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Platelet Activating Factor-Induced Neuronal Apoptosis Is Initiated

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Platelet Activating Factor-Induced Neuronal Apoptosis Is Initiated Journal of Neurochemistry, 2007, 103, 88–97 doi:10.1111/j.1471-4159.2007.04740.x Platelet activating factor-induced neuronal apoptosis is initiated independently of its G-protein coupled PAF receptor and is inhibited by the benzoate orsellinic acid Scott D. Ryan,*,1 Cory S. Harris,*, ,1 Fan Mo,* Haemi Lee,*,à Sheng T. Hou,à Nicolas G. Bazan,§ Pierre S. Haddad,¶ John T. Arnason and Steffany A. L. Bennett* *Department of Biochemistry, Microbiology, and Immunology, Neural Regeneration Laboratory and Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada Department of Biology, University of Ottawa, Ottawa, Ontario, Canada àExperimental Therapeutics Laboratory, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada §Neuroscience Center of Excellence, Louisiana State University, New Orleans, Louisiana, USA ¶Department of Pharmacology, Universite´ de Montre´al, Montre´al, Quebec, Canada Abstract panel of plant and fungal benzoic acid derivatives. We found The bioactive lipid mediator platelet activating factor (PAF) is that the PAF antagonist BN 52021 but not FR 49175 or CV recognized as a key effecter of neuronal apoptosis, yet it is not 3988 inhibited PAFR-independent neurotoxicity. Orsellinic clear whether its G-protein coupled receptor (PAFR) initiates acid, a fungal-derived benzoic acid, blocked PAF-mediated or prevents PAF neurotoxicity. Using PAFR)/) and congenic neuronal apoptosis without affecting PAFR-mediated neuro- wild-type mice, we show that PAF triggers caspase-3/7 protection. These findings demonstrate that PAF can trans- activity and neuronal death in PAFR)/) but not PAFR+/+ duce apoptotic death in primary neurons independently of its cerebellar granule neurons. Restoring receptor expression by G-protein coupled receptor, that PAFR activation is neuro- recombinant adenoviral infection protected cells from PAF protective, and that orsellinic acid effectively attenuates challenge. Neuronal death was not mediated by nitric oxide or PAFR-independent neuronal apoptosis. N-methyl-D-aspartate receptor signaling given that N-nitro- Keywords: apoptosis, benzoic acids, neurotoxicity, orsellinic L-arginine methyl ester and MK-801 did not inhibit PAF- acid, platelet activating factor, platelet activating factor induced neuronal loss in PAFR)/) neurons. To intervene in receptor. PAFR-independent neurotoxicity, the anti-apoptotic actions of J. Neurochem. (2007) 103, 88–97. three structurally distinct PAF antagonists were compared to a The platelet activating factor (PAF: 1-O-alkyl-2-acetyl- sn-glycero-3-phosphocholine) family of glycerophospholi- Received March 21, 2007; revised manuscript received May 3, 2007; pids exerts potent pro-inflammatory and neuromodulatory accepted May 4, 2007. effects in the CNS (Prescott et al. 2000). Under normal Address correspondence and reprint requests to Steffany A. L. Ben- nett, Department of Biochemistry, Microbiology and Immunology, physiological conditions, PAF participates in long-term Neural Regeneration Laboratory, University of Ottawa, 451 Smyth potentiation associated with learning and memory through Road, Ottawa, ON K1H 8M5, Canada. E-mail: [email protected] stimulation of its G-protein coupled receptor (PAFR) (Izqui- 1Both authors contributed equally to this work. erdo et al. 1995; Teather et al. 1998; Kato 1999; Chen et al. Abbreviations used: BSA, bovine serum albumin; CGNs, cerebellar 2001). When concentrations are elevated under pathological granule cells; DMSO, dimethylsulfoxide; EGFP, enhanced green fluor- escent protein; ET, ethidium homodimer; L-NAME, N-nitro-L-arginine conditions, PAF becomes neurotoxic and has been identified methyl ester; NMDA, N-methyl-D-aspartate; NO, nitric oxide; PAF, as a key mediator of neuronal death following ischemia, platelet activating factor; PAF-AH, PAF-acetylhydrolase; PAFR, platelet encephalitis, epileptic seizure, meningitis, and HIV-1 demen- activating factor receptor; PARP, poly(ADP ribose) polymerase. Ó 2007 The Authors 88 Journal Compilation Ó 2007 International Society for Neurochemistry, J. Neurochem. (2007) 103, 88–97 Orsellinic acid inhibits PAF neurotoxicity 89 tia (Birkle et al. 1998; Perry et al. 1998; Bazan et al. 2002; hepten-5,10-imine maleate, 10 lmol/L], N-nitro-L-arginine methyl Farooqui et al. 2006). ester (L-NAME, 5 mmol/L; Biomol Research Laboratories, Plymouth Targeting PAF neurotoxicity is complicated by the fact that Meeting, PA, USA), or the PAF antagonists/inhibitors BN 52021 bioactivity can be signaled through both PAFR-dependent (21 lg/mL), FR 49175 (4 lg/mL), and CV 3988 (1 lg/mL) (Biomol and PAFR-independent pathways. In non-neuronal cells, Research Laboratories). Concentrations employed were based on previous reports (Malipiero et al. 1999; Brewer et al. 2002; Bonin PAFR expression exacerbates cell death initiated by etopo- et al. 2004; Hou et al. 2006). Benzoic acids and PAF inhibitors were side and mitomycin C yet protects cells from tumor necrosis dissolved in dimethylsulfoxide (DMSO). L-NAME and MK-801 were factor a, tumour necrosis factor-related apoptosis inducing dissolved in EtOH. Cells were exposed to a final concentration of ligand (TRAIL), and extracellular PAF exposure (Southall 0.1% vehicle. All treatments were performed in serum-free media as et al. 2001; Brewer et al. 2002; Li et al. 2003). PAF also described below. interacts with intracellular binding sites (Marcheselli et al. 1990; Bratton et al. 1992; Sapir et al. 1997) initiating Congenic PAFR)/) and PAFR+/+ Mice caspase-3-dependent DNA fragmentation in the absence of Breeding pairs of PAFR)/) mice in a hybrid C57BL/6J · 129/Ol PAFR (Bonin et al. 2004). Although cyotoxic signaling can background (Ishii et al. 1998) were the kind gift of Dr Takao be reversed by ectopic PAFR expression (Brewer et al. Shimizu (University of Tokyo, Japan). To insure uniformity in 2002), in neurons, it is not known whether PAF triggers genetic background, animals were backcrossed to C57BL/6 wild- type mice (Charles River Laboratories, Senneville, QC, Canada) for apoptosis through its G-protein coupled receptor or whether 10 generations. Congenic 10th generation PAFR+/+ and PAFR)/) PAFR activation is neuroprotective. colonies were established and maintained from PAFR+/) matings. To address this issue, cerebellar granule cells (CGNs) Animals were genotyped as described by (Nagase et al. 1999). cultured from PAFR+/+ and PAFR)/) mice were treated with apoptotic concentrations of PAF in the absence of serum Primary murine cell culture PAF-acetylhydrolases (PAF-AHs). Here, we show that PAF Cerebellar granule cells were cultured from post-natal day 7–10 elicits caspase-dependent neuronal apoptosis in the absence mice as previously described (Cregan et al. 2000). Briefly, of PAFR, that endogenous PAFR expression protects cells cerebella were dissected, meninges removed, and tissue minced in from PAF neurotoxicity, and that ectopic PAFR expression ice-cold dissection solution [124 mmol/L NaCl, 5.37 mmol/L KCl, confers neuroprotection. To intervene in this death pathway 1 mmol/L NaH2PO4, 1.2 mmol/L MgSO4, 14.5 mmol/L D-glucose, 25 mmol/L HEPES, 3 mg/mL bovine serum albumin (BSA), without affecting PAFR-mediated neuroprotection, we used a pH.7.4]. Tissue was incubated in dissection solution containing 96-well screening approach to identify anti-apoptotic PAF 0.5 mg/mL trypsin (Sigma) at 37°C for 18 min. Trypsin was inhibitors. We found that the non-competitive PAFR antag- deactivated by addition of 0.52 mg/mL chicken egg white trypsin onist BN 52021 but not the PAF inhibitor FR 49175 or the inhibitor and cells were pelleted. Cells were resuspended in competitive PAFR antagonist CV 3988 prevented PAF- dissection solution containing 0.75 mg/mL DNase I (Roche, induced neuronal apoptosis. Within a panel of naturally Mississauga, ON, Canada) and triturated. CaCl2 was added to a occurring benzoic acids, we identified a novel PAF inhibitor. final concentration of 15 lmol/L. Following centrifugation, cells Orsellinic acid, a fungal-derived benzoic acid derivative, were plated in Eagle’s minimum essential medium containing selectively blocked PAF-induced neuronal apoptosis without 25 mmol/L glucose, 10% fetal bovine serum, 1% gentamycin, inhibiting PAFR-mediated neuronal survival. Together, these 2 mmol/L L-glutamine, and 20 mmol/L KCl at 37°C in a 5% CO2/ data highlight a new anti-apoptotic role for PAFR signaling 95% air atmosphere. CGNs were seeded at a density of 2 · 105 cells/cm2 in 96-well plates coated with laminin (20 lg/ and a novel pharmacological means of inhibiting PAF- mL) and poly-D-lysine (100 mg/mL; Sigma-Aldrich) and main- induced neuronal apoptosis. tained in this serum-containing media for 72 h before being exposed to PAF in serum-free media. Cultures were composed >90% neurons as established by immunocytochemistry (data not shown). Materials and methods Cell survival assay Reagents PAF (1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine; Biomol All cell culture reagents were obtained from Invitrogen (Burlington, Research Laboratories) and lyso-PAF (1-O-hexadecyl-sn-glycero-3- ON, Canada) and all chemicals were purchased through Sigma- phosphocholine; Biomol Research Laboratories) were dissolved in Aldrich (St Louis, MO, USA) unless otherwise stated. Pure benzoic treatment media (Eagle’s minimum essential medium containing acid derivatives (>95% purity as determined by HPLC analysis) were 25 mmol/L glucose, 0.025% BSA, 1% gentamycin, 2 mmol/L L- obtained from the phytochemical collections of C. Nozzilillo
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