Abstract WP100: Thymosin β4 for the Treatment of Sub-Acute Stroke in Aged Rats

Abstract

Introduction: Thymosin β4 (Tβ4) is a 5K peptide which influences cellular migration by inhibiting organization of the actin-cytoskeleton. Tβ4 has neurorestorative properties and is a potential candidate for the treatment of sub-acute stroke. Previous research demonstrated that Tβ4 improved neurological outcome in a young (3 months) rat model of embolic stroke. Hypothesis: We hypothesized that Tβ4 would improve neurological outcome in an aged rat model of embolic stroke when administered 24 hours after embolic stroke. Methods: Aged Male Wistar rats (Charles River, France 18-21 months) were subjected to embolic middle cerebral artery occlusion (MCAo). Rats were randomized to receive Tβ4 (12 mg/kg, Regenerx Biopharmaceuticals, Inc.) or control 24 hrs after MCAo and then every 3 days for 4 additional doses. The dose of 12 mg/kg was the maximal dose of Tβ4 that showed functional improvement in a young rat model of embolic stroke. Functional tests were performed weekly. The rats were sacrificed 56 days after MCAo and lesion volumes measured. Generalized Estimating Equations were used to compare the treatment effect on functional recovery and t-test for lesion volumes. Results and Conclusions: Twenty-three rats were included in the study: control group (n=12) and Tβ4 group (n=11). After randomization, there were three deaths in both the control and Tβ4 groups. The Tβ4 treatment reduced infarct volume by more than 50% (12.8% ± 9.3%, mean ± SE, p<0.05) compared to the control group (26.0% ± 4.3%). However, Tβ4 did not show improvement in functional outcome compared to control. Lesion volumes in the treated group showed a correlation to functional testing of (R=0.85, p<0.05), whereas no correlation was observed in the control group (R=0.19). Conclusions: The Tβ4 treatment of stroke aged animals significantly reduces infarct volume compared to vehicle treated stroke. Dissociation between infarct volume and functional outcome in the control group suggests, a ceiling effect of these functional tests in aged animals may obscure proper evaluation of functional outcome between the Tβ4 and control groups. Additional studies and more sensitive behavioral tests are needed to examine the dissociation between infarct volume and functional outcomes in aged ischemic rats.