Abstract W MP52: Treatment With N-acetyl-seryl-aspartyl-lysyl-proline Improves Neurological Functional Recovery in Diabetic Middle Aged Rats After Embolic Stroke

Abstract

Background and Purpose: Diabetes mellitus (DM) is a common metabolic disease among middle-aged and older populations, which leads to an increase of stroke incidence and poor stroke recovery. The present study investigated the effect of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) on stroke recovery in middle aged DM rats after embolic stroke. Methods: Male Wistar rats at age of 13 months were subjected to nicotinamide (NTM) and streptozotocin (STZ) injection . Rats with confirmed hyperglycemia status were subjected to embolic middle cerebral artery occlusion (MCAO) 30d after STZ-NTM injection. AcSDKP (2.4mg/kg) or saline were subcutaneously infused for 3d starting at 1d after stroke (n=12/group). Results: AcSDKP treatment significantly improved neurological functional recovery measured by adhesive removal test, foot-fault test, and modified neurological severity score starting at 21d after MCAO compared with saline treated rats. In addition, AcSDKP substantially reduced spatial learning deficits measured by the Morris water maze (41±4 vs 33±3% of time spent in the correct quadrant) 35d after MCAO. AcSDKP treatment significantly reduced vascular and parenchymal fibrin deposition (43±9 vs 92±11/mm 2 ) in the ipsilateral hippocampus and peri-infarct corpus callosum (CC), which was associated with reduction of IL-1 receptor associated kinase-1(IRAK1) immunoreactive vessels (95±13 vs 47±11/mm 2 ) 7d after MCAO (n=4/group). AcSDKP treatment did not reduce infarct volume, but robustly increased myelinated axonal density (14±4 vs 8±3% in hippocampus, 36±6 vs 27±7% in CC) and oligodendrocyte density (71±18 vs 46±16/mm 2 in hippocampus, 526±113 vs 394±107/mm 2 in CC) 35d after MCAO (n=8/group). In vitro, high glucose increased protein level of IRAK1 and NF-κB in primary cerebral endothelial cells, whereas AcSDKP suppressed high glucose-increased IRAK1 and NF-κB protein levels by 50%. Conclusions: AcSDKP promotes ischemic brain repair by reducing neurovascular damage in the hippocampus and white matter, which likely contributes improvement of neurological functional recovery in middle-aged DM rats. IRAK1/NF-κB signals suppressed by AcSDKP may be involved these processes.