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

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.

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

“…The realization of new players in opioid analgesia is a major development in opioid pharmacology and thus has been the focus of several excellent recent reviews (Mika, 2008;Romero-Sandoval et al, 2008;Ueda and Ueda, 2009;Watkins et al, 2009;Ji, 2010;O'Callaghan and Miller, 2010;White and Wilson, 2010;Sweitzer and De Leo, 2011). Here, we will highlight and extend previous reviews to discuss the evidence that acute opioid analgesia is substantially modified by the rapid opioid-induced initiation of central immune signaling and that upon repeated opioid exposure, continued central immune signaling leads to analgesic tolerance and enhanced pain states.…”

Propentofylline reverses delayed remyelination in streptozotocin-induced diabetic rats

“…Several in vitro and in vivo studies have shown that propentofylline [PPF, 3-methyl-1-(5'-oxohexyl)-7-propylxanthine], a xanthine derivative, presents profound neuroprotective, antioxidant and anti-inflammatory effects (16,17). Clinically it has shown efficacy in degenerative vascular dementia (18) and as a potential adjuvant treatment to Alzheimer's disease (19,20), schizophrenia (21) and multiple sclerosis (22).…”

“…Clinically it has shown efficacy in degenerative vascular dementia (18) and as a potential adjuvant treatment to Alzheimer's disease (19,20), schizophrenia (21) and multiple sclerosis (22). PPF probably depresses activation of microglial cells and astrocytes, which is associated with neuronal damage during inflammation and hypoxia and consequently decreases glial production and release of damaging proinflammatory factors (16). In the EB demyelinating Arch Endocrinol Metab.…”

Propentofylline reduces glial scar development following gliotoxic damage in the rat brainstem

“…Propentofylline [PPF, 3-methyl-1-(5´-oxohexyl)-7-propylxanthine] is a xanthine derivative with pharmacological effects distinct from those of the classical methylxanthines theophylline and caffeine 4 . In vitro and in vivo studies have demonstrated extensive neuroprotective, antiproliferative and anti-inflammatory effects of PPF in several experimental models in animals 4 .…”

“…In vitro and in vivo studies have demonstrated extensive neuroprotective, antiproliferative and anti-inflammatory effects of PPF in several experimental models in animals 4 . It was sucessfully used in degenerative vascular dementia and as a potential adjuvant treatment to Alzheimer's disease, schizophrenia and multiple sclerosis 4 .…”