Microparticles Impair Hypotensive Cerebrovasodilation and Cause Hippocampal Neuronal Cell Injury after Traumatic Brain Injury

Abstract

Endothelin-1 (ET-1), tissue plasminogen activator (tPA), and extracellular signal-regulated kinases-mitogen activated protein kinase (ERK-MAPK) are mediators of impaired cerebral hemodynamics after fluid percussion brain injury (FPI) in piglets. Microparticles (MPs) are released into the circulation from a variety of cells during stress, are pro-thrombotic and pro-inflammatory, and may be lysed with polyethylene glycol telomere B (PEG-TB). We hypothesized that MPs released after traumatic brain injury impair hypotensive cerebrovasodilation and that PEG-TB protects the vascular response via MP lysis, and we investigated the relationship between MPs, tPA, ET-1, and ERK-MAPK in that process. FPI was induced in piglets equipped with a closed cranial window. Animals received PEG-TB or saline (vehicle) 30-minutes post-injury. Serum and cerebrospinal fluid (CSF) were sampled and pial arteries were measured pre- and post-injury. MPs were quantified by flow cytometry. CSF samples were analyzed with enzyme-linked immunosorbent assay. MP levels, vasodilatory responses, and CSF signaling assays were similar in all animals prior to injury and treatment. After injury, MP levels were elevated in the serum of vehicle but not in PEG-TB-treated animals. Pial artery dilation in response to hypotension was impaired after injury but protected in PEG-TB-treated animals. After injury, CSF levels of tPA, ET-1, and ERK-MAPK were all elevated, but not in PEG-TB-treated animals. PEG-TB-treated animals also showed reduction in neuronal injury in CA1 and CA3 hippocampus, compared with control animals. These results show that serum MP levels are elevated after FPI and lead to impaired hypotensive cerebrovasodilation via over-expression of tPA, ET-1, and ERK-MAPK. Treatment with PEG-TB after injury reduces MP levels and protects hypotensive cerebrovasodilation and limits hippocampal neuronal cell injury.

Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury

“…We determined that enriched MP derived from microglia could propagate neuroinflammation in vivo. We selectively depleted enriched MP by incubating them with PEG-TB, a drug that emulsifies MP without modifying circulating leukocyte activation [ 2 , 25 ]. When we co-cultured depleted MP from LPS-stimulated BV2 microglia with recipient naïve BV2 microglia, or injected depleted MP into the cortex of uninjured mice, pro-inflammatory responses were significantly attenuated.…”

“…They are composed of the plasma membrane along with a limited amount of cytoplasm and measure 100 to 1000 nm in diameter [2]. MP are enriched in the lipid microdomains, where cholesterol, phospholipids, and receptors are clustered [3], and are distinguished from other extracellular vesicles such as exosomes (30–100 nm; endosomal origin) and apoptotic bodies (1000–2000 nm) [1].…”

“…Microparticles (MP; also called microvesicles), a type of extracellular vesicle, are small membrane-bound bodies shed from the plasma membrane and released by cells during activation or cell death [ 1 ]. They are composed of the plasma membrane along with a limited amount of cytoplasm and measure 100 to 1000 nm in diameter [ 2 ]. MP are enriched in the lipid microdomains, where cholesterol, phospholipids, and receptors are clustered [ 3 ], and are distinguished from other extracellular vesicles such as exosomes (30–100 nm; endosomal origin) and apoptotic bodies (1000–2000 nm) [ 1 ].…”

Extracellular Vesicles as Diagnostics and Therapeutics for Structural Epilepsies

“…Bohman et al measured the EV number in the serum of fluid-percussion injury (FPI)-induced piglets [69]. They found that EV numbers increased at 1 h after injury compared to baseline.…”

Neutral Sphingomyelinase Inhibition Alleviates LPS-Induced Microglia Activation and Neuroinflammation after Experimental Traumatic Brain Injury

“…Experimental neuroprotection strategies for TBI have included modulation of upstream activation mechanisms using NADPH-oxidase (NOX2) inhibitors or mGluR5 agonists (Loane et al, 2013;Kumar et al, 2016a,b), as well as strategies serving to inhibit the release of specific inflammatory factors such as pro-inflammatory cytokines (Kumar et al, 2016b). We recently showed in a murine experimental TBI model that neutralization of EVs using a novel surfactant polyethylene glycol telomere B can serve to reduce the release of pro-inflammatory factors ; this treatment was also found to be neuroprotective in a porcine model of TBI (Bohman et al, 2016).…”