Release of Plasmid DNA-Encoding IL-10 from PLGA Microparticles Facilitates Long-Term Reversal of Neuropathic Pain Following a Single Intrathecal Administration

Soderquist, Ryan G.; Sloane, Evan M.; Loram, Lisa C.; Harrison, Jackie; Dengler, Ellen C.; Johnson, S. M.; Amer, Luke D.; Young, Courtney S.; Lewis, Makenzie T.; Poole, Stephen; Frank, Marion E.; Watkins, Linda R.; Milligan, Erin D.; Mahoney, Melissa J.

doi:10.1007/s11095-010-0077-y

Cited by 86 publications

(63 citation statements)

References 75 publications

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“…Further support for such an inflammation-mediated regulation of BSCB/BBB function is that, while proinflammatory molecules promoted the openings of BSCB, antiinflammatory cytokines, TGF-␤1 or IL-10, which have been shown to be able to inhibit spinal microglial activation and to reduce the expression of proinflammatory molecules (Moore et al, 2001;Echeverry et al, 2009;Soderquist et al, 2010), prevented the disruption of BSCB triggered by nerve injury. These antiinflammatory cytokines were effective in relieving experimental neuropathic pain (Echeverry et al, 2009;Soderquist et al, 2010).…”

Section: Discussionmentioning

confidence: 97%

“…Systemic IL-1␤-induced alterations in BSCB can be mediated through a direct interaction with the IL-1␤ receptor located in the endothelium (Konsman et al, 2004) or indirectly, through IL-1␤-stimulated release of other chemokines having their corresponding recep- tors on blood vessels (Shaw and Greig, 1999;Ubogu et al, 2006). Further support for such an inflammation-mediated regulation of BSCB/BBB function is that, while proinflammatory molecules promoted the openings of BSCB, antiinflammatory cytokines, TGF-␤1 or IL-10, which have been shown to be able to inhibit spinal microglial activation and to reduce the expression of proinflammatory molecules (Moore et al, 2001;Echeverry et al, 2009;Soderquist et al, 2010), prevented the disruption of BSCB triggered by nerve injury. These antiinflammatory cytokines were effective in relieving experimental neuropathic pain (Echeverry et al, 2009;Soderquist et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Peripheral Nerve Injury Alters Blood-Spinal Cord Barrier Functional and Molecular Integrity through a Selective Inflammatory Pathway

Echeverry¹,

Shi²,

Rivest³

et al. 2011

Journal of Neuroscience

217

201

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Peripheral nerve lesion triggers alterations in the spinal microenvironment that contribute to the pathogenesis of neuropathic pain. While neurons and glia have been implicated in these functional changes, it remains largely underexplored whether the blood-spinal cord barrier (BSCB) is also involved. The BSCB is an important component in the CNS homeostasis, and compromised BSCB has been associated with different pathologies affecting the spinal cord. Here, we demonstrated that a remote injury on the peripheral nerve in rats triggered a leakage of the BSCB, which was independent of spinal microglial activation. The increase of BSCB permeability to different size tracers, such as Evans Blue and sodium fluorescein, was restricted to the lumbar spinal cord and prominent for at least 4 weeks after injury. The spinal inflammatory reaction triggered by nerve injury was a key player in modulating BSCB permeability. We identified MCP-1 as an endogenous trigger for the BSCB leakage. BSCB permeability can also be impaired by circulating IL-1␤. In contrast, antiinflammatory cytokines TGF-␤1 and IL-10 were able to shut down the openings of the BSCB following nerve injury. Peripheral nerve injury caused a decrease in tight junction and caveolae-associated proteins. Interestingly, ZO-1 and occludin, but not caveolin-1, were rescued by TGF-␤1. Furthermore, our data provide direct evidence that disrupted BSCB following nerve injury contributed to the influx of inflammatory mediators and the recruitment of spinal blood borne monocytes/macrophages, which played a major role in the development of neuropathic pain. These findings highlight the importance of inflammation in BSCB integrity and in spinal cord homeostasis.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Peripheral Nerve Injury Alters Blood-Spinal Cord Barrier Functional and Molecular Integrity through a Selective Inflammatory Pathway

Echeverry¹,

Shi²,

Rivest³

et al. 2011

Journal of Neuroscience

217

201

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“…Here we found that gene expression of both the algesic IL-6 [40,43] and the analgesic IL-10 cytokine [52,55] was increased in sural nerve specimens of patients with painful compared to painless neuropathies. IL-6 and IL-10 are both produced in Schwann cells, macrophages and T-lymphocytes in peripheral nerve.…”

Section: Discussionmentioning

confidence: 74%

Differential gene expression of cytokines and neurotrophic factors in nerve and skin of patients with peripheral neuropathies

et al. 2014

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Pathophysiologically relevant alterations in cytokine and neurotrophic factor levels have been reported in neuropathy subtypes. We characterized gene expression profiles of pro- and anti-inflammatory cytokines and neurotrophic factors in nerve and skin samples of patients with neuropathies of different etiologies. We prospectively studied 133 patients with neuropathies and compared data between subtypes and with healthy controls. All patients underwent sural nerve and/or skin punch biopsy at the lateral thigh and lower leg; controls received skin punch biopsies. Gene expression of pro- and anti-inflammatory cytokines (IL-1β, IL-2, IL-6, TNF, IL-10), neurotrophic factors (BDNF, NGF, NT3, TrkA), and erythropoietin with the erythropoietin receptor (Epo, EpoR) was analyzed. Sural nerve gene expression of the investigated cytokines and neurotrophic factors did not differ between neuropathies of different etiologies; however, IL-6 (p < 0.01) and IL-10 (p < 0.05) expression was higher in painful compared to painless neuropathies. Skin IL-6 and IL-10 gene expression was increased in patients compared to controls (p < 0.05), and IL-10 expression was higher in lower leg skin of patients with non-inflammatory neuropathies compared to inflammatory neuropathies (p < 0.05). Proximal and distal skin neurotrophic factor and Epo gene expression of patients with neuropathies was reduced compared to controls (NGF, NT3, Epo; p < 0.05). Neuropathies are associated with an increase in cytokine expression and a decrease in neurotrophic factor expression including nerve and skin.

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“…iii) The use of intrathecal viral vectors or plasmid delivery to increase appropriate antihyperalgesic targets has been shown to have utility. Thus, increased spinal expression of IL-10 (anti-inflammatory cytokine)or plasmid delivery was anti-hyperalgesic [424,[429][430][431]. Increasing MAPK (Mitogen activated protein kinase) phosphatase-1 reduces activation of P38 MAPKs and this resulted in reduced nerve injury-evoked increases in inflammatory cytokines and chemokines and hyperalgesia [432].…”

Section: Gene-based Approachesmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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Release of Plasmid DNA-Encoding IL-10 from PLGA Microparticles Facilitates Long-Term Reversal of Neuropathic Pain Following a Single Intrathecal Administration

Cited by 86 publications

References 75 publications

Peripheral Nerve Injury Alters Blood-Spinal Cord Barrier Functional and Molecular Integrity through a Selective Inflammatory Pathway

Peripheral Nerve Injury Alters Blood-Spinal Cord Barrier Functional and Molecular Integrity through a Selective Inflammatory Pathway

Differential gene expression of cytokines and neurotrophic factors in nerve and skin of patients with peripheral neuropathies

Current and Future Issues in the development of spinal agents for the management of pain

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