HMGB1 binding heptamer peptide improves survival and ameliorates brain injury in rats after cardiac arrest and cardiopulmonary resuscitation

Excessive inflammatory response produced after cardiac arrest and cardiopulmonary resuscitation (CA/CPR) is one of major causes of cerebral injury. High mobility group box 1 (HMGB1) is a pro-inflammatory cytokine and its role in brain injury after CA/CPR is unclear. Herein we investigated whether blocking HMGB1 signaling could ease brain injury after CA/CPR. Male Sprague-Dawley rats (n = 181) were subjected to 8-min Asphyxia CA model or Sham operation. The ELISA data revealed both resuscitated patients and animals had elevated HMGB1 level in sera, compared with the healthy volunteers or Sham operative rats, respectively (P < 0.01). Rats successfully resuscitated from CA were then randomly treated with either membrane permeable (TAT-fused) HMGB1 binding heptamer peptide (HBHP) or Scramble peptide. Results showed that HBHP treatment markedly improved 7-day survival rate, reduced neurological deficit scores, and prevented neuronal and dendrite loss in hippocampal CA1 region. Moreover, HBHP inhibited the activation of microglia and astrocytes and downregulated the mRNA and protein expressions of proinflammatory factors. We finally blocked toll-like receptor-4 (TLR4, one of HMGB1 receptors) with a specific antagonist TAK-242 before CA induction to confirm the detrimental effect of HMGB1 signaling and found blocking TLR4 could also attenuate the neuronal degeneration, as well as reduce NF-κB-mediated inflammatory signaling. Our findings indicate that CA/CPR can induce HMGB1 release to serum, while blocking HMGB1 signaling with peptide may improve the survival and attenuate post-resuscitation brain injury in the rat model of CA/CPR. TLR4 antagonist may also offer neuroprotective effects through weakening HMGB1-mediated proinflammatory reactions.