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

  • Sarah Sweitzer
  • Joyce De LeoEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 200)


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.


Astrocytes Cytokines Glia Microglia Neuropathic pain Opioids Tolerance 


  1. 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):617–625PubMedCrossRefGoogle Scholar
  2. 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):216–225PubMedCrossRefGoogle Scholar
  3. 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):38–47PubMedCrossRefGoogle Scholar
  4. 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):329–338PubMedCrossRefGoogle Scholar
  5. 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):163–175PubMedCrossRefGoogle Scholar
  6. 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):289–304PubMedCrossRefGoogle Scholar
  7. 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):745–751PubMedCrossRefGoogle Scholar
  8. 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):307–311PubMedCrossRefGoogle Scholar
  9. DeLeo J, Schubert P, Kreutzberg GW (1988b) Protection against ischemic brain damage using propentofylline in gerbils. Stroke 19(12):1535–1539PubMedCrossRefGoogle Scholar
  10. 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):1566–1573PubMedCrossRefGoogle Scholar
  11. 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):187–192CrossRefGoogle Scholar
  12. 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):1–7PubMedCrossRefGoogle Scholar
  13. 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):237–243PubMedCrossRefGoogle Scholar
  14. 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):523–537PubMedCrossRefGoogle Scholar
  15. 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 453–460Google Scholar
  16. 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):895–903PubMedCrossRefGoogle Scholar
  17. 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):410–422PubMedCrossRefGoogle Scholar
  18. 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):1206–1217PubMedCrossRefGoogle Scholar
  19. 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 3:7PubMedCrossRefGoogle Scholar
  20. 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):22–27PubMedCrossRefGoogle Scholar
  21. 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):1471–1478PubMedCrossRefGoogle Scholar
  22. 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):147–150PubMedCrossRefGoogle Scholar
  23. 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):1034–1036PubMedGoogle Scholar
  24. 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):609–619PubMedCrossRefGoogle Scholar
  25. 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):624–630PubMedCrossRefGoogle Scholar
  26. 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):655–664PubMedCrossRefGoogle Scholar
  27. 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):327–334PubMedCrossRefGoogle Scholar
  28. 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–S28PubMedGoogle Scholar
  29. 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 826:337–347PubMedCrossRefGoogle Scholar
  30. 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 54:167–174PubMedGoogle Scholar
  31. 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):344–348PubMedCrossRefGoogle Scholar
  32. 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):345–349PubMedCrossRefGoogle Scholar
  33. 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):97–104PubMedCrossRefGoogle Scholar
  34. 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):2899–2910PubMedGoogle Scholar
  35. 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):209–221PubMedCrossRefGoogle Scholar
  36. 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):529–539PubMedCrossRefGoogle Scholar
  37. 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):1210–1217PubMedGoogle Scholar
  38. Sweitzer SM, Pahl JL, DeLeo JA (2006) Propentofylline attenuates vincristine-induced peripheral neuropathy in the rat. Neurosci Lett 400(3):258–261PubMedCrossRefGoogle Scholar
  39. 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):1699–1702PubMedCrossRefGoogle Scholar
  40. 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):238–246PubMedCrossRefGoogle Scholar
  41. 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):1086–1092PubMedCrossRefGoogle Scholar
  42. 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):193–203Google Scholar
  43. 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):225–235PubMedCrossRefGoogle Scholar
  44. 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):18–22PubMedCrossRefGoogle Scholar
  45. 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):17–20PubMedCrossRefGoogle Scholar
  46. 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):1101–1108PubMedCrossRefGoogle Scholar

Copyright information

© Springer Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Department of Pharmacology, Physiology and NeuroscienceUniversity of South Carolina, USC School of MedicineColumbiaUSA
  2. 2.Department of Pharmacology and ToxicologyDartmouth Medical SchoolHanoverUSA

Personalised recommendations