Pyruvate enhances neurological recovery following cardiopulmonary arrest and resuscitation

Abstract

Purpose-Cerebral oxidative stress and metabolic dysfunction impede neurological recovery from cardiac arrest-resuscitation. Pyruvate, a potent antioxidant and energy-yielding fuel, has been shown to protect against oxidant-and ischemia-induced neuronal damage. This study tested whether acute pyruvate treatment during cardiopulmonary resuscitation can prevent neurological dysfunction and cerebral injury following cardiac arrest. Methods-Anesthetized, open-chest mongrel dogs underwent 5 min cardiac arrest, 5 min open chest cardiac compression (OCCC), defibrillation and 3 day recovery. Pyruvate (n = 9) or NaCl volume control (n = 8) were administered (0.125 mmol/kg/min iv) throughout OCCC and the first 55 min recovery. Sham dogs (n = 6) underwent surgery and recovery without cardiac arrestresuscitation.Results-Neurological deficit score (NDS), evaluated at 2 day recovery, was sharply increased in NaCl-treated dogs (10.3 ± 3.5) vs. shams (1.2 ± 0.4), but pyruvate treatment mitigated neurological deficit (NDS = 3.3 ± 1.2; P < 0.05 vs. NaCl). Brain samples were taken for histological examination and evaluation of inflammation and cell death at 3 d recovery. Loss of pyramidal neurons in the hippocampal CA1 subregion was greater in the NaCl controls than in pyruvate treated dogs (11.7 ± 2.3% vs. 4.3 ± 1.2%; P < 0.05). Cardiac arrest increased caspase 3 activity, matrix metalloproteinase activity, and DNA fragmentation in the CA1 subregion; pyruvate prevented caspase-3 activation and DNA fragmentation, and suppressed matrix metalloproteinase activity.Conclusion-Intravenous pyruvate therapy during cardiopulmonary resuscitation prevents initial oxidative stress and neuronal injury and enhances neurological recovery from cardiac arrest.

Beneficial effects of sodium or ethyl pyruvate after traumatic brain injury in the rat

“…Although the CCI-EP group did not differ significantly from the CCI-SP treated animals, only the former group exhibited significantly decreased activation of microglia in the hippocampus compared to the CCI-Veh controls. These results are consistent with the strong anti-inflammatory properties reported for SP (see review by Das, 2006) or EP (see reviews by Fink, 2007; Kao and Fink, 2010) in several models of disease as well as with reported anti-inflammatory effects of these compounds using in vitro and in vivo models of brain injury (Cho et al, 2006; Kim et al, 2005, 2008; Park et al, 2007; Ryu et al, 2004, 2006; Sharma et al, 2003, 2008, 2009; Shen et al, 2010; Wang et al, 2009a, 2009b; Yu et al, 2005). …”

“…The current behavioral results are compatible with the report that a 30 min infusion of SP (∼500 mg/kg) begun 1 h after closed head injury in the rat significantly improves neurobehavioral recovery (Zlotnik et al, 2008). The available data from TBI models are also congruent with reports that in vivo administration of exogenous SP can reduce brain or spinal cord damage and/or neurological deficits in a variety of injury models (Choi et al, 2010; Gonzalez-Falcon et al, 2003; Kim et al, 2005, 2007, 2010; Lee et al, 2001; Mongan et al, 2001, 2003; Park et al, 2007; Ryu et al, 2003, 2004, 2006; Sharma et al, 2008; Suh et al, 2005; Wang et al, 2009b; Yi et al, 2007; Yoo et al, 2004). …”

Pyruvate Protects the Brain Against Ischemia–Reperfusion Injury by Activating the Erythropoietin Signaling Pathway

“…In this regard, intravenous pyruvate administration during cardiopulmonary resuscitation afforded substantial neuroprotection 3d later 34 and protracted pyruvate-induced protection against focal cerebral ischemia was reported. 35 Other HIF-1-activated cytoprotective proteins could act independently of or in collaboration with EPO to protect brain from ischemia-reperfusion.…”

Erythropoietin: Powerful protection of ischemic and post-ischemic brain

“…In dogs, cardiac arrest and cardiopulmonary resuscitation produced a striking increase in hippocampal MMP activity 3 d later; pyruvate infusion during cardiac massage and the first 60 min recovery suppressed this MMP activation by 80%. 130 Sharma and Mongan 158 examined the anti-inflammatory capabilities of low-volume, hypertonic sodium pyruvate resuscitation in a rat model of hemorrhagic shock. The pyruvate treatment ameliorated liver injury, suppressed serum and hepatic pro-inflammatory cytokines, NOS and cyclooxygenase-2 activities, caspase-3 activation and poly(ADP ribose) polymerase cleavage and lipid peroxidation, and attenuated liver injury.…”