Cerebrovascular Hyper‐permeability and Memory Impairment after Cortical Contusion Injury during Hyperhomocysteinemia in Mice

Abstract

Traumatic brain injury (TBI) is the devastating public health problem worldwide. It is accompanied with inflammation, cerebrovascular dysfunction, and memory impairment. The latter is known to be greatly affected by cellular prion protein (PrPC). Elevated blood level of Homocysteine (Hcy), called hyperhomocysteinemia (HHcy) is considered to be an independent inflammatory and high risk factor for many cerebrovascular diseases. HHcy was found in TBI patients. High level of Hcy is associated with increased levels of another inflammatory marker fibrinogen (Fg). In the present study, we tested the hypothesis that HHcy exacerbates TBI‐induced macromolecular protein extravasation resulting in enhanced Fg‐PrPC complex formation leading to reduction in short‐term memory.Cerebrovascular permeability was studied in cystathionine‐β‐synthase heterozygote knockout (CBS+/−) mice, a well‐known model of HHcy. As a control we used wild type (WT, C57BL/6J) mice. Mice were subjected to cortical contusion injury (CCI) or sham operation (sham). Cerebrovascular permeability was assessed by measuring the fluorescence intensity of Alexaflour 647‐labeled bovine serum albumin (647‐BSA) in extravascular space using an intravital fluorescence microscopy. Formation of Fg‐PrPC complex in brain sample cryosections was studied using immunohistochemistry and confocal microscopy. Short‐term memory changes were evaluated by a novel object recognition test (NORT) and Y maze spontaneous alternation and two trial recognition tests.Pial venular permeability to 647‐BSA was greater in all experimental animals with CCI compared to that in respective sham‐operated mice. However, in injured CBS+/− mice the protein leakage was greater (201±6 % of baseline) than that (166±9 % of baseline) in WT animals with CCI. Enhanced Fg‐PrPC complex formation was found in WT animals after CCI compared to that in sham mice. Increased depositions of Fg and PrPC and their complex formations were detected in CBS+/− mice compared to those in control WT group. Short‐term memory deficiency after CCI was noted in both mice groups. However, reduction in short‐term memory (difference in discrimination ratios between sham and CCI groups) defined by NORT was greater (0.4±0.05) in CBS+/− mice compared to that (0.2±0.04) in control WT mice.Thus, our study reveals a novel, additive effect of HHcy in TBI‐induced memory impairment, which can be therapeutically targeted in future.Support or Funding InformationSupported in part by NIH grant NS084823, AHA grant 17SDG33670372, and UofL SOM Basic grant 57139This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.