Use of a Poly(ADP-Ribose) Polymerase Inhibitor to Suppress Inflammation and Neuronal Death After Cerebral Ischemia-Reperfusion

Abstract

Background and Purpose-Most stroke patients do not present for medical treatment until several hours after onset of brain ischemia. Consequently, neuroprotective strategies are required with comparably long therapeutic windows. Poly(ADPribose) polymerase inhibitors such as PJ34 are known to suppress microglial activation, a postischemic event that may contribute to neuronal death. We evaluated the effects of PJ34 administered 8 hours after transient forebrain ischemia. Methods-Rats were subjected to 10 minutes of forebrain ischemia and treated with PJ34 for 7 days beginning 8 hours after reperfusion. Activated microglia and infiltrating macrophages were evaluated at serial time points between zero and 14 days after ischemia by immunostaining for CD11b. CA1 neuronal survival was evaluated 7 days after ischemia. Results-Rats treated with PJ34 showed a near-complete inhibition of microglia/macrophage activation (evaluated on day 5) and an 84% reduction in CA1 neuronal death. Key Words: inflammation Ⅲ ischemia Ⅲ microglia S everal pharmacological interventions have been shown to reduce brain injury in animal models of stroke when administered at short time points, generally zero to 3 hours, after onset of ischemia. These include glutamate receptor antagonists, free radical scavengers, protease inhibitors, and the thrombolytic agent, tissue-plasminogen activator (tPA). [1][2][3][4] However, clinically useful agents must be efficacious when given at considerably longer intervals after onset of ischemia, because the vast majority of stroke patients do not present for medical treatment until substantially after this short time window. Such agents must target processes that contribute to cell death at later time points. One such process is the brain inflammatory response. Conclusions-AdministrationA prominent aspect of the brain inflammatory response is activation of microglial cells. Microglia are the resident macrophages of the central nervous system. They are derived from bone marrow precursors and have a slow interchange with the circulating macrophage pool. 5,6 Microglia in normal brain have a highly branched "ramified" morphology that can rapidly transform into an activated, amoeboid morphology in response to stressors such as ischemia. 7,8 Microglial activation precedes ischemic neuronal death, 7,9,10 and the location of microglial activation correlates with neuronal death. 7,[11][12][13] Activated microglia can promote neuronal death by releasing glutamate, the NMDA receptor modulator D-serine, cytokines, reactive oxygen species, and proteases. 8,14 -20 At later time points, infiltrating bloodborne leukocytes also contribute to the brain inflammatory response. 21,22 Many aspects of the inflammatory response are regulated by the transcription factor NF-B. NF-B requires, as a coactivating factor, the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1). Prior studies have shown a requirement for PARP-1 in NF-B-mediated microglial gene transcription, integrin expression, morphologic changes, migration, and neuroto...

Inhibition of Poly(ADP-Ribose) Polymerase Suppresses Inflammation and Promotes Recovery after Ischemic Injury

“…Brains harvested at serial time points after forebrain ischemia showed microglial activation that was evident within 24 h and peaked approximately 3 days after ischemia (Figure 2A), consistent with prior reports (Hamby et al, 2007;Sugawara et al, 2002). Administration of the PARP inhibitor, PJ34, beginning 48 h after ischemia reduced microglial activation to basal levels within 24 h (Figure 2A and 2B).…”

“…Extensive activation of PARP-1 can promote cell death in ischemia and other conditions through a process involving NAD + depletion and mitochondrial release of apoptosis inducing factor (Jagtap and Szabo, 2005). By an entirely separate mechanism, PARP-1 may also contribute to injury after ischemia through its influence on the cellular inflammatory response (Hamby et al, 2007;Moroni, 2008;Oliver et al, 1999).…”

Deletion of Nuclear Factor kappa B p50 Subunit Decreases Inflammatory Response and Mildly Protects Neurons from Transient Forebrain Ischemia-induced Damage

“…Genetic inhibition of the canonical NF-κB pathway specifically in neurons has shown protective effect in focal ischemia models [37,38], and therefore, the neuroprotective effect seen in this study was likely due to direct modulation of cell death/survival pathways in neurons as suggested previously [23][24][25]. However, the inflammatory response can exacerbate neuronal death in the hippocampus [6][7][8][9]. Microglia undergoing the socalled M1-type pro-inflammatory activation can produce a number of cytotoxic mediators [39], and it has also been recently shown that microglia can phagocytose otherwise viable neurons and thus promote delayed neuronal death [10].…”

Microglial Activation in Stroke: Therapeutic Targets

“…It is important, however, to place this approach in context. Although there is now strong evidence that the inflammatory response can exacerbate ischemic injury, [13][14][15][16][17][18] there is also evidence that some aspects of the inflammatory response are important for tissue repair. These aspects include phagocytosis of cell debris, remodeling of the extracellular matrix, and the release of cytokines and trophic factors.…”