Figure 1.

Graphical representation of the neurovascular unit and blood-brain barrier following traumatic brain injury with theoretical mechanism of action of anti-ICAM-1/catalase. The blood-brain barrier is comprised of endothelial cells that express tight junction proteins, which restrict the paracellular transfer of solutes and proteins between and blood and brain. The glia limitans, or astrocytic end feet, also contribute to the physical properties of the barrier. This establishes a delicate homeostasis in the brain that is required for normal glial and neuronal functioning. The above figure is a simplified representation of the aspects of the BBB that have been investigated in the context of endothelial targeted antioxidant enzyme therapy for TBI and is not meant to serve as a complete illustration of BBB structure or biology. (A) Following disruption to the neurovascular unit and blood-brain barrier, as occurs in TBI, secondary mechanisms of injury including oxidative stress, endothelial activation, central nervous system, and peripheral inflammation take place that propagate lesion size and increase damage in the brain. The production of reactive oxygen species by endothelial cells is one of the earliest events to occur with endothelial damage and neurotrauma, depicted here are superoxide anion (O${}_2^{-}$), hydrogen peroxide (H₂O₂), and peroxynitrite (ONOO⁻). With endothelial activation, endothelial cells upregulate the surface expression of ICAM-1, and tight junction complex disassembly leads to hyperpermeability of the blood-brain barrier. Continued oxidative stress processes result from cell death and activation of microglia and astrocytes, which produce inflammatory mediators and cytokines to recruit peripheral immune cells to the site of injury. (B) Early intervention of oxidative stress processes with the administration of anti-ICAM-1/catalase acutely following CCI-TBI provided neuroprotective, glial protective, and BBB protective effects after injury. Targeted delivery of catalase, an antioxidant enzyme that converts hydrogen peroxide (H₂O₂) to water and oxygen, to ICAM-1 preserved BBB structure and function, limited glial activation, and offered neuroprotection with increased neuronal detection in the cortical area of TBI. (C) Ribbon structure representation of anti-ICAM-1/catalase conjugate. Antibodies to ICAM-1 are depicted with covalent linkage to tetrameric recombinant catalase. (D) Following acute administration of anti-ICAM-1/catalase to mice after experimental TBI, we hypothesize that anti-ICAM-1/catalase is targeted based on antibody specificity to ICAM-1, which is upregulated on the activated endothelial cells of the BBB. Depicted here in the ribbon structure representation of the anti-ICAM-1/catalase conjugate interacting with dimeric ICAM-1 molecules on the luminal endothelial cell (EC) plasma membrane.