Endothelial Targeted Strategies to Combat Oxidative Stress: Improving Outcomes in Traumatic Brain Injury

Abstract

The endothelium is a thin monolayer of specialized cells that lines the luminal wall of blood vessels and constitutes the critical innermost portion of the physical barrier between the blood and the brain termed the blood-brain barrier (BBB). Aberrant changes in the endothelium occur in many neuropathological states, including those with high morbidity and mortality that lack targeted therapeutic interventions, such as traumatic brain injury (TBI). Utilizing ligands of surface determinants expressed on brain endothelium to target and combat injury mechanisms at damaged endothelium offers a new approach to the study of TBI and new avenues for clinical advancement. Many factors influence the targets that are expressed on endothelium. Therefore, the optimization of binding sites and ideal design features of nanocarriers are controllable factors that permit the engineering of nanotherapeutic agents with applicability that is specific to a known disease state. Following TBI, damaged endothelial cells upregulate cell adhesion molecules, including ICAM-1, and are key sites of reactive oxygen species (ROS) generation, including hydrogen peroxide. Reactive oxygen species along with pro-inflammatory mediators are known to contribute to endothelial damage and loss of BBB integrity. The use of targeted endothelial nanomedicine, with conjugates of the antioxidant enzyme catalase linked to anti-ICAM-1 antibodies, has recently been demonstrated to minimize oxidative stress at the BBB and reduce neuropathological outcomes following TBI. Here, we discuss targeted endothelial nanomedicine and its potential to provide benefits in TBI outcomes and future directions of this approach.

Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions

“…For example, anti-ICAM-1/CAT is an anti-ICAM-1 antibody conjugated to the antioxidant enzyme CAT. In an experimental model of TBI, anti-ICAM-1/CAT treatment reduced oxidative stress at the BBB and attenuated neuropathological outcomes [ 187 ].…”

Longitudinal Molecular Magnetic Resonance Imaging of Endothelial Activation after Severe Traumatic Brain Injury

“…Targeting vascular activation and permeability may show promise in TBI, with experimental data showing protective effects of targeted endothelial nanomedicine (i.e., with conjugates of the antioxidant enzyme catalase linked to anti-ICAM-1 antibodies) [34], or repurposing drugs targeting microvascular endothelial cells, i.e., the potent inhibitor of SUR1 TRPM4 (sulfonylureareceptor1 transient receptor potential melastatin 4) channels, Glibenclamide. The latter has been proven effective in the experimental setting in reducing BBB disfunctiom and vasogenic edema [35], and its effect on contusion expansion in TBI patients is under investigation (NCT03954041).…”

Nicotinamide mononucleotide (NMN) protects bEnd.3 cells against H2O2‐induced damage via NAMPT and the NF‐κB p65 signalling pathway

“…We further examined the effect of NMN on the expression of function-related factors and NF-jB inflammatory pathway factors in bEnd. 3 NAMPT is a secreted cellular enzyme that participates in stress reactions, such as inflammation, under pathological conditions to avoid apoptosis [20]. Transcription of the proinflammatory cytokines IL-1b, TNF-a and ICAM-1 is mainly regulated by the NF-jB pathway.…”

“…In turn, each metabolic disorder (insulin resistance, compensatory hyperinsulinaemia, hyperglycaemia, oxidative stress, excessive free fatty acid release and lipotoxicity) occurring in diabetes mellitus may affect endothelial functions [2]. In the brain, endothelial cells are a specialized monolayer of cells arranged on the wall of the vascular lumen and constitute the most critical portion of the physical barrier between the blood and the brain called the bloodbrain barrier (BBB) [3]. In the central nervous system, the BBB plays an important physiological role in regulating paracellular permeability, ion balance, nutrient transport and cerebral haemodynamics, and the Abbreviations BBB, blood-brain barrier; bEnd.3, mouse brain endothelial cells; CAT, catalase; CCK-8, Cell Counting Kit-8; DMEM, Dulbecco's modified Eagle's medium; eNOS, endothelial nitric oxide synthase; ICAM-1, intercellular adhesion molecule; IL-1, interleukin-1; LDH, lactate dehydrogenase; MMP, matrix metalloproteinase; NAD + , nicotinamide adenine dinucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NF-jB p65, nuclear factor kappa B p65; NMN, nicotinamide mononucleotide; ROS, reactive oxygen species; SOD, superoxide dismutase; TNF, tumour necrosis factor-a; VEGF, vascular endothelial growth factor.…”