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B-Cell Lymphoma 2 (Bcl-2) and Regulation of Apoptosis after Traumatic Brain Injury: A Clinical Perspective

1
Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
2
Neurotrauma Clinical Trials Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
3
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94110, USA
4
Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital, San Francisco, CA 94110, USA
5
Department of Neurological Surgery, University of California Diego, San Diego, CA 92093, USA
6
Department of Neurological Surgery, Columbia University Medical Center, New York, NY 10032, USA
*
Author to whom correspondence should be addressed.
Medicina 2020, 56(6), 300; https://doi.org/10.3390/medicina56060300
Received: 1 May 2020 / Revised: 5 June 2020 / Accepted: 8 June 2020 / Published: 18 June 2020
(This article belongs to the Special Issue Traumatic Brain Injury: Current Efforts in Research and Clinical Care)
Background and Objectives: The injury burden after head trauma is exacerbated by secondary sequelae, which leads to further neuronal loss. B-cell lymphoma 2 (Bcl-2) is an anti-apoptotic protein and a key modulator of the programmed cell death (PCD) pathways. The current study evaluates the clinical evidence on Bcl-2 and neurological recovery in patients after traumatic brain injury (TBI). Materials and Methods: All studies in English were queried from the National Library of Medicine PubMed database using the following search terms: (B-cell lymphoma 2/Bcl-2/Bcl2) AND (brain injury/head injury/head trauma/traumatic brain injury) AND (human/patient/subject). There were 10 investigations conducted on Bcl-2 and apoptosis in TBI patients, of which 5 analyzed the pericontutional brain tissue obtained from surgical decompression, 4 studied Bcl-2 expression as a biomarker in the cerebrospinal fluid (CSF), and 1 was a prospective randomized trial. Results: Immunohistochemistry (IHC) in 94 adults with severe TBI showed upregulation of Bcl-2 in the pericontusional tissue. Bcl-2 was detected in 36–75% of TBI patients, while it was generally absent in the non-TBI controls, with Bcl-2 expression increased 2.9- to 17-fold in TBI patients. Terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick-end labeling (TUNEL) positivity for cell death was detected in 33–73% of TBI patients. CSF analysis in 113 TBI subjects (90 adults, 23 pediatric patients) showed upregulation of Bcl-2 that peaked on post-injury day 3 and subsequently declined after day 5. Increased Bcl-2 in the peritraumatic tissue, rising CSF Bcl-2 levels, and the variant allele of rs17759659 are associated with improved mortality and better outcomes on the Glasgow Outcome Score (GOS). Conclusions: Bcl-2 is upregulated in the pericontusional brain and CSF in the acute period after TBI. Bcl-2 has a neuroprotective role as a pro-survival protein in experimental models, and increased expression in patients can contribute to improvement in clinical outcomes. Its utility as a biomarker and therapeutic target to block neuronal apoptosis after TBI warrants further evaluation. View Full-Text
Keywords: Bcl-2; Bax; Bcl-xL; apoptosis; programmed cell death; traumatic brain injury Bcl-2; Bax; Bcl-xL; apoptosis; programmed cell death; traumatic brain injury
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Deng, H.; Yue, J.K.; Zusman, B.E.; Nwachuku, E.L.; Abou-Al-Shaar, H.; Upadhyayula, P.S.; Okonkwo, D.O.; Puccio, A.M. B-Cell Lymphoma 2 (Bcl-2) and Regulation of Apoptosis after Traumatic Brain Injury: A Clinical Perspective. Medicina 2020, 56, 300.

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