Reduction of zinc accumulation in mitochondria contributes to decreased cerebral ischemic injury by normobaric hyperoxia treatment in an experimental stroke model

Abstract

Cerebral ischemia interrupts oxygen supply to the affected tissues. Our previous studies have reported that normobaric hyperoxia (NBO) can maintain interstitial partial pressure of oxygen (pO2) in the penumbra of ischemic stroke rats at the physiological level, thus affording significant neuroprotection. However, the mechanisms that are responsible for the penumbra rescue by NBO treatment are not fully understood. Recent studies have shown that zinc, an important mediator of intracellular and intercellular neuronal signaling, accumulates in neurons and leads to ischemic neuronal injury. In this study, we investigate whether NBO could regulate zinc accumulation in the penumbra and prevent mitochondrial damage in penumbral tissue using a transient cerebral ischemic rat model. Our results showed that NBO significantly reduced zinc staining positive cells and zinc-staining intensity in penumbral tissues, but not in the ischemic core. Moreover, ischemia-induced zinc accumulation in mitochondria, isolated from penumbral tissues, was greatly attenuated by NBO or a zinc specific chelator, N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). NBO or TPEN administration stabilized the mitochondrial membrane potential in the penumbra after cerebral ischemia. Finally, ischemia-induced cytochrome C release from mitochondria in penumbral tissues was significantly reduced by NBO or TPEN treatment. These findings demonstrate a novel mechanism for NBO's neuroprotection, especially to penumbral tissues, providing further evidence for the potential clinical benefit of NBO for acute ischemic stroke.

Synergistic Interaction Between Zinc and Reactive Oxygen Species Amplifies Ischemic Brain Injury in Rats

“…A sample size of 8 animals per subgroup was a priori calculated based on previous research from our group. 4,15 Six rats with unsuccessful MCAO were excluded from this study. No rats died due to surgical or stroke complications.…”

Differences in Cognitive Function of Rats with Traumatic Brain Injuries Following Hyperbaric Oxygen Therapy

“…Hyperbaric oxygen (HBO) is a historical therapeutic option in the treatment of various types of brain damage. HBO functions as follows in the treatment of brain injuries: (1) by correcting local brain tissue hypoxia, the oxygen partial pressure increases nearly 20-fold and strengthens the ability of oxygen to infiltrate local brain tissue; (2) HBO can improve the oxygen supply and blood supply in the brainstem reticular system and induce the excitability of brain cells, which plays a role in the promotion of consciousness; (3) by eliminating cerebral edema and protecting brain cells; and (4) by promoting the recovery of neural functionality and reducing sequelae [ 1 – 4 ].…”

Normobaric Oxygen May Ameliorate Cerebral Venous Outflow Disturbance-Related Neurological Symptoms

“…Normobaric oxygen (NBO), supplied by a face mask (such as simple mask) with one atmosphere pressure (1 ATA = 101.325 kPa), is a routine adjuvant therapy for various diseases, especially for brain ischemia (13)(14)(15). NBO can elevate brain tissue oxygen pressure (pO 2 ), increase cerebral blood flow and volume (CBF and CBV), protect the blood-brain barrier (BBB), attenuate ischemic injury, and ameliorate inflammation in CCI (16)(17)(18)(19)(20)(21). Similar to cerebral arterial disease-induced CCI, CVOD also induces CCI by reducing CBF, damaging the BBB, promoting inflammatory factor release, and facilitating neuron injury (1-7), whereby NBO may be capable of yielding some benefits to patients with CVOD as well (2,3,7).…”