Neuroprotective Efficacy of Regionally Targeted IGF-1 Overexpression for Traumatic Brain Injury

Insulin-like growth factor-1 (IGF-1) promotes neuronal survival, neuron and oligodendrocyte differentiation and neurogenesis, and helps to maintain myelin. IGF-1 is upregulated in response to some forms of eNS injury. While IGF-1 mRNA levels have been shown to increase after experimental traumatic brain injury (T81) (61), no information is available regarding protein levels of this important growth factor in the posttraumatic brain. We propose to quantify regionallGF-1 and IGF-1 receptor (IGF-1 R) levels at multiple time points within the first days after contusion brain injury in mice, and identify the cell types that show altered IGF-1/1GF-1 R. Our preliminary data suggest that IGF-1 is acutely and very transiently upregulated. 8y confirming and expanding these data, we will provide novel information about the onset, duration and location of trauma-induced changes in endogenous IGF-1. IGF-1 has been shown to be neuroprotective in animal models of spinal cord injury and stroke; however, no published studies have examined IGF-1's neuroprotective potential in T81. We hypothesize that enhancing IGF-1 levels in regions of the brain at risk for cell damage or death will promote neuronal survival and improve neurobehavioral outcome. We propose to test this hypothesis by using a transgenic mouse which conditionally overexpresses human IGF-1 specifically in astrocytes. This novel approach allows us to (a) eliminate confounds associated with developmental overexpression in standard transgenics, (b) avoid systemic effects of IGF-1 administration, and (c) specifically target the injured areas where astrocytosis predominates. We will quantify levels of IGF-1 and IGF-1 R in control and brain-injured overexpressing mice and then test the ability of IGF-1 overexpression to reduce cortical tissue damage, neuronal degeneration, and cytoskeletal and myelin degradation and to ameliorate cognitive and motor dysfunction induced by contusion brain injury. We present strong preliminary data that support our hypothesis that IGF-1 reduces posttraumatic cell death and improves neurobehavioral outcome following T81. In light of current phase /I clinical trials in T81 supporting the safety of IGF-1 administration in severely head injured patients (26), we believe that preclinical studies in this area could have immediate and important translational potential.