N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (AcSDKP) as a Potential Novel Treatment for Experimental Traumatic Brain Injury

Document Type

Conference Proceeding

Publication Date

6-6-2024

Publication Title

J Neurotrauma

Keywords

acetic acid, broxuridine, chlordane, fibrin, histone deacetylase 4, histone H3, proline, acetylation, angiogenesis, animal experiment, animal model, animal tissue, astrocyte, cell loss, conference abstract, controlled study, drug therapy, experimental traumatic brain injury, hippocampus, histology, immunomodulation, inflammation, lesion volume, macrophage, male, microglia, Morris water maze test, nervous system development, nervous system inflammation, nonhuman, rat, sensorimotor function, spatial learning, subcutaneous drug administration, therapy, traumatic brain injury, Wistar rat

Abstract

Objective: N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) exhibits multiple functions, such as immunomodulation, anti-inflammation, anti-fibrosis, and pro-angiogenesis. This study was aimed to determine efficacy and mechanism of AcSDKP treatment for traumatic brain injury (TBI). Methods: Young (2-3 months) male Wistar rats were subjected to moderate TBI. Subcutaneous infusion of AcSDKP at a dose of 0.8 mg/kg/day or Vehicle (0.01N acetic acid) was initiated 1h after injury and continued for 3 days. Modified neurological severity score (mNSS), foot-fault, Morris water maze tests were performed. Animals were sacrificed 1 day or 35 days after injury and brain sections processed for histological analyses of neuronal loss, neuroinflammation, BBB damage, angiogenesis, neurogenesis and histone deacetylase 4 (HDAC4). One-way ANOVA followed by post hoc Tukey's tests was used to compare the differences in functional and histological outcomes. P value <0.05 was considered significant. Results: Compared to the Vehicle treatment, AcSDKP treatment led to significant (p<0.05): 1) improvements in spatial learning in the Morris water maze test and sensorimotor function in foot-fault and mNSS tests, 2) reductions of lesion volume and hippocampal neuronal cell loss (NeuN), BBB damage (Fibrin deposit), and neuroinflammation (CD68+ microglia/macrophages and GFAP+ astrocytes), 3) enhancement of angiogenesis (BrdU/EBA staining) and neurogenesis (BrdU/NeuN staining), and 4) blockage of neuronal HDAC4 nuclear translocation, which increased histone H3 acetylation in rats after TBI. Conclusions: Our data reveal a novel mechanism that AcSDKPinduced beneficial effects on TBI recovery are associated with its selective inhibition of neuronal HDAC4 nuclear translocation.

Volume

41

Issue

15-16

First Page

A117

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