Pathology >> ALS | Alzheimer's | SCI


secondary spinal cord injury

SCI dynamicsSecondary injury, the complex cascade of cellular events following spinal cord injury (SCI), is a major source of post-insult neuron death.  Experimental work has focused on the details of individual factors or mechanisms that contribute to secondary injury, but little is known about the interactions among factors leading to the overall pathology dynamics that underlie its propagation.  Prior hypotheses suggest the pathology is dominated by interactions, with therapeutic success lying in combinations of neuroprotective treatments. In this study, we provide the first comprehensive, system-level characterization of the entire secondary injury process using a novel relational model methodology that aggregates the findings of ~250 experimental studies. Our quantitative examination of the overall pathology dynamics suggests that while the pathology is initially dominated by “fire-like”, rate-dependent interactions it quickly switches to a “flood-like”, accumulation-dependent process with contributing factors being largely independent. The figure (copyright Mitchell and Lee, 2008, J Neurotrauma) illustrates the regulatory categories that contribute to neuron death as well as the timeframe in which they are most active.

In short, pathology dynamics reveal a system instability in secondary SCI which results in the initial acute period of rapid propagation of neuron death followed by a slower wave of neuron death. Eventually, the system does re-stabilize on its own months to even a year after injury. However, the lesion size has greatly expanded from its initial volume by that point, which translates to patients having even larger losses of function. Critical to better patient outcomes is the ability to stabilize the secondary injury instability at a much earlier timeframe.

Our evaluation of ~20,000 potential single and combinatorial treatments indicates this flood-like pathology results in few highly influential factors at clinically realistic treatment time frames with multi-factor treatments being merely additive rather than synergistic in reducing neuron death. Of the combinations tested, the best were groups of reducing treatments. However, novel therapeutic strategies that target the instability, rather than individually involved factors, my be required to obtain the best results. Our ongoing work will address such strategies.

Mitchell, C.S. and R.H. Lee (2008). Pathology dynamics predict spinal cord injury therapeutic success.  J Neurotrauma 25(12): 1483-97. PMID: 19125684

Click this link to be taken to a free copy of the published paper, available in PubMed Central.