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Propentofylline: Glial Modulation, Neuroprotection, and Alleviation of Chronic Pain

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Methylxanthines

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 200))

Abstract

Propentofylline is a unique methylxanthine with clear cyclic AMP, phosphodiesterase, and adenosine actions, including enhanced synaptic adenosine signaling. Both in vitro and in vivo studies have demonstrated profound neuroprotective, antiproliferative, and anti-inflammatory effects of propentofylline. Propentofylline has shown efficacy in preclinical models of stroke, opioid tolerance, and acute and chronic pain. Clinically, propentofylline has shown efficacy in degenerative and vascular dementia, and as a potential adjuvant treatment for schizophrenia and multiple sclerosis. Possible mechanisms of action include a direct glial modulation to decrease a reactive phenotype, decrease glial production and release of damaging proinflammatory factors, and enhancement of astrocyte-mediated glutamate clearance. This chapter reviews the literature that supports a myriad of protective actions of this small molecule and implicates propentofylline as a potential therapeutic for the treatment of chronic pain. From these studies, we propose a CNS multipartite synaptic action of propentofylline that includes modulation of pre- and postsynaptic neurons, astrocytes, and microglia in the treatment of chronic pain syndromes, including, but not limited to, neuropathic pain.

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References

  • Arriagada O, Constandil L, Hernandez A, Barra R, Soto-Moyano R, Laurido C (2007) Effects of interleukin-1beta on spinal cord nociceptive transmission in intact and propentofylline-treated rats. Int J Neurosci 117(5):617–625

    Article  PubMed  CAS  Google Scholar 

  • Arruda JL, Sweitzer S, Rutkowski MD, DeLeo JA (2000) Intrathecal anti-IL-6 antibody and IgG attenuates peripheral nerve injury-induced mechanical allodynia in the rat: possible immune modulation in neuropathic pain. Brain Res 879(1–2):216–225

    Article  PubMed  CAS  Google Scholar 

  • Binns BC, Huang Y, Goettl VM, Hackshaw KV, Stephens RL Jr (2005) Glutamate uptake is attenuated in spinal deep dorsal and ventral horn in the rat spinal nerve ligation model. Brain Res 1041(1):38–47

    Article  PubMed  CAS  Google Scholar 

  • Cata JP, Weng HR, Chen JH, Dougherty PM (2006) Altered discharges of spinal wide dynamic range neurons and down-regulation of glutamate transporter expression in rats with paclitaxel-induced hyperalgesia. Neuroscience 138(1):329–338

    Article  PubMed  CAS  Google Scholar 

  • Colburn RW, DeLeo JA, Rickman AJ, Yeager MP, Kwon P, Hickey WF (1997) Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J Neuroimmunol 79(2):163–175

    Article  PubMed  CAS  Google Scholar 

  • Colburn RW, Rickman AJ, DeLeo JA (1999) The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp Neurol 157(2):289–304

    Article  PubMed  CAS  Google Scholar 

  • DeLeo J, Toth L, Schubert P, Rudolphi K, Kreutzberg GW (1987) Ischemia-induced neuronal cell death, calcium accumulation, and glial response in the hippocampus of the Mongolian gerbil and protection by propentofylline (HWA 285). J Cereb Blood Flow Metab 7(6):745–751

    Article  PubMed  CAS  Google Scholar 

  • DeLeo J, Schubert P, Kreutzberg GW (1988a) Propentofylline (HWA 285) protects hippocampal neurons of Mongolian gerbils against ischemic damage in the presence of an adenosine antagonist. Neurosci Lett 84(3):307–311

    Article  PubMed  CAS  Google Scholar 

  • DeLeo J, Schubert P, Kreutzberg GW (1988b) Protection against ischemic brain damage using propentofylline in gerbils. Stroke 19(12):1535–1539

    Article  PubMed  CAS  Google Scholar 

  • Dorazil-Dudzik M, Mika J, Schafer MK, Li Y, Obara I, Wordliczek J, Przewlocka B (2004) The effects of local pentoxifylline and propentofylline treatment on formalin-induced pain and tumor necrosis factor-alpha messenger RNA levels in the inflamed tissue of the rat paw. Anesth Analg 98(6):1566–1573

    Article  PubMed  CAS  Google Scholar 

  • Fredholm BB, Lindstrom K (1986) The xanthine derivative 1-(5'-oxohexyl)-3-methyl-7-propyl xanthine (HWA 285) enhances the actions of adenosine. Acta Pharmacol Toxicol (Copenh) 58(3):187–192

    Article  CAS  Google Scholar 

  • Garrison CJ, Dougherty PM, Kajander KC, Carlton SM (1991) Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res 565(1):1–7

    Article  PubMed  CAS  Google Scholar 

  • Garrison CJ, Dougherty PM, Carlton SM (1994) GFAP expression in lumbar spinal cord of naive and neuropathic rats treated with MK-801. Exp Neurol 129(2):237–243

    Article  PubMed  CAS  Google Scholar 

  • Garry EM, Delaney A, Blackburn-Munro G, Dickinson T, Moss A, Nakalembe I, Robertson DC, Rosie R, Robberecht P, Mitchell R, Fleetwood-Walker SM (2005) Activation of p38 and p42/44 MAP kinase in neuropathic pain: involvement of VPAC2 and NK2 receptors and mediation by spinal glia. Mol Cell Neurosci 30(4):523–537

    Article  PubMed  CAS  Google Scholar 

  • Grome J, Stefanovich V (1985) Differential effects of xanthine derivatives on local cerebral blood flow and glucose utilization in the conscious rat. In: Stefanovich V, Rudolphi R, Schubert P (eds) Adenosine: receptors and modulation of cell function. IRL, Oxford, pp 453–460

    Google Scholar 

  • Gwak YS, Hulsebosch CE (2009) Remote astrocytic and microglial activation modulates neuronal hyperexcitability and below-level neuropathic pain after spinal injury in rat. Neuroscience 161(3):895–903

    Article  PubMed  CAS  Google Scholar 

  • Gwak YS, Crown ED, Unabia GC, Hulsebosch CE (2008) Propentofylline attenuates allodynia, glial activation and modulates GABAergic tone after spinal cord injury in the rat. Pain 138(2):410–422

    Article  PubMed  CAS  Google Scholar 

  • Hashizume H, DeLeo JA, Colburn RW, Weinstein JN (2000) Spinal glial activation and cytokine expression after lumbar root injury in the rat. Spine 25(10):1206–1217

    Article  PubMed  CAS  Google Scholar 

  • Holdridge SV, Armstrong SA, Taylor AM, Cahill CM (2007) Behavioural and morphological evidence for the involvement of glial cell activation in delta opioid receptor function: implications for the development of opioid tolerance. Mol Pain 3:7

    Article  PubMed  Google Scholar 

  • Kuzumaki N, Narita M, Narita M, Hareyama N, Niikura K, Nagumo Y, Nozaki H, Amano T, Suzuki T (2007) Chronic pain-induced astrocyte activation in the cingulate cortex with no change in neural or glial differentiation from neural stem cells in mice. Neurosci Lett 415(1):22–27

    Article  PubMed  CAS  Google Scholar 

  • Meller ST, Dykstra C, Grzybycki D, Murphy S, Gebhart GF (1994) The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat. Neuropharmacology 33(11):1471–1478

    Article  PubMed  CAS  Google Scholar 

  • Miyashita K, Nakajima T, Ishikawa A, Miyatake T (1992) An adenosine uptake blocker, propentofylline, reduces glutamate release in gerbil hippocampus following transient forebrain ischemia. Neurochem Res 17(2):147–150

    Article  PubMed  CAS  Google Scholar 

  • Nagata K, Ogawa T, Omosu M, Fujimoto K, Hayashi S (1985) In vitro and in vivo inhibitory effects of propentofylline on cyclic AMP phosphodiesterase activity. Arzneimittelforschung 35(7):1034–1036

    PubMed  CAS  Google Scholar 

  • Narita M, Suzuki M, Narita M, Niikura K, Nakamura A, Miyatake M, Yajima Y, Suzuki T (2006) mu-Opioid receptor internalization-dependent and -independent mechanisms of the development of tolerance to mu-opioid receptor agonists: comparison between etorphine and morphine. Neuroscience 138(2):609–619

    Article  PubMed  CAS  Google Scholar 

  • Raghavendra V, Tanga F, DeLeo JA (2003a) Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther 306(2):624–630

    Article  PubMed  CAS  Google Scholar 

  • Raghavendra V, Tanga F, Rutkowski MD, DeLeo JA (2003b) Anti-hyperalgesic and morphine-sparing actions of propentofylline following peripheral nerve injury in rats: mechanistic implications of spinal glia and proinflammatory cytokines. Pain 104(3):655–664

    Article  PubMed  CAS  Google Scholar 

  • Raghavendra V, Tanga FY, DeLeo JA (2004) Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rats. Neuropsychopharmacology 29(2):327–334

    Article  PubMed  CAS  Google Scholar 

  • Schubert P, Rudolphi K (1998) Interfering with the pathologic activation of microglial cells and astrocytes in dementia. Alzheimer Dis Assoc Disord 12(Suppl 2):S21–S28

    PubMed  CAS  Google Scholar 

  • Schubert P, Ogata T, Rudolphi K, Marchini C, McRae A, Ferroni S (1997) Support of homeostatic glial cell signaling: a novel therapeutic approach by propentofylline. Ann N Y Acad Sci 826:337–347

    Article  PubMed  CAS  Google Scholar 

  • Schubert P, Ogata T, Miyazaki H, Marchini C, Ferroni S, Rudolphi K (1998) Pathological immuno-reactions of glial cells in Alzheimer's disease and possible sites of interference. J Neural Transm Suppl 54:167–174

    PubMed  CAS  Google Scholar 

  • Shumilla JA, Samuels I, Johnson KW, Forsayeth JR (2005) Systemic administration of propentofylline does not attenuate morphine tolerance in non-injured rodents. Neurosci Lett 384(3):344–348

    Article  PubMed  CAS  Google Scholar 

  • Si QS, Nakamura Y, Schubert P, Rudolphi K, Kataoka K (1996) Adenosine and propentofylline inhibit the proliferation of cultured microglial cells. Exp Neurol 137(2):345–349

    Article  PubMed  CAS  Google Scholar 

  • Si Q, Nakamura Y, Ogata T, Kataoka K, Schubert P (1998) Differential regulation of microglial activation by propentofylline via cAMP signaling. Brain Res 812(1–2):97–104

    Article  PubMed  CAS  Google Scholar 

  • Sung B, Lim G, Mao J (2003) Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci 23(7):2899–2910

    PubMed  CAS  Google Scholar 

  • Sweitzer SM, Colburn RW, Rutkowski M, DeLeo JA (1999) Acute peripheral inflammation induces moderate glial activation and spinal IL-1beta expression that correlates with pain behavior in the rat. Brain Res 829(1–2):209–221

    Article  PubMed  CAS  Google Scholar 

  • Sweitzer S, Martin D, DeLeo JA (2001a) Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain. Neuroscience 103(2):529–539

    Article  PubMed  CAS  Google Scholar 

  • Sweitzer SM, Schubert P, DeLeo JA (2001b) Propentofylline, a glial modulating agent, exhibits antiallodynic properties in a rat model of neuropathic pain. J Pharmacol Exp Ther 297(3):1210–1217

    PubMed  CAS  Google Scholar 

  • Sweitzer SM, Pahl JL, DeLeo JA (2006) Propentofylline attenuates vincristine-induced peripheral neuropathy in the rat. Neurosci Lett 400(3):258–261

    Article  PubMed  CAS  Google Scholar 

  • Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, Iwama H, Nishikawa T, Ichihara N, Kikuchi T, Okuyama S, Kawashima N, Hori S, Takimoto M, Wada K (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276(5319):1699–1702

    Article  PubMed  CAS  Google Scholar 

  • Tawfik VL, Nutile-McMenemy N, Lacroix-Fralish ML, Deleo JA (2007) Efficacy of propentofylline, a glial modulating agent, on existing mechanical allodynia following peripheral nerve injury. Brain Behav Immun 21(2):238–246

    Article  PubMed  CAS  Google Scholar 

  • Tawfik VL, Regan MR, Haenggeli C, Lacroix-Fralish ML, Nutile-McMenemy N, Perez N, Rothstein JD, DeLeo JA (2008) Propentofylline-induced astrocyte modulation leads to alterations in glial glutamate promoter activation following spinal nerve transection. Neuroscience 152(4):1086–1092

    Article  PubMed  CAS  Google Scholar 

  • Tawfik VL, LaCroix-Fralish ML, Bercury KK, Nutile-McMenemy N, Harris BT, DeLeo JA (2006) Induction of astrocyte differentiation by propentyfylline increases glutamate transporter expression in vitro: Heterogeneity of the quiescent phenotype. Glia 54(3):193–203

    Google Scholar 

  • Watkins LR, Martin D, Ulrich P, Tracey KJ, Maier SF (1997) Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. Pain 71(3):225–235

    Article  PubMed  CAS  Google Scholar 

  • Weng HR, Aravindan N, Cata JP, Chen JH, Shaw AD, Dougherty PM (2005) Spinal glial glutamate transporters downregulate in rats with taxol-induced hyperalgesia. Neurosci Lett 386(1):18–22

    Article  PubMed  CAS  Google Scholar 

  • Wu YP, McRae A, Rudolphi K, Ling EA (1999) Propentofylline attenuates microglial reaction in the rat spinal cord induced by middle cerebral artery occlusion. Neurosci Lett 260(1):17–20

    Article  PubMed  CAS  Google Scholar 

  • Wu HE, Thompson J, Sun HS, Terashvili M, Tseng LF (2005) Antianalgesia: stereoselective action of dextro-morphine over levo-morphine on glia in the mouse spinal cord. J Pharmacol Exp Ther 314(3):1101–1108

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Physiology and Neuroscience, University of South Carolina, USC School of Medicine, Columbia, SC, 29208, USA

    Sarah Sweitzer

  2. Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, 03755, USA

    Joyce De Leo

Authors
  1. Sarah Sweitzer
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  2. Joyce De Leo
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Corresponding author

Correspondence to Joyce De Leo .

Additional information

This chapter is dedicated to Peter Schubert for introducing propentofylline to J. De Leo and for 23 years of scientific and personal mentorship and friendship.

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Sweitzer, S., De Leo, J. (2011). Propentofylline: Glial Modulation, Neuroprotection, and Alleviation of Chronic Pain. In: Methylxanthines. Handbook of Experimental Pharmacology, vol 200. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-13443-2_8

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