Blast shockwaves propagate Ca2+ activity via purinergic astrocyte networks in human central nervous system cells

Abstract

In a recent study of the pathophysiology of mild, blast-induced traumatic brain injury (bTBI) the exposure of dissociated, central nervous system (CNS) cells to simulated blast resulted in propagating waves of elevated intracellular Ca2+. Here we show, in dissociated human CNS cultures, that these calcium waves primarily propagate through astrocyte-dependent, purinergic signaling pathways that are blocked by P2 antagonists. Human, compared to rat, astrocytes had an increased calcium response and prolonged calcium wave propagation kinetics, suggesting that in our model system rat CNS cells are less responsive to simulated blast. Furthermore, in response to simulated blast, human CNS cells have increased expressions of a reactive astrocyte marker, glial fibrillary acidic protein (GFAP) and a protease, matrix metallopeptidase 9 (MMP-9). The conjoint increased expression of GFAP and MMP-9 and a purinergic ATP (P2) receptor antagonist reduction in calcium response identifies both potential mechanisms for sustained changes in brain function following primary bTBI and therapeutic strategies targeting abnormal astrocyte activity.

Multispectral imaging of cortical vascular and hemodynamic responses to a shock wave: observation of spreading depolarization and oxygen supply-demand mismatch

“…36 Although the type of insult is different from ours, a similar mechanism might be involved. This is because overpressure of a shock wave can increase intracellular calcium (Ca 2þ ), 38,39 resulting in activation of endothelial nitric oxide synthase (NOS) and hence an increase in nitric oxide (NO). 40 Meanwhile, an intracellular increase in Ca 2þ can stimulate the generation of reactive oxygen species (ROS) in mitochondria.…”

Astroglial Ca2+-Dependent Hyperexcitability Requires P2Y1 Purinergic Receptors and Pannexin-1 Channel Activation in a Chronic Model of Epilepsy

“…Nonetheless, the reported values in these publications are similar to those obtained here. Our new findings suggest that a diffusible purinergic signal released by astrocytes themselves activates astroglial P2Y 1 R (i.e., astrocyte-to-astrocyte signaling) and upregulates the incidence of STs, which is supported by several evidences: (i) TTX-insensitive neurotransmitter release is associated with FTs confined to microdomains in astrocytic processes and not to somatic Ca 2+ oscillations (Di Castro et al, 2011 ; Álvarez-Ferradas et al, 2015 ); (ii) ATP is released by astrocytes as a mechanism for paracrine signaling in several neuropathologies, being P2YR-mediated signaling one of the main pathways for astrocyte-to-astrocyte communication in pathological conditions (Anderson et al, 2004 ; Iwabuchi and Kawahara, 2011 ; Pascual et al, 2012 ; Orellana et al, 2013 ; Delekate et al, 2014 ); and (iii) astrocytes generate Ca 2+ transients as a consequence of P2YR activation (Bowser and Khakh, 2007 ; Torres et al, 2012 ), which is also observed in pathological conditions, including epilepsy (Delekate et al, 2014 ; Álvarez-Ferradas et al, 2015 ; Ravin et al, 2016 ; Reichenbach et al, 2018 ). In addition, it has been shown that P2Y 1 R induces large and long-lasting astrocytic Ca 2+ transients that do not require action potentials for their generation (Gallagher and Salter, 2003 ; Shigetomi et al, 2018 ), which is consistent with our previous findings (Álvarez-Ferradas et al, 2015 ) and with the decrease in the frequency and percentage of STs associated with P2Y 1 R blockade in the epileptic hippocampus above described (Figure 2 ).…”

Low-energy shock waves evoke intracellular Ca2+ increases independently of sonoporation

“…Blast shock waves are generated by explosives. As a model of blast injury, the intracellular Ca 2+ increase evoked in astrocytes by blast shock waves was investigated 45,46 . The peak pressure of the blast shock waves was relatively comparable: around 1 MPa for blast shock waves and typically 3.8 MPa for shock waves in this study (Fig.…”