Selective Cerebral Vasodilatation And Anti-Apoptotic Therapy With Shockwave-Induced Release Of Nitric Oxide Using Nano Au-Polymersomes/S-Nitrosoglutathione.

Introduction: Cerebral vasoconstriction is often encountered in the post-CPR phase, which inevitably worsens neurological prognosis. Nitric oxide (NO) confers vasodilatation and anti-apoptotic protective effect, but may cause systemic hypotension. We designed an Au-polymersomes/S-nitrosoglutathione (Au-PLGA/GSNO) nanoparticle that can be selectively triggered by shockwave (SW) to release NO, and investigated its role in mitigating post-CPR cerebral vasoconstriction and apoptotic neuronal injury. Methods: Using an established rat model of asphyxia cardiac arrest and CPR, Au-PLGA/GSNO (7500 PPM, 3.33 mg/kg Au and 42 ug/kg GSNO) was infused into carotid artery together with the same volume of SonoVue 10 min after CPR, with simultaneous stimulation by SW (PiezoWave, 134 mJ/mm 2 ) distal to the infusion site. The blood pressure (BP) was continuously monitored and brain tissue perfusion recorded by OxyFLO probe. Cerebral vasculature was video-taped by CytoCam. The blood was sampled 2 h post-CPR for measurement of nitrate/nitrite. The brain was harvested for measurement of casepase-3, endothelial NO synthase (eNOS) and protein kinase B (Akt). In a subgroup the brain was harvested at 24 h for TUNEL stain. Results: Marked cerebral vasoconstriction was noted after CPR with brain perfusion reduced to about half that of baseline. With infusion of Au-PLGA/GSNO + SonoVue and SW stimulation, the cerebral vasoconstriction was ameliorated and brain perfusion improved to baseline level ( P < 0.05 vs. CPR control), while BP showed no significant difference. The plasma nitrate/nitrite 2 h post-CPR was significantly increased ( P < 0.05). The cleaved caspase-3 of the brain was reduced ( P < 0.001) and TUNEL stain of the CA1 and CA3 regions of hippocampus significantly abrogated. Interestingly, the phosphorylated (P)-eNOS and P-Akt were also increased (both P < 0.001), suggesting reciprocating activation of the upstream Akt-eNOS signaling. Conclusion: Nano Au-PLGA/GSNO with SW-induced release of NO selectively mitigates post-CPR cerebral vasoconstriction and apoptotic neuronal death without systemic hypotension. Being effective and safe, such therapeutic strategy can be applied not only in post-CPR care but in other diseases such as subarachnoid hemorrhage.