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Neuroprotection Signaling Pathway of Nerve Growth Factor and Brain-Derived Neurotrophic Factor Against Staurosporine Induced Apoptosis in Hippocampal H19-7 Cells

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Neuroprotection Signaling Pathway of Nerve Growth Factor and Brain-Derived Neurotrophic Factor Against Staurosporine Induced Apoptosis in Hippocampal H19-7 Cells EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 42, No. 8, 583-595, August 2010 Neuroprotection signaling pathway of nerve growth factor and brain-derived neurotrophic factor against staurosporine induced apoptosis in hippocampal H19-7 cells Truong LX Nguyen1, Chung Kwon Kim1, STS-induced neurotoxicity was mediated by the acti- Jun-Hee Cho4, Kyung-Hoon Lee2,3 and vation of PI3K/Akt signaling through the Trk receptor. Jee-Yin Ahn1,3,5 Keywords: brain-derived neurotrophic factor; cell 1Department of Molecular Cell Biology survival; nerve growth factors; phosphatidylinositol 3 2Department of Anatomy kinase; protein kinase B; receptor, trkA 3Center for Molecular Medicine Samsung Biomedical Research Institute Sungkyunkwan University School of Medicine Introduction Suwon 440-746, Korea The survival function of neurotrophins is mediated 4Posung High School through the activation of two cell surface receptors, Seoul 138-050, Korea 5 the Trk family and the p75 neurotrophin (p75NTR) Corresponding author: Tel, 82-31-299-6134; receptor (Levi-Montalcini, 1987; Huang and Rei- Fax, 82-31-299-6139; E-mail, [email protected] chardt, 2003). The latter binds to all neurotrophins DOI 10.3858/emm.2010.42.8.060 with low affinity, whereas the TrkA, TrkB, and TrkC receptors bind to NGF, BDNF and NT-3 respec- Accepted 15 July 2010 tively (Chao, 2003). TrkA activation is important for Available Online 19 July 2010 the survival and differentiation of neurons. When p75NTR is activated in the absence of a strong Trk Abbreviations: p75NTR, p75 neurotrophin receptor; PI3K, phos- signal, it induces apoptosis of neurons. However, phatidyl inositol 3 kinase; Trk, tropomyosin receptor kinase in the presence of Trk, p75NTR enhances the res- ponse to neurotrophins. These varying responses point to a complex interplay between neurotro- Abstract phin-stimulated survival, differentiation, and apop- tosis pathways (Kaplan and Miller, 1997). Through Neurotrophins protect neurons against excitotoxicity; Trk receptors, neurotrophins activate many intra- however the signaling mechanisms for this protection cellular signaling pathways including those con- remain to be fully elucidated. Here we report that activa- trolled by Ras, leading to the activation of the tion of the phosphatidyl inositol 3 kinase (PI3K)/Akt mitogen activated protein kinase (MAPK), pho- pathway is critical for protection of hippocampal cells spholipase C (PLC)-γ1, and phosphatidyl inositol from staurosporine (STS) induced apoptosis, charac- 3-kinase (PI3K)/Akt, thereby affecting both deve- terized by nuclear condensation and activation of the lopment and function of the nervous system caspase cascade. Both nerve growth factor (NGF) and (Patapoutian and Reichardt, 2001). However, brain-derived growth factor (BDNF) prevent STS-in- PI3K/Akt pathway is particularly important for duced apoptotic morphology and caspase-3 activity mediating neuronal survival under a wide variety of by upregulating phosphorylation of the tropomyosin circumstances (Brunet et al., 2001) and has been found to be sufficient and, in some cases, nece- receptor kinase (Trk) receptor. Inhibition of Trk re- ssary for the trophic-factor-induced cell survival of ceptor by K252a altered the neuroprotective effect of several neuronal cell types (Yao and Cooper, 1995; both NGF and BDNF whereas inhibition of the p75 neu- Dudek et al., 1997; Miller et al., 1997; Philpott et rotrophin receptor (p75NTR) had no effect. Impairment al., 1997). Akt acts both prior to the release of of the PI3K/Akt pathway or overexpression of domi- cytochrome c, by regulating Bcl-2 family member nant negative (DN)-Akt abolished the protective effect activity and mitochondrial function, and subsequent of both neurotrophins, while active Akt prevented cell to the release of cytochrome c, by regulating death. Moreover, knockdown of Akt by si-RNA was able components of the apoptosome. For instance, Akt to block the survival effect of both NGF and BDNF. phosphorylates the pro-apoptotic Bcl-2 family Thus, the survival action of NGF and BDNF against member BAD, thereby inhibiting BAD pro-apoptotic 584 Exp. Mol. Med. Vol. 42(8), 583-595, 2010 functions (Datta et al., 1997; del Peso et al., 1997). cascades including the activation of caspase-9 and Akt also directly phosphorylates and inhibits the 3. Although TrkA mRNA expression is restricted to caspase proteases including caspase 9 (Cardone sensory and sympathetic neurons in the peripheral et al., 1998). In addition to its effects on the nervous system, and cholinergic neurons in the cytoplasmic apoptotic machinery, the PI3K-Akt basal forebrain (Koh et al., 1989; Ip et al., 1993; pathway also regulates apoptosis by suppressing Muragaki et al., 1995), TrkB is broadly expressed the expression of death genes. For example, Akt in various brain regions, with a particular enri- controls a major class of transcription factors-the chment in hippocampal neurons (Barbacid, 1995). Forkhead box transcription factor by phosphory- By contrast, TrkA expression was reported to be lating FOXOs (Forkhead box, group O) and sparse or absent in hippocampal and cortical inhibiting their ability to induce the expression of neurons under physiological conditions (Ip et al., death genes (Biggs et al., 1999; Brunet et al., 1993; Cellerino, 1996; Lee et al., 1998; Friedman, 1999; Kops et al., 1999). 2000). However, neuroprotection by NGF in It has been shown that there is a basic hippocampal and cortical neurons has been difference in the response of neurons in the peri- demonstrated in vitro and in vivo (Zhang et al., pheral nervous system (PNS) and central nervous 1993; Culmsee et al., 1999, 2002; Kume et al., system (CNS) to neurotrophins (Meyer-Franke et 2000). In spite of the prominent effect of NGF and al., 1998; Goldberg and Barres, 2000). In the PNS, BDNF protecting neuronal death in many cell neuronal survival is dependent on the action of types, the possible comparative effects of these distinct neurotrophins upon different cell types. For two neurotrophins on survival of hippocampal example, nerve growth factor (NGF) promotes cell neurons, and underlying signaling mechanism survival in sympathetic and dorsal root ganglia have not yet been elucidated. In this study, we neurons (Crowley et al., 1994; Smeyne et al., determined the role of NGF and BDNF in inhibiting 1994). Accumulating evidence suggests that in the apoptotic cell death and the intracellular signaling CNS, neurons are dependent on a combination of pathway responsible for this protection under multiple factors, including neurotrophins, for their staurosporine (STS) toxicity in H19-7 hippocampal survival by controlling apoptosis. For instance, progenitor cells. The H19-7 cells were generated brain derived neurotrophic factor (BDNF) and by infecting rat E17 hippocampal cells with a neurotrophin-3 (NT-3) are critical for the survival of retroviral vector expressing a temperature sensitive newly generated granule neurons in the mouse SV40 large T antigen; therefore this cell line has a cerebellum (Bates et al., 1999). Multiple studies number of features to measure in vivo have shown that the functions of PI3K in mediating differentiation and apoptosis during development the antiapoptotic effect of NGF in trophic deprived (Eves et al., 1992, 1994). Our results showed that PNS neurons (Yao and Cooper 1995; Klesse et al., both NGF and BDNF protect hippocampal 1999; Crowder and Freeman 1998; Klesse and progenitor cells and primary hippocampal neurons Parada 1998; Meyer-Franke et al., 1998; Vaillant et from STS-induced apoptosis at the level of, or al., 1999). However, in the CNS, it has been upstream of, caspase-3. Moreover, our data reported that PI3K only partially mediates BDNF suggest that the PI3K/Akt is both necessary and mediated survival, revealing neuroprotection by sufficient for these neurotrophins mediated protec- BDNF is also partially dependent on Erk1/2 tion through Trk receptor activation. signaling (Meyer-Franke et al., 1998; Skaper et al., 1998; Takei et al., 1999). Neuronal apoptosis is not restricted to the developmental stage but also occurs in acute and Results chronic neurologic disease conditions eliciting the Staurosporine (STS) induces neuronal apoptosis in loss of neurons. In the adult CNS, neurons H19-7 cells and primary hippocampal neurons undergo excitotoxic cell death following excessive release of glutamate from presynaptic nerve Many important mechanisms involved in apoptosis termini and astrocytes (Olney and Sharpe, 1969; have been determined using STS or mycotoxin, a Choi, 1994). Excitotoxicity is considered a major general protein kinase inhibitor that triggers inducer of cell death in acute neurodegenerative apoptosis in model cell lines (Xia et al., 1995; conditions. Recent advances indicate that apoptosis Jacobsen et al., 1996; Seo and Seo, 2009). The is a prominent contributor to excitotoxicity-induced intracellular signaling of STS induced apoptosis is neuronal loss (Martin et al., 1998; Zipfel et al., dependent on cell type. To determine the effect of 2000), which is characterized by the release of STS induced apoptosis in hippocampal neurons, cytochrome C, allowing the activation of caspase we exposed cultured hippocampal cells to 100 nM Neuroprotection signaling in hippocampal cells 585 Figure 1. Staurosporine induces neuronal apoptosis. (A) Cultured hippocampal neurons were exposed to 100 nM of STS. After 8 h, apoptotic cell death was determined after nuclei staining with DAPI. All the quantitative analysis of apoptotic nuclei in this
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