How Shockwaves Open Tight Junctions of Blood–Brain Barrier: Comparison of Three Biomechanical Effects

Abstract

Revealing how blast shockwaves open the tight junction of the blood–brain barrier (BBB) is very important for understanding blast-induced traumatic brain injury (bTBI) and shockwave-assisted drug delivery; however, the underlying mechanism remains unresolved. Here, we used multiscale molecular dynamics simulations to reveal the disruption mechanism of claudin-5 protein in a relatively complex BBB model by comparing three typical effects from blast loads. The results showed that the opening of claudin-5 did not result from the direct compressive loading of the single shockwave but from indirect cavitation and stretching effects induced by shockwaves. Importantly, stretch-mediated mechanical opening from the asymmetric distribution of overpressure in temporal and spatial dimensions is a novel damage mode. In detail, the nanojet from the cavitation pushed away two adjacent endothelial cell membranes and the embedded claudin-5 was rapidly stretched. Even α-helix showed a drastic conformational breakdown and its content was only 15.9%. Structural changes of this magnitude are difficult to repair in a short time, which may be related to chronic BBB dysfunction and persistent neurological deficits. This is a more common injury, since the tensile response of membranes to blast loads is relatively common. Taken together, we provided a biomechanical underpinning for acute disruption of tight junction proteins in BBB from exposure to blast shockwaves, and this may be helpful as a therapeutic strategy for bTBI.

Focal opening of the neuronal plasma membrane by shock-induced bubble collapse for drug delivery: a coarse-grained molecular dynamics simulation

“…For TJs or transport proteins in BBB models, their damage details caused by shock-induced bubble collapse (cavitation) have been studied by previous simulations. 19,20 For membranes, more studies have focused on the effects of shock waves and bubbles due to the use of one-component models. [21][22][23] Based on multi-component models, a small number of studies have revealed the influence of components such as cholesterol 24 or peroxidized phospholipid 25 on the response of membranes to shock.…”

Molecular Modeling of Shockwave-Mediated Blood-Brain Barrier Opening for Targeted Drug Delivery

“…Obviously, it is difficult for Gem to cross the BBB through the opening action of the jet. Wei et al found the temporary loss of tight junctions function after shock and need several seconds or longer to recover, which may promote intercellular transport of hydrophilic drugs. In experiments or clinics, the solution to the low permeability of hydrophilic drugs to the BBB is mainly to use chemical agents such as mannitol to open the tight junction structure of neighboring cells .…”

“…The MARTINI 2.2 coarse-grained force field was used. , Then, a full-length homology model of claudin-5 tight junctions was built using the crystal structure of claudin-15 (PDB: 4P79). Based on a previous simulation strategy, the iterative docking simulations were performed to obtain the structure of the paracellular pore by the self-assembly of two cis-dimers (tetramer) with lowest interaction energy. Subsequently, two well-balanced bilayers mimicking endothelial cells were placed in parallel and subjected to a grid division of 12 × 12.…”

Changes of rat’s brain vesseles after air shock wave exposure

“…In the case of mild blast-induced traumatic brain injury, which was simulated using our own device, we found vascular wall disorders with diapedesis hemorrhages, the nonruptured vessels wall edema, and cerebral edema resulting from bloodbrain barrier dysfunction. Such changes in blood-brain barrier vessels are associated with direct compressive shock wave loading and indirect cavitation, which together lead to overstretching and detachment of endothelial cell membranes [30].…”

“…Many histopathological studies clearly indicate a blood-brain barrier disorder [14]. Is considered that blood-brain barrier disruption and microvascular dysfunction are key factors in the course of blast-induced traumatic brain injury and further development of neurodegeneration [5,30]. However, studies of these changes pathogenesis are multidirectional, which does not provide a holistic picture and requires further research on this issue.…”