BIOMARKER OF NEUROPROTECTANT EFFICACY

The objective of this Phase I feasibility study is to develop a sensitive biomarker for quantifying neuroprotectant drug efficacy in a rat model of traumatic brain injury (TBI). Currently, no widely
accepted biochemical marker that quantifies neuronal injury in rat TBI models
is available. We have previously shown that during axonal degeneration in
humans, the brain cytoskeletal protein MAP-tau is cleaved. Our laboratory has
developed a sensitive ELISA that specifically measures cleaved MAP-tau (C-tau)
in human CSF following head injury. Using this ELISA, we have shown that brain
C-tau levels increase in rats after sustaining cortical impact-induced TBI. By
measuring lesion volumes, Scheff et al have previously demonstrated that
cyclosporin A administration following TBI significantly ameliorates cortical
damage in the cortical impact rat model. We hypothesize that C-tau is a
reliable biomarker of TBI-induced neuronal injury in rats. We will test this
hypothesis by determining if C-tau levels demonstrate a time-dependent increase
after TBI and if a known neuroprotectant intervention, cyclosporin A, exerts
expected effects on C-tau levels. Our Specific Aims are:
Specific Aim 1: Determine whether TBI results in a time-dependent increase in
brain levels of C-tau. C-tau levels will be quantified by ELISA in TBI-affected
and control brain regions and also in sham operated animals. Specific Aim 2:
Determine if C-tau levels reliably quantify the effect of a known
neuroprotectant intervention on TBI. The neuroprotective effect of cyclosporin
A will be examined by administering either vehicle or cyclosporin A. C-tau
levels will be quantified by ELISA at the time of maximum TBI-induced C-tau
elevation determined in Specific Aim 1. C-tau levels will be compared as a
function of neuroprotectant treatment.