PMID- 36909831
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230314
IS  - 1179-5735 (Print)
IS  - 1179-5735 (Electronic)
IS  - 1179-5735 (Linking)
VI  - 15
DP  - 2023
TI  - Hippocampal vulnerability to hyperhomocysteinemia worsens pathological outcomes 
      of mild traumatic brain injury in rats.
PG  - 11795735231160025
LID - 10.1177/11795735231160025 [doi]
LID - 11795735231160025
AB  - BACKGROUND: Mild traumatic brain injury (mTBI) generally resolves within weeks. 
      However, 15-30% of patients present persistent pathological and neurobehavioral 
      sequelae that negatively affect their quality of life. Hyperhomocysteinemia 
      (HHCY) is a neurotoxic condition derived from homocysteine accumulation above 
      15 muM. HHCY can occur in diverse stressful situations, including those sustained 
      by U.S. active-duty service members on the battlefield or during routine combat 
      practice. Mild-TBI accounts for more than 80% of all TBI cases, and HHCY exists 
      in 5-7% of the general population. We recently reported that moderate HHCY 
      exacerbates mTBI-induced cortical injury pathophysiology, including increased 
      oxidative stress. Several studies have demonstrated hippocampus vulnerability to 
      oxidative stress and its downstream effects on inflammation and cell death. 
      OBJECTIVE: This study aimed to assess the deleterious impact of HHCY on 
      mTBI-associated hippocampal pathological changes. We tested the hypothesis that 
      moderate HHCY aggravates mTBI-induced hippocampal pathological changes. METHODS: 
      HHCY was induced in adult male Sprague-Dawley rats with a high methionine dose. 
      Rats were then subjected to mTBI by controlled cortical impact under sustained 
      HHCY. Blood plasma was assessed for homocysteine levels and brain tissue for 
      markers of oxidative stress, blood-brain barrier integrity, and cell death. 
      Endothelial cell ultrastructure was assessed by Electron Microscopy and working 
      memory performance using the Y maze test. RESULTS: HHCY increased the hippocampal 
      expression of nitrotyrosine in astroglial cells and decreased tight junction 
      protein occludin levels associated with the enlargement of the endothelial cell 
      nucleus. Furthermore, HHCY altered the expression of apoptosis-regulating 
      proteins alpha-ii spectrin hydrolysis, ERK1/2, and AKT phosphorylation, mirrored by 
      exacerbated mTBI-related hippocampal neuronal loss and working memory deficits. 
      CONCLUSION: Our findings indicate that HHCY is an epigenetic factor that 
      modulates mTBI pathological progression in the hippocampus and represents a 
      putative therapeutic target for mitigating such physiological stressors that 
      increase severity.
CI  - (c) The Author(s) 2023.
FAU - Tchantchou, Flaubert
AU  - Tchantchou F
AUID- ORCID: 0000-0002-9513-5535
AD  - Department of Anesthesiology, University of Maryland School of Medicine, 
      Baltimore, MD, USA. RINGGOLD: 12265
FAU - Hsia, Ru-Ching
AU  - Hsia RC
AD  - Department of Oncology and Diagnostic Services and Center for Innovative 
      Biomedical Resources, University of Maryland School of Dentistry and School of 
      Medicine, Baltimore, MD, USA. RINGGOLD: 466697
FAU - Puche, Adam
AU  - Puche A
AD  - Department of Anatomy and Neurobiology, University of Maryland School of 
      Medicine, Baltimore, MD, USA. RINGGOLD: 12264
FAU - Fiskum, Gary
AU  - Fiskum G
AD  - Department of Anesthesiology, University of Maryland School of Medicine, 
      Baltimore, MD, USA. RINGGOLD: 12264
LA  - eng
PT  - Journal Article
DEP - 20230306
PL  - United States
TA  - J Cent Nerv Syst Dis
JT  - Journal of central nervous system disease
JID - 101595026
PMC - PMC9996738
OTO - NOTNLM
OT  - electron microscopy
OT  - neuronal cell death
OT  - oxidative stress
OT  - rat
OT  - traumatic brain injury
COIS- The author(s) declared no potential conflicts of interest with respect to the 
      research, authorship, and/or publication of this article.
EDAT- 2023/03/14 06:00
MHDA- 2023/03/14 06:01
PMCR- 2023/03/06
CRDT- 2023/03/13 04:04
PHST- 2022/06/22 00:00 [received]
PHST- 2023/02/09 00:00 [accepted]
PHST- 2023/03/13 04:04 [entrez]
PHST- 2023/03/14 06:00 [pubmed]
PHST- 2023/03/14 06:01 [medline]
PHST- 2023/03/06 00:00 [pmc-release]
AID - 10.1177_11795735231160025 [pii]
AID - 10.1177/11795735231160025 [doi]
PST - epublish
SO  - J Cent Nerv Syst Dis. 2023 Mar 6;15:11795735231160025. doi: 
      10.1177/11795735231160025. eCollection 2023.