Can FDA-Approved Immunomodulatory Drugs be Repurposed/Repositioned to Alleviate Chronic Pain?

Inyang, Kufreobong E.; Folger, Joseph K.; Laumet, Geoffroy

doi:10.1007/s11481-021-10000-z

Cited by 6 publications

(5 citation statements)

References 199 publications

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“…The need for a new mechanistic framework for treating MDD is urgently required, but it has been challenging, as translation from clinically relevant animal models to clinical application has been problematic [19][20][21][22]. Among the novel compounds with antidepressant activities, the use of anti-inflammatory drugs, targeting low-level inflammation, a well-established feature of MDD [23][24][25][26][27], might be of particular value owing to the longestablished clinical experience with these widely prescribed drugs [28].…”

Section: Introductionmentioning

confidence: 99%

Hippocampal Over-Expression of Cyclooxygenase-2 (COX-2) Is Associated with Susceptibility to Stress-Induced Anhedonia in Mice

Strekalova

Павлов

Трофимов

et al. 2022

IJMS

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The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram.

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Section: Introductionmentioning

confidence: 99%

Hippocampal Over-Expression of Cyclooxygenase-2 (COX-2) Is Associated with Susceptibility to Stress-Induced Anhedonia in Mice

Strekalova

Павлов

Трофимов

et al. 2022

IJMS

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“…Cytokines are an important group of molecules that regulate the excitability of nociceptors and for this reason are intensively investigated for the treatment of pain where agonist and antagonist cytokine therapies are under development [ 59 ]. IL-10 has been shown to alleviate CIPN and rheumatoid arthritis [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…ICOSaa treatment led to resolution of mechanical hypersensitivity in paclitaxel-treated female mice and also trended towards the reversal of satellite cell gliosis in the DRG and reversed astrocyte gliosis in the dorsal horn of the spinal cord. This action on cellular measures Cytokines are an important group of molecules that regulate the excitability of nociceptors and for this reason are intensively investigated for the treatment of pain where agonist and antagonist cytokine therapies are under development [59]. IL-10 has been shown to alleviate CIPN and rheumatoid arthritis [32].…”

Section: Discussionmentioning

confidence: 99%

Inducible co-stimulatory molecule (ICOS) alleviates paclitaxel-induced neuropathic pain via an IL-10-mediated mechanism in female mice

Sankaranarayanan

Tavares‐Ferreira

Mwirigi

et al. 2023

J Neuroinflammation

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Chemotherapy-induced peripheral neuropathy (CIPN) is a primary dose-limiting side effect caused by antineoplastic agents, such as paclitaxel. A primary symptom of this neuropathy is pain. Currently, there are no effective treatments for CIPN, which can lead to long-term morbidity in cancer patients and survivors. Neuro-immune interactions occur in CIPN pain and have been implicated both in the development and progression of pain in CIPN and the resolution of pain in CIPN. We investigated the potential role of inducible co-stimulatory molecule (ICOS) in the resolution of CIPN pain-like behaviors in mice. ICOS is an immune checkpoint molecule that is expressed on the surface of activated T cells and promotes proliferation and differentiation of T cells. We found that intrathecal administration of ICOS agonist antibody (ICOSaa) alleviates mechanical hypersensitivity caused by paclitaxel and facilitates the resolution of mechanical hypersensitivity in female mice. Administration of ICOSaa reduced astrogliosis in the spinal cord and satellite cell gliosis in the DRG of mice previously treated with paclitaxel. Mechanistically, ICOSaa intrathecal treatment promoted mechanical hypersensitivity resolution by increasing interleukin 10 (IL-10) expression in the dorsal root ganglion. In line with these observations, blocking IL-10 receptor (IL-10R) activity occluded the effects of ICOSaa treatment on mechanical hypersensitivity in female mice. Suggesting a broader activity in neuropathic pain, ICOSaa also partially resolved mechanical hypersensitivity in the spared nerve injury (SNI) model. Our findings support a model wherein ICOSaa administration induces IL-10 expression to facilitate neuropathic pain relief in female mice. ICOSaa treatment is in clinical development for solid tumors and given our observation of T cells in the human DRG, ICOSaa therapy could be developed for combination chemotherapy—CIPN clinical trials.

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“…Cytokines are an important group of molecules that regulate the excitability of nociceptors and for this reason are intensively investigated for the treatment of pain where agonist and antagonist cytokine therapies are under development [17]. IL-10 has been shown to alleviate CIPN and rheumatoid arthritis [59].…”

Section: Discussionmentioning

confidence: 99%

“…Further studies will be needed to ascertain if ICOSaa treatment can also prevent the development of CIPN with paclitaxel treatment and/or if it is effective in other species. The observation of T cells in the DRGs of organ donors is promising from the perspective of clinical translation for these findings.Cytokines are an important group of molecules that regulate the excitability of nociceptors and for this reason are intensively investigated for the treatment of pain where agonist and antagonist cytokine therapies are under development[17]. IL-10 has been shown to alleviate CIPN and rheumatoid arthritis[59].…”

mentioning

confidence: 99%

Inducible co-stimulatory molecule (ICOS) alleviates Paclitaxel induced peripheral neuropathy via an IL-10-mediated mechanism in female mice

Sankaranarayanan

Tavares‐Ferreira

Mwrigi

et al. 2022

Preprint

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Chemotherapy-induced peripheral neuropathy (CIPN) is a primary dose-limiting side effect caused by antineoplastic agents, such as paclitaxel. This causes damage to peripheral nerves and the dorsal root ganglia (DRG). Currently, there are no effective treatments for CIPN, which can lead to long-term morbidity in cancer patients and survivors. Neuro-immune interactions occur in CIPN and have been implicated both in the development and progression of the disease and disease resolution. We investigated the potential role of Inducible co-stimulatory molecule (ICOS) in the resolution of CIPN pain-like behaviors in mice. ICOS is an immune checkpoint molecule that is expressed on the surface of activated T cells and promotes proliferation and differentiation of T cells. We found that intrathecal administration of ICOS agonist antibody (ICOSaa) alleviates mechanical hypersensitivity caused by paclitaxel and facilitates the resolution of mechanical sensitivity in female mice. Administration of ICOSaa reduced astrocyte-gliosis in the spinal cord and satellite cell gliosis in the DRG of mice previously treated with paclitaxel. Mechanistically, ICOSaa intrathecal treatment promoted pain resolution by increasing interleukin 10 (IL-10) expression in the dorsal root ganglion. In line with these observations, blocking IL-10 receptor (IL-10R) activity occluded the effects of ICOSaa treatment on CIPN behavior in female mice. Suggesting a broader activity in neuropathic pain, ICOSaa also partially resolved mechanical hypersensitivity in the spared nerve injury (SNI) model. Our findings support a model wherein ICOSaa administration induces IL-10 expression to facilitate neuropathic pain relief in female mice. ICOSaa treatment is in clinical development for solid tumors and given our observation of T cells in the human DRG, ICOSaa therapy could be developed for combination chemotherapy - CIPN clinical trials.HighlightsICOS agonist antibody (ICOSaa) promotes pain resolution in female miceDRG T cells appear to enter an anti-inflammatory phenotype by ICOSaa treatmentICOSaa treatment increases DRG levels of IL-10 cytokineICOSaa effects in female mice are blocked by IL-10 sequestering treatment

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Can FDA-Approved Immunomodulatory Drugs be Repurposed/Repositioned to Alleviate Chronic Pain?

Cited by 6 publications

References 199 publications

Hippocampal Over-Expression of Cyclooxygenase-2 (COX-2) Is Associated with Susceptibility to Stress-Induced Anhedonia in Mice

Hippocampal Over-Expression of Cyclooxygenase-2 (COX-2) Is Associated with Susceptibility to Stress-Induced Anhedonia in Mice

Inducible co-stimulatory molecule (ICOS) alleviates paclitaxel-induced neuropathic pain via an IL-10-mediated mechanism in female mice

Inducible co-stimulatory molecule (ICOS) alleviates Paclitaxel induced peripheral neuropathy via an IL-10-mediated mechanism in female mice

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