Molecular Mechanisms Underlying Cell Death in Spinal Networks in Relation to Locomotor Activity After Acute Injury in vitro

Abstract

Understanding the pathophysiological changes triggered by an acute spinal cord injury is a primary goal to prevent and treat chronic disability with a mechanism-based approach. After the primary phase of rapid cell death at the injury site, secondary damage occurs via autodestruction of unscathed tissue through complex cell-death mechanisms that comprise caspase-dependent and caspase-independent pathways. To devise novel neuroprotective strategies to restore locomotion, it is, therefore, necessary to focus on the death mechanisms of neurons and glia within spinal locomotor networks. To this end, the availability of in vitro preparations of the rodent spinal cord capable of expressing locomotor-like oscillatory patterns recorded electrophysiologically from motoneuron pools offers the novel opportunity to correlate locomotor network function with molecular and histological changes long after an acute experimental lesion. Distinct forms of damage to the in vitro spinal cord, namely excitotoxic stimulation or severe metabolic perturbation (with oxidative stress, hypoxia/aglycemia), can be applied with differential outcome in terms of cell types and functional loss. In either case, cell death is a delayed phenomenon developing over several hours. Neurons are more vulnerable to excitotoxicity and more resistant to metabolic perturbation, while the opposite holds true for glia. Neurons mainly die because of hyperactivation of poly(ADP-ribose) polymerase-1 (PARP-1) with subsequent DNA damage and mitochondrial energy collapse. Conversely, glial cells die predominantly by apoptosis. It is likely that early neuroprotection against acute spinal injury may require tailor-made drugs targeted to specific cell-death processes of certain cell types within the locomotor circuitry. Furthermore, comparison of network size and function before and after graded injury provides an estimate of the minimal network membership to express the locomotor program.

A study of methylprednisolone neuroprotection against acute injury to the rat spinal cord in vitro

“…These observations suggest that spinal networks operate in a condition of criticality (Massobrio et al, 2015;Valverde et al, 2015) whereby even modest losses are transduced into major functional deficit. This notion is consistent with the view of minimal network membership necessary to express locomotor patterns (Kuzhandaivel et al, 2011). Once that value is surpassed, no locomotor activity can be observed anymore.…”

“…Excitotoxic damage is distinct from PM-evoked damage because the former primarily affects neurons rather than glia (Kuzhandaivel et al, 2011). In the kainate-lesioned model, MPSS exerted no neuronal protection and modest inhibition of the limited white matter pyknosis.…”

“…Thus, our protocols used a transient application of a pathological medium or of the excitotoxic agent kainate (Kuzhandaivel et al, 2011) followed by a 24-h washout with oxygenated Kreb's that, in the present study, included MPSS (6 or 10 lM that corresponds to the clinical use). Cell protection by MPSS application was mainly expressed as a significant decrease in the number of pyknotic nuclei in the ventrolateral white matter, although a substantial number of dead cells remained.…”

Contemporary Views on the Pathogenesis of Trauma to the Spinal Cord and Peripheral Nerve Trunks

“…PARP-1, as noted above, takes part in the repair of fragmented DNA in physiological conditions. Massive nucleotide chain damage leads to extreme activation of PARP-1, which can kill cells via two pathways: either by dissipating energy due to the consumption of nicotinamide adenine dinucleotide (NAD) and ATP, i.e., necrosis, or via PARP-1-dependent release of apoptosis-inducing factor (AIF), i.e., apoptosis [68].…”

Gene expression profiling ofliver X receptor αandBcl-2-associated X proteinin experimental transection spinal cord-injured rats

“…19 Cellular signals consequential from DNA damage, hypoxia, or other types of cell stress can result in triggering of intrinsic pathway by stimulating Bax in the mitochondrial outer membrane. 20 Most studies on Bax have been focused on the presence and activity of Bax protein and its transport from the cytoplasm to the mitochondrial membrane; however, the level of its gene expression after SCI has been little understood. Therefore, this study was designed to define the temporal and spatial distribution of Bax and LXRα mRNA changes following transection model of SCI in rats.…”