Chelating Intracellularly Accumulated Zinc Decreased Ischemic Brain Injury Through Reducing Neuronal Apoptotic Death

Abstract

Background and Purpose-Zinc has been reported to possess both neurotoxic and neuroprotective capabilities. The effects of elevated intracellular zinc accumulation following transient focal cerebral ischemia remain to be fully elucidated. Here, we investigated whether removing zinc with the membrane-permeable zinc chelator, N,N,Nʹ,Nʹ-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN), would decrease the intracellular levels of zinc in the ischemic tissue, leading to reduced brain damage and improved neurological outcomes. Methods-Rats were pretreated with TPEN or vehicle before or after a 90-minute middle cerebral artery occlusion. Cerebral infarct volume, neurological functions, neuronal apoptosis, poly(ADP-ribose) polymerase activity, and cytosolic labile zinc were assessed after ischemia and reperfusion. Results-Cerebral ischemia caused a dramatic cytosolic labile zinc accumulation in the ischemic tissue, which was decreased markedly by TPEN (15 mg/kg) pretreatment. Chelating zinc lead to reduced infarct volume compared with vehicle-treated middle cerebral artery occlusion rats, accompanied by much improved neurological assessment and motor function, which were sustained for 14 days after reperfusion. We also determined that reducing zinc accumulation rescued neurons from ischemia-induced apoptotic death by reducing poly(ADP-ribose) polymerase-1 activation. Conclusions-Ischemia-induced high accumulation of intracellular zinc significantly contributed to ischemic brain damage through promotion of neuronal apoptotic death. Removing zinc may be an effective and novel approach to reduce ischemic brain injury. (Stroke. 2014;45:1139-1147.)

Protection of the brain following cerebral ischemia through the attenuation of PARP-1-induced neurovascular unit damage in rats

“…The latter finding is consistent with previous studies demonstrating that PARP-1 enzymatic activity is increased after ischemia, although PARP-1 protein expression is not altered (Hu et al, 2013;Nagayama et al, 2000;Zhao et al, 2014). The activation of PARP-1 after ischemia may be relevant to the subsequent neurovascular deficits.…”

Zinc Is Indispensable in Exercise-Induced Cardioprotection against Intermittent Hypoxia-Induced Left Ventricular Function Impairment in Rats

“…These results are similar to findings of a previous study that found zinc supplementation reversed diabetes-induced cardiac and renal oxidative damage, inflammation, and fibrosis [18]. In another study, cerebral ischaemia caused dramatic cytosolic zinc accumulation in ischaemic tissue that was reduced markedly by 15 mg∙kg −1 TPEN pretreatment [27]. In our study, IH did not cause zinc accumulation in the LV.…”

“…Each group was further subdivided into three groups that received i.p. injections of vehicle (Veh; a mix of ethanol: glycerol: H 2 O in the ratio 1:3:6; n = 5) [26], zinc chloride (Zn; 10 mg∙kg -1 ; n = 5), or the membrane-permeable zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN; 5 mg∙kg -1 , n = 5) [18, 27]. The injections were administered to IHCON and IHEXE rats 30 min before IH exposure.…”

Trehalose elevates brain zinc levels following controlled cortical impact in a mouse model of traumatic brain injury

“…12 However, contradictory studies indicate that at 7 days post-TBI Zn chelation is associated with an upregulation of neuroprotective genes in rat brain, 13 and a 14-day Zn chelation trial in rat cerebral ischemia was associated with reduced neuronal apoptosis. 14 However, these studies were performed in younger animals, and their relevance to aged animals, where there is increased risk of negative outcomes following TBI, remains unknown. There have been two human clinical trials assessing the therapeutic roles of Zn post-TBI, 15 both of which have had significant positive patient outcomes.…”