15‐Deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2) protects neurons from oxidative death via an Nrf2 astrocyte‐specific mechanism independent of PPARγ

Abstract

Astrocytes are critical for the antioxidant support of neurons. Recently, we demonstrated that low level hydrogen peroxide (H 2 O 2 ) facilitates astrocyte-dependent neuroprotection independent of the antioxidant transcription factor Nrf2, leaving the identity of the endogenous astrocytic Nrf2 activator to question. In this study, we show that an endogenous electrophile, 15-deoxy-D12,14-prostaglandin J2 (15d-PGJ2), non-cell autonomously protects neurons from death induced by depletion of the major antioxidant glutathione. Nrf2 knockdown in astrocytes abrogated 15d-PGJ2's neuroprotective effect as well as 15d-PGJ2 facilitated Nrf2-target gene induction. In contrast, knockdown of the transcription factor peroxisome proliferator activated-receptor gamma (PPARc), a well-characterized 15d-PGJ2 target, did not alter 15d-PGJ2 non-cell autonomous neuroprotection. In addition, several PPARc agonists of the thiazolidinedione (TZD) family failed to induce neuroprotection. Unexpectedly, however, the TZD troglitazone (which contains a chromanol moiety found on vitamin E) induced astrocyte-mediated neuroprotection, an effect which was mimicked by the vitamin E analogs alpha-tocopherol or alpha-tocotrienol. Our findings lead to two important conclusions: (i) 15d-PGJ2 induces astrocyte-mediated neuroprotection via an Nrf2 but not PPARc mediated pathway, suggesting that 15d-PGJ2 is a candidate endogenous modulator of Nrf2 protective pathways in astrocytes; (ii) selective astrocyte treatment with analogs or compounds containing the chromanol moiety of vitamin E facilitates non-cell autonomous neuroprotection. Keywords: astrocytes, neuroprotection, Nrf2, PPARc, vitamin E. J. Neurochem. (2013) 124, 536-547.Astrocytes play an integral role in the CNS by regulating blood flow in response to neuronal activity, modulating synaptogenesis and synaptic activity, and providing metabolic intermediates to neurons (Dringen et al. 2000;Barres 2008;Sofroniew and Vinters 2010). In stroke and other CNS disorders, astrocytes contribute to neuroprotection in part by providing antioxidant support, removing excess extracellular levels of the excitotoxic neurotransmitter glutamate and providing a barrier to inflammation (Sofroniew and Vinters 2010). However, astrocytes may also play a detrimental role by contributing to cytokine and chemokine release and forming a barrier to neuronal regeneration (Sofroniew and Vinters 2010 Abbreviations used: 15d-PGJ2, 15-deoxy-D12,14-prostaglandin J2; ARE, antioxidant response element; CNS, central nervous system; COX, cyclooxygenase; H 2 O 2 , hydrogen peroxide; HMOX or HO-1, heme oxygenase-1; L-PGDS, lipocalin prostaglandin D2 synthase; Nrf2, nuclear factor erythroid 2 related factor 2; PPARc, peroxisome proliferator activated-receptor gamma; siRNA, short interfering RNA; TZD, thiazolidinedione.

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

“…Another example is the anti-inflammatory prostaglandin 15d-PGJ 2 , which positively regulates the NRF2 pathway producing a conformational change in KEAP1 protein that allows the translocation of NRF2 to nucleus [38]. Furthermore, NRF2 knockdown in astrocytes abrogated the neuroprotective effect of 15d-PGJ 2 , as well as 15d-PGJ 2 -facilitated ARE-dependent antioxidant enzyme gene induction [9]. Both pathways are regulated by paliperidone in animal models of acute/chronic stress and could be implicated, at least in part, in the effects reported here [25,29].…”

“…PPARγ may be also activated by the antidiabetic thiazolidinedione drugs, which exert anti-inflammatory, antiexcitotoxic, and proenergetic effects in the brains of stressed rats [7,8]. The antioxidant profile of 15d-PGJ 2 / PPARγ may be related to its ability to regulate the nuclear factor erythroid-related factor 2 (NRF2), in brain [9]. Inactive NRF2 is retained in the cytoplasm by association with the kelch-like ECH-associated protein 1 (KEAP1), but during inflammation or oxidative stress, the phosphorylation of some intracellular kinases, such as phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT), elicits the translocation of NRF2 to the nucleus.…”

15-Deoxy-Δ12,14-prostaglandin J2 alleviates hepatic ischemia-reperfusion injury in mice via inducing antioxidant response and inhibiting apoptosis and autophagy

“…Studies have reported that, due to its special α,β- unsaturated carbonyl groups that act as an electrophilic center, 15d-PGJ2 could bind to the cysteine residue of Keap1, separate the Keap1-Nrf2 complex, and thus liberate Nrf2 from Keap1-dependent repression so that Nrf2 accumulates in the nucleus [44] . Indeed, our study observed and detected the nuclear expression of Nrf2 ( Figure 5B, 5C).…”

Redox-Dependent Anti-Inflammatory Signaling Actions of Unsaturated Fatty Acids

“…Similar concentrations of 15d-PGJ 2 enhance reactive oxygen species and induce human neuronal cell death through the modification of Cys35 and Cys69 within thioredoxin, an enzyme important for protection against oxidative stress (112). In contrast, lower concentrations of cyPG administration afford astrocyte-dependent neuroprotection in a GSH depletion model of cell death (113). Thus, excessive α,β-unsaturated ketone concentrations impart proinflammatory effects, impacting disease pathophysiology (114, 115) and emphasizing the need for strict control of the levels of these mediators in vivo.…”