Manganese Porphyrin Promotes Post Cardiac Arrest Recovery in Mice and Rats

Abstract

Introduction Cardiac arrest (CA) and resuscitation induces global cerebral ischemia and reperfusion, causing neurologic deficits or death. Manganese porphyrins, superoxide dismutase mimics, are reportedly able to effectively reduce ischemic injury in brain, kidney, and other tissues. This study evaluates the efficacy of a third generation lipophilic Mn porphyrin, MnTnBuOE-2-PyP5+, Mn(III) ortho meso-tetrakis (N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE, BMX-001), in both mouse and rat models of CA. Methods Forty-eight animals were subjected to 8 min of CA and resuscitated subsequently by chest compression and epinephrine infusion. Vehicle or MnBuOE was given immediately after resuscitation followed by daily subcutaneous injections. Body weight, spontaneous activity, neurologic deficits, rotarod performance, and neuronal death were assessed. Kidney tubular injury was assessed in CA mice. Data were collected by the investigators who were blinded to the treatment groups. Results Vehicle mice had a mortality of 20%, which was reduced by 50% by MnBuOE. All CA mice had body weight loss, spontaneous activity decline, neurologic deficits, and decreased rotarod performance that were significantly improved at three days post MnBuOE daily treatment. MnBuOE treatment reduced cortical neuronal death and kidney tubular injury in mice (p < 0.05) but not hippocampus neuronal death (23% MnBuOE vs. 34% vehicle group, p = 0.49). In rats, they had a better body-weight recovery and increased rotarod latency after MnBuOE treatment when compared to vehicle group (p < 0.01 vs. vehicle). MnBuOE-treated rats had a low percentage of hippocampus neuronal death (39% MnBuOE vs. 49% vehicle group, p = 0.21) and less tubular injury (p < 0.05) relative to vehicle group. Conclusions We demonstrated the ability of MnBuOE to improve post-CA survival, as well as functional outcomes in both mice and rats, which jointly account for the improvement not only of brain function but also of the overall wellbeing of the animals. While MnBuOE bears therapeutic potential for treating CA patients, the females and the animals with comorbidities must be further evaluated before advancing toward clinical trials.

Evidence of Spaceflight-Induced Adverse Effects on Photoreceptors and Retinal Function in the Mouse Eye

“…More frequent injections may be required to protect retinal function more effectively. Daily [ 52 , 53 ] or twice-weekly [ 54 ] administration schedules have been reported to have significant protective effects from oxidative damage in other disease models. Free radicals produced in the ocular tissues by the mechanism other than ROS, which include reactive nitrogen species, and reactive carbonyl species [ 55 ], may be equally important in inducing cellular damage in the retina.…”

Mn(III) Porphyrin, MnTnBuOE-2-PyP5+, Commonly Known as a Mimic of Superoxide Dismutase Enzyme, Protects Cardiomyocytes from Hypoxia/Reoxygenation Induced Injury via Reducing Oxidative Stress

“…Four of those trials are on radio- and chemoprotection of normal tissue by BMX-001 in cancer patients bearing glioma, multiple brain metastases, anal cancer, and head and neck cancer [ 31 ]. Mn porphyrins have a beneficial effect against various diseases, including cardiovascular diseases [ 32 , 33 , 34 ]. However, the cardioprotective effect has not yet been tested in myocardial ischemia/reperfusion injury.…”

Neuroprotective Approaches for Brain Injury After Cardiac Arrest: Current Trends and Prospective Avenues

“…BMX001 is a manganese porphyrin compound with potent antioxidant properties by attenuating ROS formation. In an 8-minute KCl-induced CA mice model, intraperitoneal injection of BMX001 (0.1 mg/kg) immediately after resuscitation followed by subcutaneous injections twice per day for 3 days at a dose of 0.2 mg/kg/day significantly improved body weight loss, spontaneous activity decline, neurologic deficits, and decreased rotarod performance with reduced cortical neuronal death [ 42 ]. The results were consistent in the 8-minute KCl-CA rat model with BMX001 in the same study that treated rats having a better body-weight recovery and increased rotarod latency with a low percentage of hippocampus neuronal death.…”

“…Anti-oxidative drugs play a crucial role in mitigating neuronal cell death by counteracting the harmful effects of ROS. In rodent CA models, the anti-oxidants including the combination therapy of niacin and selenium [ 41 ], BMX001 [ 42 ], DMM [ 43 ], rosuvastatin [ 44 ], PD98059 [ 55 - 57 ], D-NAC [ 50 ], and DCA [ 62 ] attenuated cellular apoptosis, and neuronal damage. Anti-oxidant compound 147 [ 60 ] and edaravone [ 45 ] decreased apoptotic proteins caspase-8, caspase-3, and Bax while increasing the levels of antiapoptotic protein Bcl-2 in rodent CA models.…”