Skip to main content

Advertisement

SpringerLink
Log in

Mechanisms of Platelet-Derived Growth Factor-BB in Restoring HIV Tat-Cocaine-Mediated Impairment of Neuronal Differentiation

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Diminished adult neurogenesis is known to play a key role in the pathogenesis of diverse neurodegenerative disorders such as HIV-associated neurological disorders (HAND). Cocaine, often abused by HIV-infected patients, has been suggested to worsen HIV-associated CNS disease. Mounting evidence also indicates that HIV infection can lead not only to neuronal dysfunction or loss, but can also negatively impact neurogenesis, resulting in generation of fewer adult neural progenitor cells (NPCs) in the dentate gyrus of the hippocampus, brain area critical for memory and learning. The crucial role of platelet-derived growth factor-BB (PDGF-BB) in providing tropic support for the neurons as well as in promoting NPC proliferation has been demonstrated by us previously. However, whether PDGF-BB regulates neuronal differentiation especially in the context of HAND and drug abuse remains poorly understood. In this study, we demonstrate that pretreatment of rat hippocampal NPCs with PDGF-BB restored neuronal differentiation that had been impaired by HIV Tat and cocaine. To further study the intracellular mechanism(s) involved in this process, we examined the role of transient receptor potential canonical (TRPC) channels in mediating neuronal differentiation in the presence of PDGF-BB. TRPC channels are Ca2+-permeable, nonselective cationic channels that elicit a variety of physiological functions. Parallel but distinct ERK, Akt signaling pathways with downstream activation of CREB were found to be critical for neuronal differentiation. Pharmacological blocking of TRPC channels resulted in suppression of PDGF-mediated differentiation and PDGF-BB-induced activation of ERK and Akt, culminating also to inhibition of PDGF-induced activation of CREB. Taken together, these findings underpin the role of TRPC channel as a novel target regulating cell differentiation mediated by PDGF-BB. This finding could have implications for development of therapeutic interventions aimed at restoration of Tat and cocaine-mediated impairment of neurogenesis in drug abusing HAND patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Dhillon NK et al (2007) Cocaine-mediated enhancement of virus replication in macrophages: implications for human immunodeficiency virus-associated dementia. J Neurovirol 13(6):483–495

    Article  CAS  PubMed  Google Scholar 

  2. Yao H et al (2011) Cocaine hijacks sigma1 receptor to initiate induction of activated leukocyte cell adhesion molecule: implication for increased monocyte adhesion and migration in the CNS. J Neurosci 31(16):5942–5955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yang L et al. (2015) Role of sigma receptor in cocaine-mediated induction of glial fibrillary acidic protein: implications for HAND. Mol Neurobiol

  4. Yao H et al (2010) Molecular mechanisms involving sigma receptor-mediated induction of MCP-1: implication for increased monocyte transmigration. Blood 115(23):4951–4962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Venkatesan A et al (2007) Adult hippocampal neurogenesis: regulation by HIV and drugs of abuse. Cell Mol Life Sci 64(16):2120–2132

    Article  CAS  PubMed  Google Scholar 

  6. Bath KG, Lee FS (2010) Neurotrophic factor control of adult SVZ neurogenesis. Dev Neurobiol 70(5):339–349

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Yao H et al (2012) Platelet-derived growth factor-BB restores human immunodeficiency virus Tat-cocaine-mediated impairment of neurogenesis: role of TRPC1 channels. J Neurosci 32(29):9835–9847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Smits A et al (1991) Neurotrophic activity of platelet-derived growth factor (PDGF): rat neuronal cells possess functional PDGF beta-type receptors and respond to PDGF. Proc Natl Acad Sci U S A 88(18):8159–8163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pan YW et al (2012) Inhibition of adult neurogenesis by inducible and targeted deletion of ERK5 mitogen-activated protein kinase specifically in adult neurogenic regions impairs contextual fear extinction and remote fear memory. J Neurosci 32(19):6444–6455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shioda N, Han F, Fukunaga K (2009) Role of Akt and ERK signaling in the neurogenesis following brain ischemia. Int Rev Neurobiol 85:375–387

    Article  CAS  PubMed  Google Scholar 

  11. Sakamoto K, Karelina K, Obrietan K (2011) CREB: a multifaceted regulator of neuronal plasticity and protection. J Neurochem 116(1):1–9

    Article  CAS  PubMed  Google Scholar 

  12. Pan Z, Yang H, Reinach PS (2011) Transient receptor potential (TRP) gene superfamily encoding cation channels. Hum Genomics 5(2):108–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Boudes M et al (2013) Crucial role of TRPC1 and TRPC4 in cystitis-induced neuronal sprouting and bladder overactivity. PLoS One 8(7), e69550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhu X et al (2009) PDGF-mediated protection of SH-SY5Y cells against Tat toxin involves regulation of extracellular glutamate and intracellular calcium. Toxicol Appl Pharmacol 240(2):286–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yang L et al (2013) Involvement of miR-9/MCPIP1 axis in PDGF-BB-mediated neurogenesis in neuronal progenitor cells. Cell Death Dis 4, e960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chao J et al (2014) Platelet-derived growth factor-BB restores HIV Tat-mediated impairment of neurogenesis: role of GSK-3beta/beta-catenin. J Neuroimmune Pharmacol 9(2):259–268

    Article  PubMed  Google Scholar 

  17. Park D et al (2010) Nestin is required for the proper self-renewal of neural stem cells. Stem Cells 28(12):2162–2171

    Article  CAS  PubMed  Google Scholar 

  18. Ming GL, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70(4):687–702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Oliveira SL et al (2013) Functions of neurotrophins and growth factors in neurogenesis and brain repair. Cytometry A 83(1):76–89

    Article  PubMed  Google Scholar 

  20. Krathwohl MD, Kaiser JL (2004) HIV-1 promotes quiescence in human neural progenitor cells. J Infect Dis 190(2):216–226

    Article  CAS  PubMed  Google Scholar 

  21. Funa K, Sasahara M (2014) The roles of PDGF in development and during neurogenesis in the normal and diseased nervous system. J Neuroimmune Pharmacol 9(2):168–181

    Article  PubMed  Google Scholar 

  22. Mohapel P et al (2005) Platelet-derived growth factor (PDGF-BB) and brain-derived neurotrophic factor (BDNF) induce striatal neurogenesis in adult rats with 6-hydroxydopamine lesions. Neuroscience 132(3):767–776

    Article  CAS  PubMed  Google Scholar 

  23. Font MA, Arboix A, Krupinski J (2010) Angiogenesis, neurogenesis and neuroplasticity in ischemic stroke. Curr Cardiol Rev 6(3):238–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Selvaraj S et al (2012) Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling. J Clin Invest 122(4):1354–1367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fortin DA et al (2012) Brain-derived neurotrophic factor activation of CaM-kinase kinase via transient receptor potential canonical channels induces the translation and synaptic incorporation of GluA1-containing calcium-permeable AMPA receptors. J Neurosci 32(24):8127–8137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Boney CM, Smith RM, Gruppuso PA (1998) Modulation of insulin-like growth factor I mitogenic signaling in 3T3-L1 preadipocyte differentiation. Endocrinology 139(4):1638–1644

    Article  CAS  PubMed  Google Scholar 

  27. Reffas S, Schlegel W (2000) Compartment-specific regulation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) by ERK-dependent and non-ERK-dependent inductions of MAPK phosphatase (MKP)-3 and MKP-1 in differentiating P19 cells. Biochem J 352(Pt 3):701–708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Agell N et al (2002) Modulation of the Ras/Raf/MEK/ERK pathway by Ca(2+), and calmodulin. Cell Signal 14(8):649–654

    Article  CAS  PubMed  Google Scholar 

  29. Fukuchi M, Tabuchi A, Tsuda M (2005) Transcriptional regulation of neuronal genes and its effect on neural functions: cumulative mRNA expression of PACAP and BDNF genes controlled by calcium and cAMP signals in neurons. J Pharmacol Sci 98(3):212–218

    Article  CAS  PubMed  Google Scholar 

  30. Kim SY et al (2002) Activation of p38 MAP kinase in the rat dorsal root ganglia and spinal cord following peripheral inflammation and nerve injury. Neuroreport 13(18):2483–2486

    Article  CAS  PubMed  Google Scholar 

  31. Sodhi A, Biswas SK (2002) Monocyte chemoattractant protein-1-induced activation of p42/44 MAPK and c-Jun in murine peritoneal macrophages: a potential pathway for macrophage activation. J Interferon Cytokine Res 22(5):517–526

    Article  CAS  PubMed  Google Scholar 

  32. Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35(4):605–623

    Article  CAS  PubMed  Google Scholar 

  33. Kingsley-Kallesen ML, Kelly D, Rizzino A (1999) Transcriptional regulation of the transforming growth factor-beta2 promoter by cAMP-responsive element-binding protein (CREB) and activating transcription factor-1 (ATF-1) is modulated by protein kinases and the coactivators p300 and CREB-binding protein. J Biol Chem 274(48):34020–34028

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants DA036157 and DA033150 from the National Institutes of Health.

Authorship

Contribution: L.Y. designed and performed research and wrote the manuscript; X.C. performed research; G.H.designed all primers and performed research; Y.C. and K.L performed research and S.B. planned and designed the research and wrote the manuscript.

Author information

Author notes

    Authors and Affiliations

    1. Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center (DRC 8011), University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA

      Lu Yang, Guoku Hu, Yu Cai, Ke Liao & S Buch

    2. The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

      Xufeng Chen

    Authors
    1. Lu Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Xufeng Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Guoku Hu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yu Cai
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Ke Liao
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. S Buch
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to S Buch.

    Ethics declarations

    Conflict of Interest

    The authors declare that they have no competing interests.

    Additional information

    Lu Yang and Xufeng Chen contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Yang, L., Chen, X., Hu, G. et al. Mechanisms of Platelet-Derived Growth Factor-BB in Restoring HIV Tat-Cocaine-Mediated Impairment of Neuronal Differentiation. Mol Neurobiol 53, 6377–6387 (2016). https://doi.org/10.1007/s12035-015-9536-0

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12035-015-9536-0

    Keywords

    Search

    Navigation