Propentofylline-induced astrocyte modulation leads to alterations in glial glutamate promoter activation following spinal nerve transection

Tawfik, Vivianne L.; Regan, Melissa R.; Haenggeli, Christine; LaCroix-Fralish, Michael L.; Nutile-McMenemy, Nancy; Perez, Natalie; Rothstein, Jeffrey D.; DeLeo, Joyce A.

doi:10.1016/j.neuroscience.2008.01.065

Cited by 78 publications

(74 citation statements)

References 31 publications

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“…These potential non–cell‐autonomous effects of dysfunctional astrocytes and microglia in JNCL are expected to synergize with intrinsic neuronal defects to culminate in cell loss 48. These changes led to our interest in investigating the utility of PDE4 inhibitors, because prior studies have shown their efficacy in attenuating microglial proinflammatory activity, augmenting astrocyte glutamate transporter expression, and delivering prosurvival signals to neurons 15, 16, 38. Our findings support a key role for cAMP in dictating motor dysfunction, glial activation, and lysosomal pathology in the Cln3 Δex7/8 brain, and support the feasibility of PDE4 inhibitors as potential therapeutics for the treatment of JNCL patients.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of phosphodiesterase‐4 inhibitors in juvenile Batten disease (CLN3)

Aldrich

Bosch

Fallet

et al. 2016

Annals of Neurology

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ObjectiveJuvenile neuronal ceroid lipofuscinosis (JNCL), or juvenile Batten disease, is a pediatric lysosomal storage disease caused by autosomal recessive mutations in CLN3, typified by blindness, seizures, progressive cognitive and motor decline, and premature death. Currently, there is no treatment for JNCL that slows disease progression, which highlights the need to explore novel strategies to extend the survival and quality of life of afflicted children. Cyclic adenosine monophosphate (cAMP) is a second messenger with pleiotropic effects, including regulating neuroinflammation and neuronal survival. Here we investigated whether 3 phosphodiesterase‐4 (PDE4) inhibitors (rolipram, roflumilast, and PF‐06266047) could mitigate behavioral deficits and cell‐specific pathology in the Cln3Δex7/8 mouse model of JNCL.MethodsIn a randomized, blinded study, wild‐type (WT) and Cln3Δex7/8 mice received PDE4 inhibitors daily beginning at 1 or 3 months of age and continuing for 6 to 9 months, with motor deficits assessed by accelerating rotarod testing. The effect of PDE4 inhibitors on cAMP levels, astrocyte and microglial activation (glial fibrillary acidic protein and CD68, respectively), lysosomal pathology (lysosomal‐associated membrane protein 1), and astrocyte glutamate transporter expression (glutamate/aspartate transporter) were also examined in WT and Cln3Δex7/8 animals.ResultscAMP levels were significantly reduced in the Cln3Δex7/8 brain, and were restored by PF‐06266047. PDE4 inhibitors significantly improved motor function in Cln3Δex7/8 mice, attenuated glial activation and lysosomal pathology, and restored glutamate transporter expression to levels observed in WT animals, with no evidence of toxicity as revealed by blood chemistry analysis.InterpretationThese studies reveal neuroprotective effects for PDE4 inhibitors in Cln3Δex7/8 mice and support their therapeutic potential in JNCL patients. Ann Neurol 2016;80:909–923

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Section: Discussionmentioning

confidence: 99%

Efficacy of phosphodiesterase‐4 inhibitors in juvenile Batten disease (CLN3)

Aldrich

Bosch

Fallet

et al. 2016

Annals of Neurology

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“…Taken together, these findings support the notion that the decreased expression or function of astrocytic EAATs in the spinal cord resulting from peripheral nerve injury/ inflammation can enhance glutamatergic synaptic neurotransmission and subsequent glutamate-related neuronal adaptation related to pathological pain. It has been reported that propentofylline, an atypical methylxanthine shown to attenuate astrocytic activation as well as pathological pain (10,19), induced the expression of GLT-1 and GLAST in the spinal dorsal horn following spinal nerve transection (35). Furthermore, repeated administration of amitriptyline, a tricyclic antidepressant used as a first-line drug for the treatment of neuropathic pain, reversed the down-regulation of GLT-1 and GLAST in spared nerve injury-model rats (38).…”

Section: Astrocytic Glutamate and Glycine Transporters In Pathologicamentioning

confidence: 97%

“…These findings suggest that glutamate uptake through spinal EAATs plays an important role in maintaining normal pain transmission under physiological conditions. Furthermore, it has been shown that the down-regulation or functional deficiency of glial glutamate transporters in the spinal dorsal horn is associated with diverse models of pathological pain (32,34,35). We have examined the effects of GLT-1 gene transfer into the rat spinal cord using recombinant adenoviruses in inflammatory and neuropathic pain models.…”

Section: Astrocytic Glutamate and Glycine Transporters In Pathologicamentioning

confidence: 99%

Spinal Astrocytes as Therapeutic Targets for Pathological Pain

Nakagawa

Kaneko

2010

J Pharmacol Sci

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Abstract. Development of next-generation analgesics requires a better understanding of the molecular and cellular mechanisms underlying pathological pain. Accumulating evidence suggests that the activation of glia contributes to the central sensitization of pain signaling in the spinal cord. The role of microglia in pathological pain has been well documented, while that of astrocytes still remains unclear. After peripheral nerve inflammation or injury, spinal microglia are initially activated and subsequently sustained activation of astrocytes is precipitated, which are implicated in the induction and maintenance of pathological pain. Astrocytic activation is caused by the production of diffusible factors from primary afferent neurons (neuron-to-astrocyte signals) and activated microglia (microglia-to-astrocyte signals). Although astrocyte-to-neuron signals implicated in pathological pain is poorly understood, activated astrocytes, as well as microglia, produce proinflammatory cytokines and chemokines, which lead to adaptation of the dorsal horn neurons. Furthermore, it has been suggested that glial glutamate transporters in the spinal astrocytes are down-regulated in pathological pain and that up-regulation or functional enhancement of these transporters prevents pathological pain. This review will briefly discuss novel findings on the role of spinal astrocytes in pathological pain and their potential as a therapeutic target for novel analgesics.

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“…Some insight may be gained by the application of imaging techniques such as the use of PET ligands at the peripheral benzodiazepine receptor to studies of the temporal pattern of "activation" in patients, but the true therapeutic opportunities offered by this phenomenon can only be realized by well-designed clinical trials coupled to validated biomarkers in patients. Two such examples of pioneering studies in this area involve the compounds ibudilast (95) and propentofylline (96). Propentofylline attenuates pain behaviors in rodent models of neuropathic pain (97,98) and has been shown to modulate inhibitory tone following spinal injury (99) by reducing glial activation via alterations in glutamate promoter activation (96).…”

Section: Mechanisms Based On Activated Microgliamentioning

confidence: 99%

“…Two such examples of pioneering studies in this area involve the compounds ibudilast (95) and propentofylline (96). Propentofylline attenuates pain behaviors in rodent models of neuropathic pain (97,98) and has been shown to modulate inhibitory tone following spinal injury (99) by reducing glial activation via alterations in glutamate promoter activation (96).…”

Section: Mechanisms Based On Activated Microgliamentioning

confidence: 99%

The discovery and development of analgesics: new mechanisms, new modalities

Burgess¹,

Williams²

2010

J. Clin. Invest.

105

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Despite intensive research into pain mechanisms and significant investment in research and development, the majority of analgesics available to prescribers and patients are based on mechanistic classes of compounds that have been known for many years. With considerable ingenuity and innovation, researchers continue to make the best of the mechanistic approaches available, with novel formulations, routes of administration, and combination products. Here we review some of the mechanisms and modalities of analgesics that have recently entered into clinical development, which, coupled with advances in the understanding of the pathophysiology of chronic pain, will hopefully bring the promise of new therapeutics that have the potential to provide improved pain relief for those many patients whose needs remain poorly met. IntroductionDrug discovery and development continue to be a challenge, with increasingly high investments in R&D and increased numbers of submissions failing to translate into the delivery of novel chemical entities onto the market. The wide availability of generic and overthe-counter analgesics based on non-steroidal antiinflammatories (NSAIDs), acetaminophen, and "weak" opiates (and their combinations) provides many individuals with an accessible source of relief for mild to moderate pain. However, many patients with chronic conditions such as osteoarthritis remain poorly treated (1, 2).Opiates continue to provide an important choice for the treatment of moderate to severe pain but are associated with a number of unwanted side effects such as constipation, nausea, vomiting, itching, and somnolence (3), and negative effects on patients' wellbeing, including sleep quality and ability to concentrate, which can be of such significance that they result in treatment discontinuation (4). Indeed, a recent Internet survey indicated that patients taking opiates for pain (and prescribing physicians) are willing to "trade-off " pain relief for a better toleration profile, with 50% of patients and physicians reporting that improved side effects represent the biggest unmet need (5).Neuropathic pain has a complex pathophysiology and is difficult to treat (6). It has been estimated that about one-third of patients are likely to achieve 50% pain relief with monotherapy (7); for example, in patients treated with the first-line therapy pregabalin, the patient global impression of change rating of much improved or very much improved was about 35% in postherpetic neuralgia, 50% in painful diabetic neuropathy, and 40% in fibromyalgia (8). A recent review identified a 66% increase in published randomized, placebo-controlled trials in a range of neuropathic pain populations over the last five years and concluded that only a limited improvement in the relief of pain had been achieved and that a large proportion of patients remained poorly treated (9).The challenge for drug discovery and development can therefore be very simply stated: we need to bring forward analgesics that will provide more effective pain relief, are safe...

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Propentofylline-induced astrocyte modulation leads to alterations in glial glutamate promoter activation following spinal nerve transection

Cited by 78 publications

References 31 publications

Efficacy of phosphodiesterase‐4 inhibitors in juvenile Batten disease (CLN3)

Efficacy of phosphodiesterase‐4 inhibitors in juvenile Batten disease (CLN3)

Spinal Astrocytes as Therapeutic Targets for Pathological Pain

The discovery and development of analgesics: new mechanisms, new modalities

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