Abstract
BackgroundTraumatic spinal cord injury (SCI)-induced overproduction of endogenous deleterious substances triggers secondary cell death to spread damage beyond the initial injury site. Substantial experimental evidence supports reactive species (RS) as important mediators of secondary cell death after SCI. This study established quantitative temporal and spatial profiles of cell loss, characterized apoptosis, and evaluated the effectiveness of a broad spectrum RS scavenger - Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) and a combination of MnTBAP plus nitro-L-arginine to prevent cell loss and neurological dysfunction following contusion SCI to the rat spinal cord.ResultsBy counting the number of surviving cells in spinal cord sections removed at 1, 6, 12, 24, 48, 72 h and 1 week post-SCI and at 0 – 4 mm from the epicenter, the temporal and spatial profiles of motoneuron and glia loss were established. Motoneurons continued to disappear over a week and the losses decreased with increasing distance from the epicenter. Significant glia loss peaked at 24 to 48 h post-SCI, but only at sections 0–1.5 mm from the epicenter. Apoptosis of neurons, motoneurons and astrocytes was characterized morphologically by double immuno-staining with cell-specific markers and apoptosis indicators and confirmed by transmission electron microscopy. DNA laddering, ELISA quantitation and caspase-3 activation in the spinal cord tissue indicated more intense DNA fragments and greater caspase-3 activation in the epicenter than at 1 and 2 cm away from the epicenter or the sham-operated sections. Intraperitoneal treatment with MnTBAP + nitro-L-arginine significantly reduced motoneuron and cell loss and apoptosis in the gray and white matter compared with the vehicle-treated group. MnTBAP alone significantly reduced the number of apoptotic cells and improved functional recovery as evaluated by three behavioral tests.ConclusionsOur temporal and spatial profiles of cell loss provide data bases for determining the time and location for pharmacological intervention. Our demonstration that apoptosis follows SCI and that MnTBAP alone or MnTBAP + nitro-L-arginine significantly reduces apoptosis correlates SCI-induced apoptosis with RS overproduction. MnTBAP significantly improved functional recovery, which strongly supports the important role of antioxidant therapy in treating SCI and the candidacy of MnTBAP for such treatment.
Highlights
Traumatic spinal cord injury (SCI)-induced overproduction of endogenous deleterious substances triggers secondary cell death to spread damage beyond the initial injury site
Despite the much lower penetration of the blood-spinal cord barrier (BSB) by MnTBAP compared with MP, its higher stability allows a lower dose of MnTBAP to produce a higher concentration in the CSF than does higher doses of MP [42]
The counts were compared between sham controls and the post-SCI groups for all time points at each distance and by distance at each time point using one way repeated measures analysis of variance (RMANOVA) followed by the posthoc Tukey test
Summary
Traumatic spinal cord injury (SCI)-induced overproduction of endogenous deleterious substances triggers secondary cell death to spread damage beyond the initial injury site. The initial mechanical injury directly kills cells and destroys various elements of the tissue, and induces overproduction of endogenous deleterious substances, which trigger secondary damage processes that lead to secondary cell death, thereby spreading damage beyond the initial injury site [1,2]. The concentration of endogenous deleterious substances produced upon the initial trauma reaches a maximum, and gradually declines with distance from the epicenter; in like manner, the type of cell death may depend on the distance from the injury epicenter. It is critical to explore the temporal and spatial profiles of cell death by necrosis and apoptosis for each type of cell to precisely define the time window and the damage area for therapeutic intervention
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