The Protective Role of Catalase against Cerebral Ischemia in Vitro and in Vivo

Abstract

RN and NBM contributed equally to this manuscriptThe present study aims to assess the protective role of the antioxidant enzyme catalase (CAT) with relation to hydrogen peroxide ("202) degradation in oxygen plus water on electrophysiological and fluorescence changes induced by in vitro ischemia and on brain damage produced by transient in vivo ischemia. Neuroprotective effects of CAT were determined by means of electrophysiological recordings and confocal fluorescence microscopy in the hippocampal slice preparation. Ischemia was simulated in vitro by oxygen/glucose deprivation (OGD). In vivo ischemia was produced by transient middle cerebral artery occlusion (MCAo). A protection of the rat CAl field excitatory postsynaptic potential (tEPSP) loss caused by a prolonged OGD (40 min) was observed after exogenous CAT (500 U/mL) bath-applied before a combined exposure to OGD and "202 (3 mM). Of note, neither "202 nor exogenous CAT alone had a protective action when OGD lasted for 40 min. The CAT-induced neuroprotection was confirmed in a transgenic mouse model over-expressing human CAT (Tg(CAT»). In the presence of"202' the hippocampus of Tg(CAT) showed an increased resistance against OGD compared to that of wild-type (WT) animals. Moreover, CAT treatment reduced for about 50 min tEPSP depression evoked by repeated applications of "202 in normoxia. A lower sensitivity to "202-induced depression of tEPSPs was also indicated by the rightward shift of concentration-response curve in Tg(CAT) compared to WT mice. Noteworthy, Tg(CAT) mice had a reduced infarct size after MCAo. Our data suggest new strategies to reduce neuronal damage produced by transient brain ischemia through the manipulation of CAT enzyme.Brain ischemia triggers a complex cascade of events leading to neuronal injury (1). Strong evidence supports a crucial contribution of reactive oxygen species (ROS) and antioxidants to neuronal death following ischemialreperfusion (IR) (2). The ROS hydrogen peroxide (HP2)' generated as a byproduct of aerobic metabolism, is decomposed to water and molecular oxygen (0) by the antioxidant

Therapeutic potential of targeting hydrogen peroxide metabolism in the treatment of brain ischaemia

“…(I) The figure shows · O 2 ‐ radical formation decrease measured in the CA1 hippocampal region by using fluorescent probe DHE after 1 h of superfusion, in OGD (40 min) exposed‐Tg(CAT) slices (lower) as compared with WT group (upper) ( n = 3 mice per experimental group, P < 0.05). Scale bar: 25 µm [G–I modified from Armogida et al . (2011); copyright IJIP , used with permission].…”

“…Of note, systemic infusion of CAT failed to improve neurological deficits after complete ischaemia (Forsman et al ., 1988), but resulted in a decrease of myocardial injury following coronary ischaemia (Gardner et al ., 1983). In the light of our recent findings demonstrating a CAT‐mediated neuroprotective effect of H 2 O 2 in oxygen‐deprived brain slices of the substantia nigra, hippocampus, striatum and in an in vivo model of transient focal brain ischaemia (Geracitano et al ., 2005; Nisticò et al ., 2008; Amantea et al ., 2009), we have also investigated whether either the exogenous administration or the overexpression of CAT is protective in in vitro and in vivo brain ischaemic models (Armogida et al ., 2011). Along with previous studies, our findings indicate that hippocampal synaptic transmission was restored only when CAT (500 U·mL −1 , 15 min) was bath‐applied before a relative long period of OGD (40 min, that in control condition kills the neurons) in combination with H 2 O 2 (3 mM) (Figure 3G).…”

Pycnogenol® Supplementation Attenuates Memory Deficits and Protects Hippocampal CA1 Pyramidal Neurons via Antioxidative Role in a Gerbil Model of Transient Forebrain Ischemia

“…It is well accepted that antioxidant enzymes, such SODs and CAT as free radical scavengers play a prominent role in neuroprotection against ischemic injury in brains. For example, ischemic brain injuries following transient global or focal ischemia in brains are apparently ameliorated in genetically engineered mouse and rat models overexpressing SOD1, SOD2, or CAT [ 48 , 49 , 50 ]. Moreover, it has been reported that enhanced levels of SOD and CAT by pretreatment with some plant extracts are closely involved in neuroprotection against ischemic injury following transient global ischemia in brains of rats and gerbils [ 51 , 52 , 53 ].…”

Redox Signaling in Neurotransmission and Cognition During Aging

“…Similar to SOD, knockout and overexpression of GPx influence the susceptibility to nervous system oxidative damage, without necessarily influencing normal aging ( 155 ). Knockout of CAT is relatively benign, possibly due to compensation by GPx, although overexpression of CAT is neuroprotective against ischemia ( 11 ). Interestingly, transgenic mice, which express CAT, specifically in the mitochondria, exhibit reduced effects of aging on heart, muscle, and metabolism, as well as increased longevity ( 67 , 151 , 244 , 277 , 280 ) and enhanced hippocampal-dependent memory ( 203 ).…”