P38 Mitogen Activated Protein Kinase alpha (MAPKα) Inhibition to Promote Neurologic Recovery in Rat Stroke Transient Middle Cerebral Artery Occlusion (t-MCAO) Model (P5.228)

Objective: Evaluate p38 MAPKα antagonism to promote neurologic recovery when administered outside the neuroprotection window in the rat stroke t-MCAO model.Background: BDNF promotes neural plasticity and recovery after stroke (Berretta, 2013); and IL-1β is upregulated after stroke and in vitro inhibits BDNF effects on neuronal/synaptic plasticity via induction of p38 MAPK (Tong, 2012). While p38 antagonists in pre-clinical studies are neuroprotective when administered up to 12 hours after stroke induction, effects of p38 antagonists when administered outside the neuroprotection window are unknown. VX-745 is an investigational clinical stage brain penetrant specific chemical antagonist of p38 MAPKα that in vitro inhibits IL-1β production and signaling (Alam, 2015).Methods: Transient ischemia induced in 3-month old SD rats. Starting at 48 hours after stroke induction, surviving rats treated orally twice daily for 40 days with vehicle, 1.5 mg/kg VX-745 or 4.5 mg/kg VX-745 (n=22/group). Neuro-score obtained at Day 2; weeks 4 and 6, when additionally Stepping, Body Swing and Forelimb Placing Tests performed. Statistical analysis by two-way ANOVA for repeated measures, followed by Bonferroni post-hoc tests.Results: Three rats (two vehicle, one 4.5 VX-745) died within two weeks of treatment initiation and not included in the analysis. Average Neuro-score was not different at Day 2: 14.3, 13.9 and 13.9 in vehicle, 1.5 and 4.5 VX-745; improving to 12.1, 10.0 and 9.1 at Week 4; and to 11.4, 9.4 and 8.5 at Week 6 (pu003c0.001 for each VX-745 group vs. vehicle at each time point). Highly significant (pu003c0.001) effects also seen for both VX-745 groups at Weeks 4 and 6 in the Stepping, Body Swing and Forelimb Placing Tests.Conclusions: Antagonism of p38 MAPKα with VX-745, administered from 48 hours to 6 weeks post-ischemia induction, improved recovery of motor and somatosensory function in rat t-MCAO model.Study Supported by: EIP Pharma Disclosure: Dr. Alam has received personal compensation from EIP Pharma. Mr. Krakovsky has received personal compensation for activities with Pharmaseed Ltd as an employee. Dr. Lamensdorf has received personal compensation for activities with Pharmaseed Ltd as an employee. Dr. Levy has received personal compensation for activities with Pharmaseed Ltd. as an employee.