Acute neural and proteostasis mRNA levels predict chronic locomotor recovery after contusive spinal cord injury.

One of the difficulties in identifying novel therapeutic strategies to treat CNS trauma is the need for behavioral assays to assess chronic functional recovery. In vitro assays and/or acute behavioral assessments cannot accurately predict long term functional outcome. Using data from 13 independent T9 moderate contusive SCI studies, we asked whether the ratio of acute (24-72 hours post-injury) changes in the levels of neuron-, oligodendrocyte-, astrocyte-specific and/or endoplasmic reticulum stress response (ERSR) mRNAs could predict the extent of chronic functional recovery. Increased levels of neuron, oligodendrocyte, and astrocyte mRNAs all correlated with enhanced BMS scores. Reduced levels of the ERSR mRNAs Atf4 and Chop correlate with improved chronic locomotor function. Neither neural or ERSR mRNAs were predictive for chronic recovery across all behavioral changes. However, the ratio of oligodendrocyte/ERSR mRNAs did predict 'improved', 'no change', or 'worse' functional recovery. Neuronal/ERSR mRNA ratios predicted functional improvement, but could not distinguish between 'worse' or 'no change' outcomes. Astrocyte/ERSR mRNA ratios were not predictive. This approach can be used to confirm biological action of injected drugs in vivo and to optimize dose and therapeutic window. It may prove useful in cervical and lumbar SCI and in other traumatic CNS injuries such as TBI and stroke, where prevention of neuronal loss is paramount to functional recovery. Although, the current analysis was directed towards ERSR whose activity was targeted in all but one study, acute mRNA markers for other pathophysiological cascades may be as predictive of chronic recovery when those cascades are targeted for neuroprotection.