Platelet Endothelial Cell Adhesion Molecule-1 and Oligodendrogenesis: Significance in Alcohol Use Disorders

Abstract

Alcoholism is a chronic relapsing disorder with few therapeutic strategies that address the core pathophysiology. Brain tissue loss and oxidative damage are key components of alcoholism, such that reversal of these phenomena may help break the addictive cycle in alcohol use disorder (AUD). The current review focuses on platelet endothelial cell adhesion molecule 1 (PECAM-1), a key modulator of the cerebral endothelial integrity and neuroinflammation, and a targetable transmembrane protein whose interaction within AUD has not been well explored. The current review will elaborate on the function of PECAM-1 in physiology and pathology and infer its contribution in AUD neuropathology. Recent research reveals that oligodendrocytes, whose primary function is myelination of neurons in the brain, are a key component in new learning and adaptation to environmental challenges. The current review briefly introduces the role of oligodendrocytes in healthy physiology and neuropathology. Importantly, we will highlight the recent evidence of dysregulation of oligodendrocytes in the context of AUD and then discuss their potential interaction with PECAM-1 on the cerebral endothelium.

Keywords: PECAM-1; alcohol; blood–brain barrier; endothelium; myelin; oligodendroglia.

Figure 1

(a–g) Photomicrographs of prefrontal cortex tissue from adult male Wistar rats stained for platelet endothelial cell adhesion molecule 1 (PECAM-1); 1:500 rabbit anti-PECAM-1; cyanine 2 (CY2), rat endothelial cell antigen (RECA); 1:500 mouse anti-RECA; cyanine 3 (CY3) and 4',6-diamidino-2-phenylindole (DAPI); 1:2000). (a–d) Single slice confocal images of PECAM-1 (a), RECA (b) and merge (c); z-scan of the colabeling showing an orthogonal view along the xz and yz axis in (d). The orthogonal view demonstrates equal penetration of both the antibodies PECAM-1 and RECA, and confirms colabeling (MERGE) of PECAM-1 and RECA shown in panel (c). Scale bar in (c) is 20 μm, applies (a–g). (e–g) Epifluorescent images of PECAM-1 (e), RECA (f) and DAPI (g). (h) Confocal image of colabeling of PECAM-1 (CY2) and 28-day-old 5-Bromo-2´-Deoxyuridine (BrdU) cell (1:500 sheep anti-BrdU; CY3) in the prefrontal cortex of the adult male Wistar rat. Scale bar in (c) is 30um in (h). Arrows point to BrdU cells. Panel (h) demonstrates location of BrdU (28-day-old bromodeoxyuridine labeled) cells in close proximity to PECAM-1 cells in the prefrontal cortex of the adult rat brain, and additional phenotypic analysis of BrdU cells shows that they develop into premyelinating oligodendrocytes [26]. The later part of the review discusses the relationship between oligodendrocytes and PECAM-1 and their potential role in alcohol use disorder (AUD).

Figure 2

Schematic of an endothelial cell in the periphery with expression of PECAM-1 and alterations in signaling and expression of proteins by alcohol (EtOH) experience. Blue arrows indicate direct actions of EtOH in the cell, red arrows indicate secondary actions of EtOH in the cell. Hypothetical involvement of PECAM-1 in alcohol-induced inflammatory signals is indicated in brackets in the endothelial cell.

Figure 3

Schematic of blood vessel in the brain and hypothetical mechanisms of alcohol (EtOH) in the brain that are associated with alcohol-induced enhanced expression of PECAM-1. Attention is paid to include increases in expression of nuclear factor kappa b (NF-kB), activation of microglia and transendothelial migration of leukocytes as inflammatory responses post alcohol experience. Open headed arrows indicate the cell type; closed headed arrows indicate a mechanism followed by direction of effect; red thick arrows indicate increases in protein expression or effect on the signaling mechanism. OPCs, oligodendrocyte progenitor cells; OLGs, oligodendrocytes; HMGB-1, high mobility group box 1.