deuterohemin and Reperfusion-Injury

Cerebral ischemia-reperfusion injury (CIRI) is a brain injury that usually occurs during thrombolytic therapy for acute ischemic stroke and impacts human health. Oxidative stress is one of the major causative factors of CIRI. DhHP-3 is a novel peroxidase-mimicking enzyme that exhibits robust reactive oxygen species (ROS) scavenging ability in vitro. Here, we established in vitro and in vivo models of cerebral ischemia-reperfusion to mechanistically investigate whether DhHP-3 can alleviate CIRI. DhHP-3 could reduce ROS, down-regulate apoptotic proteins, suppress p53 phosphorylation, attenuate the DNA damage response (DDR), and inhibit apoptosis in SH-SY5Y cells subjected to oxygen-glucose deprivation/re-oxygenation (OGD/R) and in the brain of Sprague Dawley rats subjected to transient middle cerebral artery occlusion. In conclusion, DhHP-3 has bioactivity of CIRI inhibition through suppression of the ROS-induced apoptosis.

Topics: Animals; Apoptosis; Brain Ischemia; Humans; Ischemic Stroke; Neuroblastoma; Oxidative Stress; Peptides; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury

As a novel reactive oxygen species (ROS) scavenger, deuterohemin His peptide‑6 (DhHP‑6) has been demonstrated to prolong the lifespan of Caenorhabditis elegans and has also exhibited protective effects in myocardial ischemia‑reperfusion injury. Whether similar effects occur during cerebral ischemia‑reperfusion (CIR) injury remains to be elucidated. The present study evaluated the function of DhHP‑6 and its underlying mechanisms in a middle cerebral artery occlusion (MCAO) model in rats. The focal transient MCAO model was implemented using the Longa method of ischemia for 2 h followed by reperfusion for 22 h in male Wistar rats. DhHP‑6 was administered at the onset of reperfusion via intraperitoneal injection. The infarct volume, brain edema, brain apoptosis and neurological function were evaluated 24 h following stroke. To further determine the role of DhHP‑6 in CIR injury, the levels of ROS and malondialdehyde (MDA), the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH‑Px), and the protein expression levels of B‑cell lymphoma 2 (Bcl‑2)‑associated X protein (Bax), cleaved caspase‑3, cytochrome c, Bcl‑2 and phosphorylated‑Akt/Akt were measured in ischemic cortex tissues. The results demonstrated that DhHP‑6 significantly improved infarct volume, brain edema and neurological deficits, and reduced the percentage of TUNEL‑positive cells. The levels of ROS and MDA were decreased, whereas no significant changes in the activities of SOD, CAT and GSH‑Px were observed. The levels of Bax, cleaved caspase‑3, and cytochrome c were downregulated, whereas the levels of Bcl‑2 and p‑Akt/Akt were upregulated. The results of the present study indicated that DhHP‑6 may offer therapeutic potential for cerebral ischemia. The neuroprotective effects of DhHP‑6 maybe mediated by its anti‑oxidative properties, anti‑apoptotic activities, or activation of the phosphoinositide 3‑kinase/Akt survival pathway.

Topics: Animals; Apoptosis; Brain; Caspase 3; Catalase; Disease Models, Animal; Glutathione Peroxidase; Hemin; Infarction, Middle Cerebral Artery; Male; Malondialdehyde; Neuroprotective Agents; Oxidative Stress; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Stroke; Superoxide Dismutase; Up-Regulation