Annexin A1 Bioactive Peptide Promotes Resolution of Neuroinflammation in a Rat Model of Exsanguinating Cardiac Arrest Treated by Emergency Preservation and Resuscitation

Abstract

Neuroinflammation initiated by damage-associated molecular patterns, including high mobility group box 1 protein (HMGB1), has been implicated in adverse neurological outcomes following lethal hemorrhagic shock and polytrauma. Emergency preservation and resuscitation (EPR) is a novel method of resuscitation for victims of exsanguinating cardiac arrest, shown in preclinical studies to improve survival with acceptable neurological recovery. Sirtuin 3 (SIRT3), the primary mitochondrial deacetylase, has emerged as a key regulator of metabolic and energy stress response pathways in the brain and a pharmacological target to induce a neuronal pro-survival phenotype. This study aims to examine whether systemic administration of an Annexin-A1 bioactive peptide (ANXA1sp) could resolve neuroinflammation and induce sirtuin-3 regulated cytoprotective pathways in a novel rat model of exsanguinating cardiac arrest and EPR. Adult male rats underwent hemorrhagic shock and ventricular fibrillation, induction of profound hypothermia, followed by resuscitation and rewarming using cardiopulmonary bypass (EPR). Animals randomly received ANXA1sp (3 mg/kg, in divided doses) or vehicle. Neuroinflammation (HMGB1, TNFα, IL-6, and IL-10 levels), cerebral cell death (TUNEL, caspase-3, pro and antiapoptotic protein levels), and neurologic scores were assessed to evaluate the inflammation resolving effects of ANXA1sp following EPR. Furthermore, western blot analysis and immunohistochemistry were used to interrogate the mechanisms involved. Compared to vehicle controls, ANXA1sp effectively reduced expression of cerebral HMGB1, IL-6, and TNFα and increased IL-10 expression, which were associated with improved neurological scores. ANXA1sp reversed EPR-induced increases in expression of proapoptotic protein Bax and reduction in antiapoptotic protein Bcl-2, with a corresponding decrease in cerebral levels of cleaved caspase-3. Furthermore, ANXA1sp induced autophagic flux (increased LC3II and reduced p62 expression) in the brain. Mechanistically, these findings were accompanied by upregulation of the mitochondrial protein deacetylase Sirtuin-3, and its downstream targets FOXO3a and MnSOD in ANXA1sp-treated animals. Our data provide new evidence that engaging pro-resolving pharmacological strategies such as Annexin-A1 biomimetic peptides can effectively attenuate neuroinflammation and enhance the neuroprotective effects of EPR after exsanguinating cardiac arrest.

Potential relationship between Sirt3 and autophagy in ovarian cancer (Review)

“…As for Sirt3, a number of studies have indicated that there is a close relationship between Sirt3 and the p62-autophagy pathway. A previous study demonstrated that treatment with ANXA1sp, an annexin-A1 bioactive peptide, reduced the expression of p62 and concomitantly upregulated the expression of the mitochondrial protein deacetylase Sirt3 (80). This suggested that Sirt3 is involved in autophagy by downregulating p62.…”

Enhancing the Bystander and Abscopal Effects to Improve Radiotherapy Outcomes

“…The role of damage-associated molecular patterns in neuro-inflammation has been implicated in adverse neurological outcomes following lethal hemorrhagic shock and polytrauma. Data obtained in (150) provide new suggestion that appealing pro-resolving pharmacological approaches such as Annexin-A1 biomimetic peptides can effectively reduce neuro-inflammation and new data show a new multifaceted role for ANXA1 as a therapeutic and a prophylactic drug due to its capacity to stimulate endogenous pro-resolving, anti-thrombo-inflammatory circuits in cerebral ischemia-reperfusion injury (151). Finally, the chance of exploiting ANXA1 as a novel therapeutic molecule in diabetes and for treatment of microvascular disease has been announced (152).…”

Rationale for the Use of Radiation-Activated Mesenchymal Stromal/Stem Cells in Acute Respiratory Distress Syndrome

“…Recently, the role of ANXA1 in the treatment of acute radiation-induced lung damage has been studied and the causes of its action examined [ 67 ]. Neuroinflammation initiated by damage-associated molecular patterns has been implicated in adverse neurological outcomes following lethal hemorrhagic shock and polytrauma [ 68 ]. Results obtained by Ma Q. et al [ 68 ] show that attractive proresolving pharmacological approaches, such as annexin-A1 biomimetic peptides, can efficiently attenuate neuroinflammation and reveal a novel complex role for ANXA1 as a therapeutic and a prophylactic drug due to its ability to strengthen endogenous proresolving, anti-thrombo-inflammatory mechanisms in cerebral ischemia–reperfusion injury.…”

“…Neuroinflammation initiated by damage-associated molecular patterns has been implicated in adverse neurological outcomes following lethal hemorrhagic shock and polytrauma [ 68 ]. Results obtained by Ma Q. et al [ 68 ] show that attractive proresolving pharmacological approaches, such as annexin-A1 biomimetic peptides, can efficiently attenuate neuroinflammation and reveal a novel complex role for ANXA1 as a therapeutic and a prophylactic drug due to its ability to strengthen endogenous proresolving, anti-thrombo-inflammatory mechanisms in cerebral ischemia–reperfusion injury. Finally, it has been announced that recombinant human ANXA1 may represent a novel candidate for the treatment of diabetes type 2 and/or its complications [ 69 , 70 ].…”