Acute administration of catalase targeted to ICAM-1 attenuates neuropathology in experimental traumatic brain injury

Abstract

Traumatic brain injury (TBI) contributes to one third of injury related deaths in the US. Treatment strategies for TBI are supportive, and the pathophysiology is not fully understood. Secondary mechanisms of injury in TBI, such as oxidative stress and inflammation, are points at which intervention may reduce neuropathology. Evidence suggests that reactive oxygen species (ROS) propagate blood-brain barrier (BBB) hyperpermeability and inflammation following TBI. We hypothesized that targeted detoxification of ROS may improve the pathological outcomes of TBI. Following TBI, endothelial activation results in a time dependent increase in vascular expression of ICAM-1. We conjugated catalase to anti-ICAM-1 antibodies and administered the conjugate to 8 wk old C57BL/6J mice 30 min after moderate controlled cortical impact injury. Results indicate that catalase targeted to ICAM-1 reduces markers of oxidative stress, preserves BBB permeability, and attenuates neuropathological indices more effectively than non-targeted catalase and anti-ICAM-1 antibody alone. Furthermore, the study of microglia by two-photon microscopy revealed that anti-ICAM-1/catalase prevents the transition of microglia to an activated phenotype. These findings demonstrate the use of a targeted antioxidant enzyme to interfere with oxidative stress mechanisms in TBI and provide a proof-of-concept approach to improve acute TBI management that may also be applicable to other neuroinflammatory conditions.

Combining vascular targeting and the local first pass provides 100-fold higher uptake of ICAM-1-targeted vs untargeted nanocarriers in the inflamed brain

“…Given this increasing prevalence of endovascular intervention, IA administration of drug carriers has a potential role in the treatment of a variety of CNS disorders 8,26 . Acute and chronic central nervous diseases, including stroke 27 , meningitis 19 , traumatic brain injury 28 , Alzheimer's diseases 15 and multiple sclerosis 29 are all accompanied by neurovascular inflammation. Inflammatory mediators and abnormal hemodynamics induce or augment surface exposure of endothelial cellular adhesion molecules such as ICAM-1, VCAM-1, ALCAM, P-selectin, and Eselectin, among others 30 .…”

Stimulation of dopamine D2 receptor via quinpirole protects against brain damage after brain injury in mice

“…The BBB breakdown restoration via quinpirole might be due to reduction of neuroinflammation and active gliosis in the brain. The previous study also observed that brain injury is critically associated with deregulated tight junction proteins [54]. Due to mark tissue disruption after brain injury [41], the Nissl stained cortical section of the injured brains indicated that there was a significant increase in lesion volume while quinpirole treatment significantly restored the lesion volume suggesting that quinpirole is important to repair the brain after injury and restore the tight junction proteins to inhibit cytokines infiltration and other blood-born biochemical agents.…”

Andrographolide Alleviates Acute Brain Injury in a Rat Model of Traumatic Brain Injury: Possible Involvement of Inflammatory Signaling

“…It is well known that edema formation, increased oxidative stress, calcium influx, excitotoxicity, inflammation and cell death or apoptosis contribute to the process of secondary injury ( Werner and Engelhard, 2007 ; Lutton et al, 2017 ). Brain edema exacerbation is a major and severe pathophysiological change induced by TBI ( Lutton et al, 2017 ). In our study, we found that Andro reduced TBI-induced brain edema, moreover, Andro decreased the expression of albumin after injury, indicating that Andro rehabilitate the BBB integrity.…”

“…Secondary brain injury is a complicated cellular processes and biochemical cascades which occur in minutes and last for days following the traumatic events, resulting in exacerbated damage, progressive neurodegeneration and cell death ( Kabadi and Faden, 2014 ). The mechanism of TBI-induced secondary injury includes glutamate excitotoxicity ( Hyder et al, 2007 ), oxidative stress ( Zhang et al, 2018 ), blood-brain barrier (BBB) disruption ( Lutton et al, 2017 ), neuroinflammation and mitochondrial dysfunction ( Lozano et al, 2015 ). It is well known that neuroinflammation occurs in both primary and secondary injury following TBI, as well as in other neurodegenerative diseases ( Eikelenboom et al, 2010 ; Perry et al, 2010 ).…”