Activation of Poly(ADP‐Ribose) Polymerase in the Rat Hippocampus May Contribute to Cellular Recovery Following Sublethal Transient Global Ischemia

298

326

It is well established that tissue damage and functional outcome after experimental or clinical stroke are shaped by biologic sex. We investigated the novel hypothesis that ischemic cell death from neuronally derived nitric oxide (NO) or poly-ADP ribose polymerase (PARP-1) activation is sexually dimorphic and that interruption of these molecular death pathways benefits only the male brain. Female neuronal nitric oxide synthase (nNOS) knockout (nNOSÀ/À) mice exhibited exacerbated histological injury after middle cerebral artery occlusion (MCAO) relative to wild-type (WT) females, unlike the protection observed in male nNOSÀ/À littermates. Similarly, treatment with the nNOS inhibitor (7-nitroindozole, 25 mg/kg) increased infarction in female C57Bl6 WT mice, but protected male mice. The mechanism for this sexually specific response is not mediated through changes in protein expression of endothelial NOS or inducible NOS, or differences in intraischemic cerebral blood flow. Unlike male PARP-1 knockouts (PARP1À/À), female PARP1À/À littermates sustained grossly increased ischemic damage relative to sex-matched WT mice. Treatment with a PARP inhibitor (PJ-34, 10 mg/kg) resulted in identical results. Loss of PARP-1 resulted in reversal of the neuroprotective activity by the female sex steroid, 17b estradiol. These data suggest that the previously described cell death pathways involving NO and PARP ischemic neurotoxicity may be operant solely in male brain and that the integrity of nNO/PARP-1 signaling is paradoxically protective in the female.

Section: Discussionsupporting

confidence: 93%

Ischemic Nitric Oxide and Poly (ADP-Ribose) Polymerase-1 in Cerebral Ischemia: Male Toxicity, Female Protection

McCullough

Zeng

Blizzard

et al. 2005

298

326

“…While further study is needed to directly establish how lactate achieves comparable neuroprotection to PARP inhibition, one parsimonious explanation is that a concomitant increase in brain lactate offsets the decrease in NAD + due to overactivation of PARP by acting as an alternative energy substrate that can effectively bypass glycolysis and be fed directly to the citric acid cycle to maintain cellular ATP levels (Ying et al, 2005). Lactate is inexpensive, readily available, and unlike directly inhibiting PARP activation, does not have the theoretical limitation of potentially impairing DNA repair mechanisms (Nagayama et al, 2000). Results of this study suggest that lactate may be an effective intervention for patients with severe hypoglycemia.…”

Section: Discussionmentioning

confidence: 99%

Prevention of Acute/Severe Hypoglycemia-Induced Neuron Death by Lactate Administration

Won

Jang

Yoo

et al. 2012

Hypoglycemia-induced cerebral neuropathy can occur in patients with diabetes who attempt tight control of blood glucose and may lead to cognitive dysfunction. Accumulating evidence from animal models suggests that hypoglycemia-induced neuronal death is not a simple result of glucose deprivation, but is instead the end result of a multifactorial process. In particular, the excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1) consumes cytosolic nicotinamide adenine dinucleotide (NAD + ), resulting in energy failure. In this study, we investigate whether lactate administration in the absence of cytosolic NAD + affords neuroprotection against hypoglycemiainduced neuronal death. Intraperitoneal injection of sodium L-lactate corrected arterial blood pH and blood lactate concentration after hypoglycemia. Lactate administered without glucose was not sufficient to promote electroencephalogram recovery from an isoelectric state during hypoglycemia. However, supplementation of glucose with lactate reduced neuronal death by B80% in the hippocampus. Hypoglycemia-induced superoxide production and microglia activation was also substantially reduced by administration of lactate. Taken together, these results suggest an intriguing possibility: that increasing brain lactate following hypoglycemia offsets the decrease in NAD + due to overactivation of PARP-1 by acting as an alternative energy substrate that can effectively bypass glycolysis and be fed directly to the citric acid cycle to maintain cellular ATP levels.

“…The loss of DNA repair function has been previously reported to negatively affect neuronal survival in hippocampus (Meli et al, 2003;Nagayama et al, 2000). Since DNA-binding domains are different in PARP-1 and -2, it is also possible that the lack of specific ribosylation of one or more unique PARP-2 substrates underlies the detrimental effect observed in the hippocampus of PARP-2 À/À mice after global cerebral ischemia.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of PARP-1 activation by genetic deletion or pharmacological inhibition confers protection in a large number of in vivo and in vitro models of ischemia/reperfusion (Virag and Szabó, 2002). Poly(ADP-ribose) polymerase-1 deficiency or inhibition is clearly neuroprotective in focal cerebral ischemia in male (but not female) animals (Eliasson et al, 1997;Endres et al, 1997;Goto et al, 2002;Nakajima et al, 2005;Tokime et al, 1998;Komjáti et al, 2004;McCullough et al, 2005), whereas mixed results have been observed in global cerebral ischemia (Moroni et al, 2001;Nagayama et al, 2000;Plaschke et al, 2000;Kofler et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Differential Effect of PARP-2 Deletion on Brain Injury after Focal and Global Cerebral Ischemia

Kofler

Otsuka

Zhang

et al. 2005

Poly(ADP-ribose) polymerase-2 (PARP-2) is a member of the PARP enzyme family, and, similarly to PARP-1, catalyzes the formation of ADP-ribose polymers in response to DNA damage. While PARP-1 overactivation contributes to ischemic cell death, no information is available regarding the role of PARP-2. In this study, we evaluated the impact of PARP-2 deletion on histopathological outcome from two different experimental models of cerebral ischemia. Male PARP-2 À/À mice and wild-type (WT) littermates were subjected to either 2 h of middle cerebral artery occlusion (MCAO) followed by 22 h reperfusion, or underwent 10 mins of KCl-induced cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) and 3-day survival. After MCAO, infarct volume was reduced in PARP-2 À/À mice (38%712% of contralateral hemisphere) compared with WT (64%716%). After CA/CPR, PARP-2 deletion significantly increased neuronal cell loss in the hippocampal CA1 field (65%736% ischemic neurons) when compared with WT mice (31%733%), with no effect in either striatum or cortex. We conclude that PARP-2 is a novel executioner of cell death pathways in focal cerebral ischemia, but might be a necessary survival factor after global ischemia to mitigate hippocampal delayed cell death.