal Cord Injury in the Rat

Abstract

We examined the effects of minocycline, an anti-inflammatory drug, on functional recovery following spinal cord injury (SCI). Rats received a mild, weight-drop contusion injury to the spinal cord and were treated with the vehicle or minocycline at a dose of 90 mg/kg immediately after SCI and then twice at a dose of 45 mg/kg every 12 h. Injecting minocycline after SCI improved hind limb motor function as determined by the Basso-Beattie-Bresnahan (BBB) locomotor open field behavioral rating test. Twenty four to 38 days after SCI, BBB scores were significantly higher in minocycline-treated rats as compared with those in vehicle-treated rats. Morphological analysis showed that lesion size increased progressively in both vehicle-treated and minocycline-treated spinal cords. However, in response to treatment with minocycline, the lesion size was significantly reduced at 21-38 days after SCI when compared to the vehicle control. Minocycline treatment significantly reduced the number of terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL)-positive cells 24 h after SCI as compared to that of the vehicle control. DNA gel electrophoresis also revealed a marked decrease in DNA laddering in response to treatment with minocycline. In addition, minocycline treatment significantly reduced the specific caspase-3 activity after SCI as compared to that of vehicle control. Furthermore, RT-PCR analyses revealed that minocycline treatment increased expression of interleukin-10 mRNA but decreased tumor necrosis factor-alpha expression. These data suggest that, after SCI, minocycline treatment modulated expression of cytokines, attenuated cell death and the size of lesions, and improved functional recovery in the injured rat. This approach may provide a therapeutic intervention enabling us to reduce cell death and improve functional recovery after SCI.

Umbilical Cord Blood Stem Cell Mediated Downregulation of Fas Improves Functional Recovery of Rats after Spinal Cord Injury

“…Moderate spinal cord injury was induced using the weight drop device (NYU Impactor) as reported previously (8,15). Rats were assigned to different groups as described in Table 1.…”

“…Studies of apoptosis in white matter after dorsal cordotomy or after transection suggest that glial apoptosis occurs, at least in part, as a consequence of axonal degeneration (10,11). Several studies have implicated the apoptotic role of caspases in the injured spinal cord (12)(13)(14)(15)(16)(17)(18)(19)(20)(21). An increase in the number of cells expressing Fas was observed within 72 hours of SCI (22).…”

Mesenchymal Stem Cells from Rat Bone Marrow Downregulate Caspase-3-mediated Apoptotic Pathway After Spinal Cord Injury in Rats

“…Apoptosis in white matter after dorsal cordotomy or after transection suggest that glial apoptosis occurs, at least in part, as a consequence of axonal degeneration (10,11). Several studies have implicated the apoptotic role of caspases in the injured spinal cord (12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Fas expression, activation of caspases 3 and 8, and apoptosis occur in a temporally similar fashion after SCI (22).…”

Hyperphosphorylated neurofilament NF-H as a biomarker of the efficacy of minocycline therapy for spinal cord injury

“…From the following day, either control saline or 45 mg kg À1 body weight minocycline was administered twice a day up to 3 days post injury (dpi). 12,14 To evaluate the motor recovery, animals were observed by one individual masked to the treatments on 1, 3, 7, 14, 21 and 28 dpi. Lower limb functions were assessed by the Basso, Beattie and Bresnahan scale.…”

“…3,[12][13][14] As minocycline is known to prevent secondary damage in neural tissue by inhibiting microglial activation, 3,12 we assumed that the administration of this drug may also reduce biomarkers of tissue damage.…”