There are currently 5.3 million Americans living with a disability as a result of a TBI, at a cost of $48.3 billion annually. The economic and social burden on the patient, their family, and society, is staggering and there is currently no effective treatment for TBI. COG133, a peptide derived from the receptor-binding region of apolipoprotein E (apoE) has both anti-inflammatory and neuroprotective properties in vitro and in vivo. COG133 attenuates central nervous system response to injury by modulating glial activation and the associated release of glutamate, reactive oxygen species, and inflammatory cytokines, as well as exerting direct neuroprotective effects. COG133 is neuroprotective when administered 30 minutes following TBI in mice. Mice treated with COG133 exhibited faster recovery times and performance on behavioral tests recovered to pre-injury levels, compared to saline treated mice who never fully recovered. Preliminary data supports our hypothesis that the therapeutic window of COG133 can be expanded beyond 30 minutes by conjugation to a protein transduction domain (PTD). PTDs are short basic peptides that promote the intracellular delivery of cargo that does not cross the cell membrane. However, transport through the blood brain barrier (BBB) is a more complex process and the number of PTDs tested for BBB transport in vivo has been relatively few. Therefore, the appropriate PTD for COG133 transport needs to be determined empirically. 1. We will use a completely randomized design to assess the effect of the PTD-COG133 conjugates on suppression of nitrite production in murine microglial BV2 cells. 2. We will use a completely randomized design to assess the effect of PTD-COG133 conjugates (3 will be chosen based on the in vitro results) and time elapsed between TBI and treatment on rotorod score and weight. Currently, there are no definitive neuroprotective agents available to treat TBI. COG133 represents a novel therapeutic strategy for the treatment of TBI, thereby fulfilling an unmet medical need for the 1.5 million Americans who sustain a TBI each year. The enhanced delivery of COG133 by conjugation to a PTD may expand the therapeutic window of COG133, as well as expand the range neurological disorders to include those that lack the overt BBB breach seen in TBI. ? ? ?
