Figure 3.

Ex-4 Post-treatment protects against concussive mild TBI (mTBI)-induced cognitive loss, as assessed by novel object recognition at 7 day and 30 day testing post mTBI in two separate groups of mice (a similar protection was provided in a blast-TBI model that closely mimics military personnel trauma). Concussive (30 g weight drop) mTBI induces an impairment in visual memory (red column), as assessed by the novel object recognition paradigm, that was fully ameliorated when Ex-4 was administered (green column) pre-trauma (A (7 days), B (30 days)) and post-trauma (C (7 days), C (30 days)). Mice undergoing cognitive testing initiated on day 7 were euthanized on day 14, and their hippocampus was subjected to gene expression analyses.

The mouse Ex-4 dose was 3.5 pM/kg/min (subcutaneously administered as a steady-state dose), which is 21 ug/kg/day and equivalent to a dose of 1.7 ug/kg/day in a human following normalization of body surface area between mouse and human. This dose compares favorably to once weekly exenatide LAR: 2 mg/week that provides a 60 kg human subject 4.8 ug/kg/day. Significantly impaired behavior compared to sham (uninjured) controls: Fisher's LSD post hoc, *p<0.05, **p<0.01]. Performance of mice was quantitatively assessed 7 and 30 days following mTBI as a preference index, calculated as (time near the new object−time near the old object)/(time near the new object+time near the old object). Values are mean±SEM, [adapted from 161].