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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.

Introduction: Cerebral vasoconstriction in the post-resuscitation phase worsens neurological outcome. Nitric oxide (NO) plays important roles mediating vasodilatation and anti-apoptotic protection. We therefore designed an Au-polymersomes/S-nitrosoglutathione (Au-PLGA/GSNO) nanoparticle that can be triggered by ultrasound (US) to release NO, and investigated its roles in mitigating cerebral vasoconstriction and neuronal apoptosis post-CPR. Hypothesis: Spatiotemporally controlled, US-triggered NO release by Au-PLGA/GSNO improves post-CPR cerebral perfusion and confers anti-apoptotic neuroprotection. Methods: Using an established rat model of asphyxia cardiac arrest and CPR, Au-PLGA/GSNO (7500 PPM, 0.4 ml) was infused with simultaneous US (1 MHz) stimulation at the brain 10 min after ROSC. Brain tissue perfusion was continuously recorded by OxyFLO probe and cerebral vasculature videoed by CytoCam. The blood was sampled 2 h post-CPR for measurement of nitrate/nitrite, and the brain 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: After CPR, marked cerebral vasoconstriction was noted on CytoCam while brain perfusion significantly reduced to ~0.5 folds that of baseline. After Au-PLGA/GSNO infusion and US stimulation, cerebral vasoconstriction was ameliorated and the brain perfusion significantly enhanced ( P < 0.05 vs. CPR control). The plasma NO indicated by nitrate/nitrite 2 h post-CPR was significantly increased ( P < 0.01) while cleaved caspase-3/caspase-3 of the brain markedly reduced ( P < 0.001). TUNEL stain of the hippocampus CA1 and CA3 regions were also remarkably abrogated, suggesting anti-apoptotic neuroprotection. Specifically, the phosphorylated (p)-eNOS/eNOS and p-Akt/Akt were also increased ( P < 0.01 and 0.001, respectively), indicating reciprocating activation of Akt-eNOS signaling upstream of NO. Conclusion: Spatiotemporally controlled US-triggered NO release by Au-PLGA/GSNO mitigates cerebral vasoconstriction, improves brain perfusion and confers anti-apoptotic neuroprotection post-CPR via reciprocating Akt-eNOS-NO signaling.