PDGF Suppresses Oxidative Stress Induced Ca<sup>2+</sup> Overload and Calpain Activation in Neurons

Zheng, Lian-Shun; Ishii, Yoko; Zhao, Qing-Li; Kondo, Takashi; Sasahara, Masakiyo

doi:https://doi.org/10.1155/2013/367206

Oxidative Medicine and Cellular Longevity

On this page

Abstract Introduction Results Discussion Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2013 | Article ID 367206 | https://doi.org/10.1155/2013/367206

PDGF Suppresses Oxidative Stress Induced Ca²⁺ Overload and Calpain Activation in Neurons

Lian-Shun Zheng,^1,2Yoko Ishii,²Qing-Li Zhao,³Takashi Kondo,³and Masakiyo Sasahara²

Academic Editor: Luisa Minghetti

Received04 Oct 2013

Accepted04 Dec 2013

Published24 Dec 2013

Abstract

Oxidative stress is crucially involved in the pathogenesis of neurological diseases such as stroke and degenerative diseases. We previously demonstrated that platelet-derived growth factors (PDGFs) protected neurons from H₂O₂-induced oxidative stress and indicated the involvement of PI3K-Akt and MAP kinases as an underlying mechanism. Ca²⁺ overload has been shown to mediate the neurotoxic effects of oxidative stress and excitotoxicity. We examined the effects of PDGFs on H₂O₂-induced Ca²⁺ overload in primary cultured neurons to further clarify their neuroprotective mechanism. H₂O₂-induced Ca²⁺ overload in neurons in a dose-dependent manner, while pretreating neurons with PDGF-BB for 24 hours largely suppressed it. In a comparative study, the suppressive effects of PDGF-BB were more potent than those of PDGF-AA. We then evaluated calpain activation, which was induced by Ca²⁺ overload and mediated both apoptotic and nonapoptotic cell death. H₂O₂-induced calpain activation in neurons in a dose-dependent manner. Pretreatment of PDGF-BB completely blocked H₂O₂-induced calpain activation. To the best of our knowledge, the present study is the first to demonstrate the mechanism underlying the neuroprotective effects of PDGF against oxidative stress via the suppression of Ca²⁺ overload and inactivation of calpain and suggests that PDGF-BB may be a potential therapeutic target of neurological diseases.

1. Introduction

Oxidative stress and excitotoxicity play important roles in the pathogenesis of a number of neurological diseases, including ischemic infarction, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s, Huntington’s, and Parkinson’s diseases [1–3]. Ca²⁺ has been shown to mediate the cytotoxicity of oxidative stress and excitotoxicity, and cellular Ca²⁺ overload or the perturbation of intracellular Ca²⁺ compartmentalization induced by these noxious stimuli can cause cytotoxicity and trigger cell death including both apoptotic and necrotic cell death [4–6]; however, these mechanisms of cellular injury have yet to be elucidated in adequate detail to prevent and treat neurological diseases [7, 8].

Calpains are calcium-regulated cysteine proteases that have been implicated in the regulation of cell death pathways including apoptosis and necrosis [9, 10]. An elevated intracellular calcium concentration will hyperactivate calpains. The activation of calpains was shown to be involved in various pathological conditions, including ischemic brain injuries and chronic neurodegenerative diseases, for example, Alzheimer’s disease [9, 11]. Previous studies reported that calpain inhibitors were neuroprotective in free radical injury models associated with mitochondrial dysfunction [12], apoptotic injury following spinal cord trauma [13], and traumatic brain injury [14]. Neural degeneration and apoptosis were shown to be ameliorated in calpain-1 null mice following traumatic brain injury [15]. Therefore, suppressing Ca²⁺ overload and the activation of calpain are a crucial strategy to overcome neurological diseases mediated by oxidative stress and excitotoxicity.

The platelet-derived growth factor (PDGF) family members, PDGF-A, -B, -C, and -D, are assembled as disulfide-linked homo- or heterodimers, and two receptor tyrosine kinases, PDGFR-α and -β, which can form homo- and heterodimeric receptor complexes, have been identified [16]. PDGFR-αα was previously shown to be activated by PDGF-AA, -AB, -CC, and -BB, PDGFR-αβ by PDGF-AB, -BB, and -CC, and PDGFR-ββ by PDGF-BB and -DD.

Previous studies demonstrated that PDGF and PDGFRs were widely expressed in the central nervous system (CNS) [17–19]. A neuroprotective role has been hypothesized based on the findings of a number of studies; either the suppression of PDGF-B or conditional deletion of the PDGFR-β gene resulted in the enhanced vulnerability of the CNS to excitotoxicity or ischemia [20–22]. Furthermore, our recent studies demonstrated that PDGF-AA and -BB protected cultured neurons against oxidative stress and suppressed H₂O₂-induced caspase-3 activation through PDGFR-α or -β expressed on these cells [23]. In this study, PI3-K/Akt and MAP kinase pathways were suggested to mediate neuroprotective effects. PDGF-CC was reported to exert neuroprotective effects through the activation of GSK3beta both in vivo and vitro [24]. However, the neuroprotective mechanism underlying PDGFR signaling has not yet been clarified.

We herein identified another neuroprotective pathway mediated by PDGFs. PDGF-AA and PDGF-BB suppressed the Ca²⁺ overload induced by H₂O₂ in primary cultured mouse cortical neurons. Furthermore, PDGF-BB attenuated the H₂O₂-induced activation of calpain, which is one of the key molecules of neuronal dysfunction induced by oxidative stress and Ca²⁺ overload [10]. Therefore, this study provides a novel insight into the mechanism underlying the neuroprotective effects of PDGF against oxidative stress.

2. Experimental Procedures

2.1. Mice

We used wild-type C57BL/6J mice (Sankyo Laboratory, Toyama, Japan). Mice were maintained with free access to laboratory pellet chow and water and exposed to a 12 h light/12 h dark cycle. All animal procedures were performed according to the Institutional Animal Care and Use Committee Guidelines at the University of Toyama under an approved protocol.

2.2. Cell Cultures

Cell cultures were established as previously mentioned [23]. Briefly, cerebral cortices were dissected from neonatal mice on postnatal day 1, enzymatically dissociated in 0.1% trypsin (Nacalai Tesque, Kyoto, Japan) for 5 min at 37°C, and were then mechanically dissociated with fire-polished Pasteur pipettes. Following centrifugation (150 ×g for 5 min), cells were resuspended in Dulbecco’s modified Eagle’s medium (DMEM)/F12 medium (1 : 1; Invitrogen, Carlsbad, CA) containing 10% fetal bovine serum (FBS; HyClone, Yokohama, Japan) and were maintained in serum-free neurobasal medium supplemented with 1% B27 supplement (Invitrogen), 2 mM L-glutamine (Sigma, Louis, MO), 100 units/mL penicillin (Invitrogen), and 0.1 mg/mL streptomycin (Invitrogen). Cells were then plated on glass-bottomed culture dishes (P35G-0-10-C, MatTek, Ashland, MA) at a density of cells/cm² to determine the intracellular concentration of the calcium ion (). To determine calpain activity, cells were plated on 24-well plates (BD Biosciences, San Jose, CA) at a density of cells/cm². All dishes and plates were precoated with 0.001% poly-L-lysine (Sigma). Fresh medium was added every 3 days and cultures were maintained. Fewer than 5% of cultured cells were glia because more than 95% were MAP-2-positive neurons with morphologically mature features, such as extending neurites, at 7 days in vitro (DIV).

2.3. Drug Treatments

Recombinant human PDGF-AA and PDGF-BB were purchased from Chemicon (Temecula, CA). Oxidative stress was induced by a treatment with H₂O₂ for 24 h at DIV 7 as previously described [23]. To investigate the effects of PDGF on H₂O₂-induced , neurons were pretreated with PDGF for 24 h. After loading Fura-2-AM (Dojindo, Kumamoto, Japan), cells were transferred into fresh media containing H₂O₂. PDGF was not included in this fresh medium in order to avoid the acute effects of freshly provided PDGF on . To determine the effects of PDGF on H₂O₂-induced calpain activity, neurons pretreated with PDGF for 24 or 48 h were exposed to H₂O₂ prepared in media containing PDGF for 24 h and were then processed to determine calpain activity.

2.4. Ca²⁺ Imaging Analysis: Determination of the Intracellular Concentration of Calcium Ions

was evaluated as described elsewhere [25, 26]. Briefly, 1 μM Fura-2-AM (Dojindo) solution was prepared using loading buffer, which was HEPES-buffered Ringer solution supplemented with 0.2% bovine serum albumin (Sigma), Eagle’s minimal essential amino acids (Flow Laboratories, Surrey UK), and 2 mM L-glutamine. HEPES-buffered Ringer solution (pH 7.4) contained 118 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl₂, 1.13 mM MgCl₂, 1 mM Na₂HPO₄, 5.5 mM glucose, and 10 mM HEPES-KOH. After the 24 h PDGF pretreatment, cells were washed with PBS and loaded with 1 μM Fura-2-AM solution for 15 min at room temperature (25°C). Cells were washed twice with PBS, which was then replaced with cultured media supplemented with or without H₂O₂ for up to 30 min. Digital images of Fura-2 fluorescence were acquired and analyzed by a digital image processor (Argus 50/CA, Hamamatsu Photonics, Hamamatsu, Japan) coupled with an inverted fluorescent microscope [25]. The ratio of 510 nm emission fluorescence at 340 nm excitation to that at 380 nm excitation, F (340/380), was used as an indicator of in cortical neurons. Pseudocolor images of individual cells and mean F (340/380) values were obtained 15 and 30 min after the treatment with H₂O₂.

2.5. Calpain Activity Assay

Activated calpain released into the cytosol was extracted, and the activities of calpain-1 and -2 were determined using the Calpain Activity Assay kit (Biovision, Milpitas, CA) according to the manufacturer’s instruction. Briefly, cultured neurons were incubated with lysis buffer for 20 min at 4°C. Clarified cell lysates after centrifugation were incubated with reaction buffer containing a substrate of calpain (Ac-LLY-AFC) for 1 h at 37°C in the dark. Upon cleavage of the substrate, the fluorogenic portion (7-amino-4-trifluoromethyl coumarin) yielded 505 nm fluorescence emission at 400 nm excitation. Fluorescence emission was measured by a standard fluorimeter (FilterMax F5, Molecular Devices, Sunnyvale, CA). Control reactions were performed for each sample in the presence of an inhibitor of calpain-1 and -2 to monitor any calpain-independent proteolysis of the fluorogenic peptide. Values from control reactions were subtracted from total activity values to specifically determine calpain activity for each sample. Results are expressed as relative fluorescence units per milligram of lysate protein.

3. Statistical Analysis

Quantitative data were expressed as means ± SEM, and each experiment was repeated at least three times. A one-way ANOVA followed by Fisher’s PLSD test used for statistical analysis, with values less than 0.05 was being considered significant.

4. Results

4.1. PDGF-BB Attenuated the H₂O₂-Induced Increase in the Intracellular Calcium Ion Concentration

The neuroprotective effects of PDGFs against H₂O₂ have been reported previously [23]; therefore, we examined the effects of PDGFs on the H₂O₂-induced overload of , which has been implicated in oxidative stress-induced cellular injury [27, 28]. On in situ pseudocolor images, control neurons that were not exposed to H₂O₂ frequently showed low , and many neurons showed high after H₂O₂ at 15 and 30 min (Figure 1(a)). The number of neurons showing high after H₂O₂ appeared to be decreased by the 24 h pretreatment with PDGF-BB at both 15 and 30 min (Figure 1(a)). The means of evaluated from these images demonstrated that the PDGF-BB pretreatment did not affect in the control neurons without H₂O₂ exposure (Figure 1(b)). The H₂O₂ treatment increased in neurons in a dose-dependent manner up to 5 and 20 μM at 15 and 30 min, respectively, (Figure 1(b)). This H₂O₂-induced overload was completely abolished by the PDGF-BB pretreatment under all conditions examined.

(a)

(b)

(c)

(d)

Figure 1

Effects of PDGF-AA and PDGF-BB on the H₂O₂-induced increase in . was determined using Fura-2-AM fluorescent dye. (a) Pseudocolor images representing the relative indicated by the fluorescence ratio between 340 and 380 nm (F340/380) in individual cortical neurons 15 and 30 min after the H₂O₂ treatment. Following a 24 h preincubation with 50 ng/mL PDGF-BB, neurons were loaded with Fura-2-AM and exposed to different concentrations of H₂O₂ (5, 10, and 20 μM). The inserted bar indicates the relationship between colors and fluorescent intensity ratios at 340 and 380 nm. (b) Histogram analyses of the mean F340/380 of (a). Three pictures were taken from each well, and the means of the F340/380 of each neuron were calculated. Data are expressed as means ± SEM derived from three different sets of experiments. (c) To compare the effects of PDGF-AA and PDGF-BB on overload induced by H₂O₂, cells were pretreated with 50 ng/mL PDGF-AA or PDGF-BB for 24 h followed by exposure to 10 μM H₂O₂ for 15 and 30 min. (d) Histogram analysis of (c). Data are expressed as means ± SEM of three independent experiments. and versus the untreated control; versus the same H₂O₂ exposure without the PDGF pretreatment; and versus the same H₂O₂ exposure with the PDGF-AA pretreatment.

We then compared the effect of PDGF-AA and -BB on overload after the H₂O₂ treatment. On in situ pseudo-color images of relative , many neurons showed high after the 10 μM H₂O₂ treatment (Figure 1(c)). Either the PDGF-AA or PDGF-BB pretreatment appeared to decrease the number of neurons showing high after 10 μM H₂O₂ (Figure 1(c)). Analyses of the mean indicated that either the PDGF-AA or PDGF-BB pretreatment did not affect in the control neurons without H₂O₂ treatment (Figure 1(d)). The H₂O₂ treatment significantly induced overload at 15 and 30 min. PDGF-AA significantly inhibited this overload. This inhibition was partial, and after H₂O₂ in neurons pretreated with PDGF-AA was significantly higher than that in control neurons without the H₂O₂ treatment. in neurons pretreated with PDGF-BB was significantly lower than that in neurons pretreated with PDGF-AA at 15 and 30 min and was similar to that in the controls at 30 min.

4.2. PDGF-BB Attenuated the H₂O₂-Induced Increase in Active Calpain

Because the PDGF pretreatment suppressed H₂O₂-induced overload, we examined whether PDGF suppressed calpain activation, which is a downstream mediator of overload that induces cellular injury. We determined the activities of calpain-1 and -2, as these were shown to be the major subtypes of the calpain family that mediate neurological diseases [9]. The H₂O₂ treatment activated calpain in cultured neurons in a dose-dependent manner from 5 μM to 20 μM, and their activities remained high to similar extents from 20 μM to 80 μM of H₂O₂ (Figure 2(a)). H₂O₂-induced calpain activation in neurons pretreated for 24 h with PDGF-BB significantly decreased from 5 to 20 μM of H₂O₂ to a similar level as that in neurons without the H₂O₂ treatment (Figure 2(b)). Although H₂O₂-induced calpain activation in neurons pretreated for 48 h with PDGF-BB appeared to be decreased to lower levels than the control, this difference was not significant (Figure 2(c)).

(a)

(b)

(c)

Figure 2

Effects of PDGF-BB on H₂O₂-induced calpain activation. Calpain-1 activity was measured 24 h after exposure to H₂O₂ as described in the Experimental procedures. (a) Calpain activity induced by the indicated amounts of H₂O₂ (5, 10, 20, 40, and 80 μM) exposure increased calpain activation in cortical neurons in a dose-dependent manner from 5–20 μM. ((b), (c)) Calpain activity in neuronal cultures pretreated with 50 ng/mL PDGF-BB 24 h (b) and 48 h (c) before exposure to H₂O₂ PDGF-BB completely blocked calpain activity induced by H₂O₂. Data are expressed as means ± SEM of three independent experiments. and versus the untreated control; and versus the same H₂O₂ exposure without the PDGF-BB pretreatment.

5. Discussion

In the present study, we examined a PDGF-mediated neuroprotective pathway against H₂O₂-induced oxidative stress. Increased cytosolic Ca²⁺ and subsequent calpain activation represent one of the major pathways underlying reactive oxidative species (ROS)-mediated cell death [9]. In the present study, the H₂O₂-induced Ca²⁺ increase and calpain activation in cultured neurons were markedly suppressed by PDGF and were suggested to be the targets of a neuroprotective mechanism by PDGF.

The oxidative stress-induced Ca²⁺ overload in cultured neurons was markedly suppressed by PDGF-BB and, to a lesser extent, by PDGF-AA. The oxidative stress-induced inward Ca²⁺ current has been shown to trigger several downstream lethal reactions, including nitrosative and oxidative stress, mitochondrial dysfunction, and protease and phospholipase activation, which culminate in cell death [5, 28]. This Ca²⁺-pathway may be one of the central mechanisms underlying the death of neurons subjected to ischemia and energy deprivation. The Ca²⁺ chelator BAPTA/AM was shown to induce a decrease in intracellular Ca²⁺ and almost completely blocked H₂O₂-induced apoptosis [29]. Thus, the inhibition of Ca²⁺ overload may be one mechanism underlying PDGF-mediated neuroprotection [30], and this mechanism could correspond, at least partly, to the PDGF-induced suppression of neuronal cell death exposed to H₂O₂ [23]. A previous study demonstrated that NGF and bFGF protected cultured hippocampal neurons by suppressing increases in Ca²⁺ due to glucose deprivation, which was consistent with our results [31].

In the present study, PDGF-AA significantly suppressed H₂O₂-induced Ca²⁺ overload. PDGF-BB suppressed Ca²⁺ overload more potently than PDGF-AA. PDGF-BB was previously shown to activate two types of PDGFRs to high levels, while PDGF-AA activated PDGFR-α, but not PDGFR-β in cultured neurons [23]. Accordingly, two types of PDGFR were suggested to mediate the suppressive effects of Ca²⁺ overload, respectively, and the additive effects of the two activated PDGFRs may explain the more potent effects of PDGF-BB than those of PDGF-AA. Alternatively, distinctive signaling downstream of these two PDGFRs may account for the different effects of PDGF-AA and -BB; for example, PDGFR-β was shown to potently activate the PI3-Akt pathway, whereas it activated the MAP kinase pathway to a similar extent to that of PDGFR-α, as demonstrated in a PDGFR-β knockout study in cultured neurons [23].

Calpain has been shown to be activated by either ROS or NMDA-induced Ca²⁺ overload [32]. Calpain 1 (μ-calpain) and calpain 2 (m-calpain) exist as a proenzyme heterodimer (80 kDa–29 kDa) in resting cells, and they are activated by Ca²⁺ in autolytic processing (to produce a heterodimer 78 kDa–18 kDa) [9, 10]. This activated calpain further disturbs mitochondrial Ca²⁺ metabolism and plays a pivotal role in inducing distinctive types of cell death including apoptosis, necrosis, and autophagy [9, 10, 33]; for example, calpain-1 mediated the cleavage of autophagy-related gene 5, which is a critical switch from protective autophagy to cell death in the presence of apoptotic stimuli [33]. In our previous study conducted in the same experimental condition as present study, PDGF-BB suppressed both apoptotic and nonapoptotic cell death induced by H₂O₂ [23]. Accordingly, these findings indicate that the suppressive effects of PDGF on calpain activity may correspond to the neuroprotective effects of PDGF including apoptotic and non-apoptotic prosurvival mechanisms.

Evidence is accumulating to show that Ca²⁺ overload and the activation of calpain mediate excitotoxic neuronal injury [9, 34–36]. PDGF-B protected primary cultured neurons from NMDA-induced excitotoxicity [37]. We reported that the suppression of PDGF-B mRNA expression by antisense oligonucleotides exaggerated NMDA-induced excitotoxicity in neonatal rat brains [20] and that adult mouse brains that expressed reduced levels of neuronal PDGFR-β had more lesions after NMDA-induced excitotoxicity or cryogenic injury [21]. Accordingly, the effects of PDGF on Ca²⁺ overload and calpain activation shown in the present study may correspond to the underlying mechanism of PDGF to suppress excitotoxicity. An inward Ca²⁺ current after oxidative stress was shown to be evoked through NMDA receptors and transient receptor potential (TRP) channels, which belong to a group of ion channels [1, 38]. PDGF suppressed the inward Ca²⁺ current through NMDA receptors [39, 40], which may be involved in the antiexcitotoxic effect of PDGF; however, further studies are required to clarify the effects of PDGF on neuronal cell metabolism [30].

A previous report demonstrated that PDGF-AA and PDGF-BB protected hippocampal neurons subjected to glucose deprivation or exposed to the hydroxyl radical-promoting agent, FeSO₄, due to the induction of antioxidant enzymes [41]. The activation of Akt and MAP kinase was shown to mediate prosurvival effects in neurons exposed to H₂O₂-induced oxidative stress [23]. PDGF-CC exerted neuroprotective effects via the activation of GSK3beta [24]. Therefore, the presently reported effects on Ca²⁺ and calpain metabolism were suggested to be a novel neuroprotective mechanism of PDGF. Calpain and Ca²⁺ elevations have been shown to mediate both acute and chronic cell death, such as ischemic/traumatic brain injuries and Alzheimer’s disease, respectively [9, 10]. Our studies identified PDGF as a potential therapeutic intervention in neurons exposed to oxidative stress. Further studies are needed to investigate the role of PDGF-BB in the pathway of neuronal death induced by oxidative stress.

PDGF-BB is one of the intrinsic neurotrophic factors abundantly expressed in the brain and is upregulated in response to brain insults [17, 42]. In parallel to the on-going clinical phase I/II trial of PDGF-BB in Parkinson’s patients [43], further basic studies are required to find out the effective therapeutic strategies targeting PDGF-BB.

Acknowledgments

The authors thank members of the Department of Pathology and Life Science Research Center, University of Toyama, for thoughtful discussion and careful animal care. This project was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Contract Grant nos. 23590444 (to Yoko Ishii) and 25293093 (to Masakiyo Sasahara).

References

L. M. Sayre, G. Perry, and M. A. Smith, “Oxidative stress and neurotoxicity,” Chemical Research in Toxicology, vol. 21, no. 1, pp. 172–188, 2008.
View at: Publisher Site | Google Scholar
P. H. Chan, K. Niizuma, and H. Endo, “Oxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival,” Journal of Neurochemistry, vol. 109, no. 1, pp. 133–138, 2009.
View at: Publisher Site | Google Scholar
S. Gandhi and A. Y. Abramov, “Mechanism of oxidative stress in neurodegeneration,” Oxidative Medicine and Cellular Longevity, vol. 2012, Article ID 428010, 11 pages, 2012.
View at: Publisher Site | Google Scholar
C. Krieger and M. R. Duchen, “Mitochondria, Ca²⁺ and neurodegenerative disease,” European Journal of Pharmacology, vol. 447, no. 2-3, pp. 177–188, 2002.
View at: Publisher Site | Google Scholar
S. Orrenius, B. Zhivotovsky, and P. Nicotera, “Regulation of cell death: the calcium-apoptosis link,” Nature Reviews Molecular Cell Biology, vol. 4, no. 7, pp. 552–565, 2003.
View at: Publisher Site | Google Scholar
R. Rizzuto, D. de Stefani, A. Raffaello, and C. Mammucari, “Mitochondria as sensors and regulators of calcium signaling,” Nature Review Molecular Cell Biology, vol. 13, no. 9, pp. 566–578, 2012.
View at: Publisher Site | Google Scholar
A. Reynolds, C. Laurie, R. Lee Mosley, and H. E. Gendelman, “Oxidative stress and the pathogenesis of neurodegenerative disorders,” International Review of Neurobiology, vol. 82, pp. 297–325, 2007.
View at: Publisher Site | Google Scholar
I. Nikić, D. Merkler, C. Sorbara et al., “A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis,” Nature Medicine, vol. 17, no. 4, pp. 495–499, 2011.
View at: Publisher Site | Google Scholar
Y. Huang and K. K. W. Wang, “The calpain family and human disease,” Trends in Molecular Medicine, vol. 7, no. 8, pp. 355–362, 2001.
View at: Publisher Site | Google Scholar
M. B. Bevers and R. W. Neumar, “Mechanistic role of calpains in postischemic neurodegeneration,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 4, pp. 655–673, 2008.
View at: Publisher Site | Google Scholar
P. S. Vosler, Y. Gao, C. S. Brennan et al., “Ischemia-induced calpain activation causes eukaryotic (translation) initiation factor 4G1 (eIF4GI) degradation, protein synthesis inhibition, and neuronal death,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 44, pp. 18102–18107, 2011.
View at: Publisher Site | Google Scholar
C. Volbracht, E. Fava, M. Leist, and P. Nicotera, “Calpain inhibitors prevent nitric oxide-triggered excitotoxic apoptosis,” NeuroReport, vol. 12, no. 17, pp. 3645–3648, 2001.
View at: Google Scholar
S. K. Ray, D. D. Matzelle, E. A. Sribnick, M. K. Guyton, J. M. Wingrave, and N. L. Banik, “Calpain inhibitor prevented apoptosis and maintained transcription of proteolipid protein and myelin basic protein genes in rat spinal cord injury,” Journal of Chemical Neuroanatomy, vol. 26, no. 2, pp. 119–124, 2003.
View at: Publisher Site | Google Scholar
K. E. Saatman, J. Creed, and R. Raghupathi, “Calpain as a therapeutic target in traumatic brain injury,” Neurotherapeutics, vol. 7, no. 1, pp. 31–42, 2010.
View at: Publisher Site | Google Scholar
K. H. Yamada, D. A. Kozlowski, S. E. Seidl et al., “Targeted gene inactivation of calpain-1 suppresses cortical degeneration due to traumatic brain injury and neuronal apoptosis induced by oxidative stress,” Journal of Biological Chemistry, vol. 287, no. 16, pp. 13182–13193, 2012.
View at: Publisher Site | Google Scholar
M. Tallquist and A. Kazlauskas, “PDGF signaling in cells and mice,” Cytokine and Growth Factor Reviews, vol. 15, no. 4, pp. 205–213, 2004.
View at: Publisher Site | Google Scholar
M. Sasahara, J. W. U. Fries, E. W. Raines et al., “PDGF B-chain in neurons of the central nervous system, posterior pituitary, and in a transgenic model,” Cell, vol. 64, no. 1, pp. 217–227, 1991.
View at: Google Scholar
H.-J. Yeh, K. G. Ruit, Y.-X. Wang, W. C. Parks, W. D. Snider, and T. F. Deuel, “PDGF a-chain gene is expressed by mammalian neurons during development and in maturity,” Cell, vol. 64, no. 1, pp. 209–216, 1991.
View at: Google Scholar
L. J. Reigstad, J. E. Varhaug, and J. R. Lillehaug, “Structural and functional specificities of PDGF-C and PDGF-D, the novel members of the platelet-derived growth factors family,” The FEBS Journal, vol. 272, no. 22, pp. 5723–5741, 2005.
View at: Publisher Site | Google Scholar
T. Egawa-Tsuzuki, M. Ohno, N. Tanaka et al., “The PDGF B-chain is involved in the ontogenic susceptibility of the developing rat brain to NMDA toxicity,” Experimental Neurology, vol. 186, no. 1, pp. 89–98, 2004.
View at: Publisher Site | Google Scholar
Y. Ishii, T. Oya, L. Zheng et al., “Mouse brains deficient in neuronal PDGF receptor-β develop normally but are vulnerable to injury,” Journal of Neurochemistry, vol. 98, no. 2, pp. 588–600, 2006.
View at: Publisher Site | Google Scholar
J. Shen, Y. Ishii, G. Xu et al., “PDGFR-Β as a positive regulator of tissue repair in a mouse model of focal cerebral ischemia,” Journal of Cerebral Blood Flow and Metabolism, vol. 32, no. 2, pp. 353–367, 2012.
View at: Publisher Site | Google Scholar
L. Zheng, Y. Ishii, A. Tokunaga et al., “Neuroprotective effects of PDGF against oxidative stress and the signaling pathway involved,” Journal of Neuroscience Research, vol. 88, no. 6, pp. 1273–1284, 2010.
View at: Publisher Site | Google Scholar
Z. Tang, P. Arjunan, C. Lee et al., “Survival effect of PDGF-CC rescues neurons from apoptosis in both brain and retina by regulating GSK3β phosphorylation,” Journal of Experimental Medicine, vol. 207, no. 4, pp. 867–880, 2010.
View at: Publisher Site | Google Scholar
Y. Arai, T. Kondo, K. Tanabe et al., “Enhancement of hyperthermia-induced apoptosis by local anesthetics on human histiocytic lymphoma U937 cells,” Journal of Biological Chemistry, vol. 277, no. 21, pp. 18986–18993, 2002.
View at: Publisher Site | Google Scholar
Q.-L. Zhao, Y. Fujiwara, and T. Kondo, “Mechanism of cell death induction by nitroxide and hyperthermia,” Free Radical Biology and Medicine, vol. 40, no. 7, pp. 1131–1143, 2006.
View at: Publisher Site | Google Scholar
M. Ankarcrona, J. M. Dypbukt, E. Bonfoco et al., “Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function,” Neuron, vol. 15, no. 4, pp. 961–973, 1995.
View at: Google Scholar
C. Chinopoulos and V. Adam-Vizi, “Calcium, mitochondria and oxidative stress in neuronal pathology: novel aspects of an enduring theme,” The FEBS Journal, vol. 273, no. 3, pp. 433–450, 2006.
View at: Publisher Site | Google Scholar
S.-E. Choi, S.-H. Min, H.-C. Shin, H.-E. Kim, M. W. Jung, and Y. Kang, “Involvement of calcium-mediated apoptotic signals in H₂O₂-induced MIN6N8a cell death,” European Journal of Pharmacology, vol. 547, no. 1–3, pp. 1–9, 2006.
View at: Publisher Site | Google Scholar
K. Funa and M. Sasahara, “The toles of PDGF in development and during neurogenesis in the normal and diseased nervous system,” The Jourmnal of Neuroimmune Pharmacology, 2013.
View at: Publisher Site | Google Scholar
B. Cheng, D. C. McMahon, and M. P. Mattson, “Modulation of calcium current, intracellular calcium levels and cell survival by glucose deprivation and growth factors in hippocampal neurons,” Brain Research, vol. 607, no. 1-2, pp. 275–285, 1993.
View at: Google Scholar
R. Kowara, Q. Chen, M. Milliken, and B. Chakravarthy, “Calpain-mediated truncation of dihydropyrimidinase-like 3 protein (DPYSL3) in response to NMDA and H₂O₂ toxicity,” Journal of Neurochemistry, vol. 95, no. 2, pp. 466–474, 2005.
View at: Publisher Site | Google Scholar
C. Liang, “Negative regulation of autophagy,” Cell Death and Differentiation, vol. 17, no. 12, pp. 1807–1815, 2010.
View at: Publisher Site | Google Scholar
V. Nimmrich, R. Szabo, C. Nyakas et al., “Inhibition of calpain prevents N-methyl-D-aspartate-induced degeneration of the nucleus basalis and associated behavioral dysfunction,” Journal of Pharmacology and Experimental Therapeutics, vol. 327, no. 2, pp. 343–352, 2008.
View at: Publisher Site | Google Scholar
B. D'Orsi, H. Bonner, L. P. Tuffy et al., “Calpains are downstream effectors of bax-dependent excitotoxic apoptosis,” Journal of Neuroscience, vol. 32, no. 5, pp. 1847–1858, 2012.
View at: Publisher Site | Google Scholar
Y. Miao Y, L. D. Dong, J. Chen et al., “Involvement of calpain/p35-p25/Cdk5/NMDAR signaling pathway in glutamate-induced neurotoxicity in cultured rat retinal neurons,” PLoS ONE, vol. 7, no. 8, Article ID e42318, 2012.
View at: Publisher Site | Google Scholar
H. C. Tseng and M. A. Dichter, “Platelet-derived growth factor-BB pretreatment attenuates excitotoxic death in cultured hippocampal neurons,” Neurobiology of Disease, vol. 19, no. 1-2, pp. 77–83, 2005.
View at: Publisher Site | Google Scholar
B. A. Miller and W. Zhang, “TRP channels as mediators of oxidative stress,” Advances in Experimental Medicine and Biology, vol. 704, pp. 531–544, 2011.
View at: Publisher Site | Google Scholar
C. F. Valenzuela, A. Kazlauskas, S. J. Brozowski et al., “Platelet-derived growth factor receptor is a novel modulator of type a γ-aminobutyric acid-gated ion channels,” Molecular Pharmacology, vol. 48, no. 6, pp. 1099–1107, 1995.
View at: Google Scholar
C. Fernando Valenzuela, Z. Xiong, J. F. MacDonald et al., “Platelet-derived growth factor induces a long-term inhibition of N-methyl-D-aspartate receptor function,” Journal of Biological Chemistry, vol. 271, no. 27, pp. 16151–16159, 1996.
View at: Publisher Site | Google Scholar
B. Cheng and M. P. Mattson, “PDGFs protect hippocampal neurons against energy deprivation and oxidative injury: evidence for induction of antioxidant pathways,” Journal of Neuroscience, vol. 15, no. 11, pp. 7095–7104, 1995.
View at: Google Scholar
K. Iihara, M. Sasahara, N. Hashimoto, Y. Uemura, H. Kikuchi, and F. Hazama, “Ischemia induces the expression of the platelet-derived growth factor-B chain in neurons and brain macrophages in vivo,” Journal of Cerebral Blood Flow and Metabolism, vol. 14, no. 5, pp. 818–824, 1994.
View at: Google Scholar
K. Farrell and R. A. Barker, “Stem cells and regenerative therapies for Parkinson’s disease,” Degenerative Neurological and Neuromuscular Disease, vol. 2, pp. 79–92, 2012.
View at: Google Scholar

Copyright

Copyright © 2013 Lian-Shun Zheng et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

1487

Downloads

1673

Citations