scholarly journals Parthenolide Relieves Pain and Promotes M2 Microglia/Macrophage Polarization in Rat Model of Neuropathy

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Katarzyna Popiolek-Barczyk ◽  
Natalia Kolosowska ◽  
Anna Piotrowska ◽  
Wioletta Makuch ◽  
Ewelina Rojewska ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Protein Level ◽  
Intracellular Signaling ◽  
Microglial Cell ◽  
Pain Treatment ◽  
Macrophage Polarization ◽  
Phosphorylated Form ◽  
Macrophages Polarization ◽  
M2 Microglia ◽  
Primary Microglial Cell

Neuropathic pain treatment remains a challenge because pathomechanism is not fully understood. It is believed that glial activation and increased spinal nociceptive factors are crucial for neuropathy. We investigated the effect of parthenolide (PTL) on the chronic constriction injury to the sciatic nerve (CCI)-induced neuropathy in rat. We analyzed spinal changes in glial markers and M1 and M2 polarization factors, as well as intracellular signaling pathways. PTL (5 µg;i.t.) was preemptively and then daily administered for 7 days after CCI. PTL attenuated the allodynia and hyperalgesia and increased the protein level of IBA1 (a microglial/macrophage marker) but did not change GFAP (an astrocyte marker) on day 7 after CCI. PTL reduced the protein level of M1 (IL-1β, IL-18, and iNOS) and enhanced M2 (IL-10, TIMP1) factors. In addition, it downregulated the phosphorylated form of NF-κB, p38MAPK, and ERK1/2 protein level and upregulated STAT3. In primary microglial cell culture we have shown that IL-1β, IL-18, iNOS, IL-6, IL-10, and TIMP1 are of microglial origin. Summing up, PTL directly or indirectly attenuates neuropathy symptoms and promotes M2 microglia/macrophages polarization. We suggest that neuropathic pain therapies should be shifted from blanketed microglia/macrophage suppression toward maintenance of the balance between neuroprotective and neurotoxic microglia/macrophage phenotypes.

scholarly journals Biphalin, a Dimeric Enkephalin, Alleviates LPS-Induced Activation in Rat Primary Microglial Cultures in Opioid Receptor-Dependent and Receptor-Independent Manners

2017 ◽  
Vol 2017 ◽  
pp. 1-19 ◽  
Author(s):  
Katarzyna Popiolek-Barczyk ◽  
Anna Piotrowska ◽  
Wioletta Makuch ◽  
Joanna Mika
Keyword(s):  
Neuropathic Pain ◽  
Opioid Receptor ◽  
Pain Therapy ◽  
Cell Activation ◽  
Microglial Cell ◽  
Preclinical Model ◽  
No Production ◽  
Dependent Manner ◽  
Analgesic Effects ◽  
Primary Microglial Cell

Neuropathic pain is relatively less responsive to opioids than other types of pain, which is possibly due to a disrupted opioid system partially caused by the profound microglial cell activation that underlines neuroinflammation. We demonstrated that intrathecally injected biphalin, a dimeric enkephalin analog, diminished symptoms of neuropathy in a preclinical model of neuropathic pain in rats (CCI, chronic constriction injury of the sciatic nerve) at day 12 postinjury. Using primary microglial cell cultures, we revealed that biphalin did not influence cell viability but diminished NO production and expression of Iba1 in LPS-stimulated cells. Biphalin also diminished MOP receptor level, as well as pronociceptive mediators (iNOS, IL-1β, and IL-18) in an opioid receptor-dependent manner, and it was correlated with diminished p-NF-κB, p-IκB, p-p38MAPK, and TRIF levels. Biphalin reduced IL-6, IL-10, TNFα, p-STAT3, and p-ERK1/2 and upregulated SOCS3, TLR4, and MyD88; however, this effect was not reversed by naloxone pretreatment. Our study provides evidence that biphalin diminishes neuropathy symptoms, which might be partially related to reduced pronociceptive mediators released by activated microglia. Biphalin may be a putative drug for future pain therapy, especially for the treatment of neuropathic pain, when the lower analgesic effects of morphine are correlated with profound microglial cell activation.

scholarly journals Minocycline Enhances the Effectiveness of Nociceptin/Orphanin FQ during Neuropathic Pain

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Katarzyna Popiolek-Barczyk ◽  
Ewelina Rojewska ◽  
Agnieszka M. Jurga ◽  
Wioletta Makuch ◽  
Ferenz Zador ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Cell Activation ◽  
Microglial Cell ◽  
Lumbar Spinal Cord ◽  
Orphanin Fq ◽  
Binding Assays ◽  
Analgesic Effects ◽  
Primary Microglial Cell ◽  
Lumbar Spinal

Nociceptin/orphanin FQ (N/OFQ) antinociception, which is mediated selectively by the N/OFQ peptide receptor (NOP), was demonstrated in pain models. In this study, we determine the role of activated microglia on the analgesic effects of N/OFQ in a rat model of neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve. Repeated 7-day administration of minocycline (30 mg/kg i.p.), a drug that affects microglial activation, significantly reduced pain in CCI-exposed rats and it potentiates the analgesic effects of administered N/OFQ (2.5–5 μg i.t.). Minocycline also downregulates the nerve injury-induced upregulation of NOP protein in the dorsal lumbar spinal cord. Ourin vitrostudy showed that minocycline reducedNOPmRNA, but not protein, level in rat primary microglial cell cultures. In [35S]GTPγS binding assays we have shown that minocycline increases the spinal N/OFQ-stimulated NOP signaling. We suggest that the modulation of the N/OFQ system by minocycline is due to the potentiation of its neuronal antinociceptive activity and weakening of the microglial cell activation. This effect is beneficial for pain relief, and these results suggest new targets for the development of drugs that are effective against neuropathic pain.

scholarly journals Therapeutic Strategies for Neuropathic Pain: Potential Application of Pharmacosynthetics and Optogenetics

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Gum Hwa Lee ◽  
Sang Seong Kim
Keyword(s):  
Neuropathic Pain ◽  
Sequence Analysis ◽  
Ion Channel ◽  
G Protein ◽  
Intracellular Signaling ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Pain Treatment ◽  
Neuronal Damage ◽  
Rna Sequence

Chronic pain originating from neuronal damage remains an incurable symptom debilitating patients. Proposed molecular modalities in neuropathic pain include ion channel expressions, immune reactions, and inflammatory substrate diffusions. Recent advances in RNA sequence analysis have discovered specific ion channel expressions in nociceptors such as transient receptor potential (TRP) channels, voltage-gated potassium, and sodium channels. G protein-coupled receptors (GPCRs) also play an important role in triggering surrounding immune cells. The multiple protein expressions complicate therapeutic development for neuropathic pain. Recent progress in optogenetics and pharmacogenetics may herald the development of novel therapeutics for the incurable pain. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) facilitate the artificial manipulation of intracellular signaling through excitatory or inhibitory G protein subunits activated by biologically inert synthetic ligands. Expression of excitatory channelrhodopsins and inhibitory halorhodopsins on injured neurons or surrounding cells can attenuate neuropathic pain precisely controlled by light stimulation. To achieve the discrete treatment of injured neurons, we can exploit the transcriptome database obtained by RNA sequence analysis in specific neuropathies. This can recommend the suitable promoter information to target the injury sites circumventing intact neurons. Therefore, novel strategies benefiting from pharmacogenetics, optogenetics, and RNA sequencing might be promising for neuropathic pain treatment in future.

Serotonergic System and Its Role in Epilepsy and Neuropathic Pain Treatment: A Review Based on Receptor Ligands

2015 ◽  
Vol 21 (13) ◽  
pp. 1723-1740 ◽  
Author(s):  
Katarzyna Panczyk ◽  
Sylwia Go.lda ◽  
Anna Waszkielewicz ◽  
Dorota Zelaszczyk ◽  
Agnieszka Gunia-Krzyz.ak ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Pain Treatment ◽  
Serotonergic System ◽  
Receptor Ligands

scholarly journals Initiators of Classical and Lectin Complement Pathways Are Differently Engaged after Traumatic Brain Injury—Time-Dependent Changes in the Cortex, Striatum, Thalamus and Hippocampus in a Mouse Model

2020 ◽  
Vol 22 (1) ◽  
pp. 45
Author(s):  
Agata Ciechanowska ◽  
Katarzyna Ciapała ◽  
Katarzyna Pawlik ◽  
Marco Oggioni ◽  
Domenico Mercurio ◽  
...  
Keyword(s):  
Brain Injury ◽  
Microglial Cell ◽  
Lectin Pathway ◽  
Brain Areas ◽  
Mannose Binding ◽  
Primary Microglial Cell ◽  
Cellular Markers ◽  
The Brain ◽  
Binding Lectin ◽  
Complement Pathways

The complement system is involved in promoting secondary injury after traumatic brain injury (TBI), but the roles of the classical and lectin pathways leading to complement activation need to be clarified. To this end, we aimed to determine the ability of the brain to activate the synthesis of classical and lectin pathway initiators in response to TBI and to examine their expression in primary microglial cell cultures. We have modeled TBI in mice by controlled cortical impact (CCI), a clinically relevant experimental model. Using Real-time quantitative polymerase chain reaction (RT-qPCR) we analyzed the expression of initiators of classical the complement component 1q, 1r and 1s (C1q, C1r, and C1s) and lectin (mannose binding lectin A, mannose binding lectin C, collectin 11, ficolin A, and ficolin B) complement pathways and other cellular markers in four brain areas (cortex, striatum, thalamus and hippocampus) of mice exposed to CCI from 24 h and up to 5 weeks. In all murine ipsilateral brain structures assessed, we detected long-lasting, time- and area-dependent significant increases in the mRNA levels of all classical (C1q, C1s, C1r) and some lectin (collectin 11, ficolin A, ficolin B) initiator molecules after TBI. In parallel, we observed significantly enhanced expression of cellular markers for neutrophils (Cd177), T cells (Cd8), astrocytes (glial fibrillary acidic protein—GFAP), microglia/macrophages (allograft inflammatory factor 1—IBA-1), and microglia (transmembrane protein 119—TMEM119); moreover, we detected astrocytes (GFAP) and microglia/macrophages (IBA-1) protein level strong upregulation in all analyzed brain areas. Further, the results obtained in primary microglial cell cultures suggested that these cells may be largely responsible for the biosynthesis of classical pathway initiators. However, microglia are unlikely to be responsible for the production of the lectin pathway initiators. Immunofluorescence analysis confirmed that at the site of brain injury, the C1q is localized in microglia/macrophages and neurons but not in astroglial cells. In sum, the brain strongly reacts to TBI by activating the local synthesis of classical and lectin complement pathway activators. Thus, the brain responds to TBI with a strong, widespread and persistent upregulation of complement components, the targeting of which may provide protection in TBI.

scholarly journals Cancer Derived Exosomes Induce Macrophages Immunosuppressive Polarization to Promote Bladder Cancer Progression

2021 ◽  
Author(s):  
Ziming Jiang ◽  
Yiming Zhang ◽  
Yu Zhang ◽  
Zhankui Jia ◽  
Zhengguo Zhang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Progression ◽  
Macrophage Polarization ◽  
Tumor Model ◽  
Tumor Xenograft ◽  
Potential Therapeutic Target ◽  
Macrophages Polarization ◽  
Exosomal Mirnas ◽  
Bladder Cancer Cells ◽  
And Function

Abstract Background: Exosomes mediated crosstalk between tumor cells and other stromal cells including tumor associated macrophages (TAM) plays an essential role in reprogramming tumor microenvironment (TME) to facilitate tumor progression. However, the mechanism of tumor derived exosomes promotes bladder cancer progression have not been defined.Methods: Exosomes were extracted from bladder cancer cells MB49 conditioned medium by ultracentrifugation. The effects of MB49-derived exosomes on macrophages polarization were analyzed by qPCR, flow cytometry, and Western blot. The immunosuppressive phenotype and function of MB49-derived exosomes stimulated macrophages were verified by tumor xenograft assays and T cell co-culture experiments. Exosomal miRNAs were analyzed by microarray to identify potential targets regulating macrophage polarization.Results: MB49-derived exosomes could be ingested by macrophages, consequently promoting macrophages immunosuppressive polarization. Mechanically, the MB49-derived exosomes induced macrophage M2 polarization was mediated by down-regulation of PTEN and activation of AKT/STAT3/6 signaling. Moreover, hindrance of the generation or secretion of exosomes by GW4869 inhibited macrophages differentiation into immunosuppressive phenotype and function, thereby suppressed tumor growth in a mouse subcutaneous tumor model.Conclusion: Our study confirmed the contribution of bladder cancer derived exosomes on the establishment of immunosuppressive TME and provided a potential therapeutic target for bladder cancer treatment.

scholarly journals Monoaminergic and Opioidergic Modulation of Brainstem Circuits: New Insights Into the Clinical Challenges of Pain Treatment?

2021 ◽  
Vol 2 ◽  
Author(s):  
Isaura Tavares ◽  
José Tiago Costa-Pereira ◽  
Isabel Martins
Keyword(s):  
Neuropathic Pain ◽  
Pain Control ◽  
Pain Treatment ◽  
Reticular Nucleus ◽  
Serotoninergic System ◽  
High Plasticity ◽  
Descending Facilitation ◽  
Pain Models ◽  
Dual Action ◽  
Control Circuits

The treatment of neuropathic pain remains a clinical challenge. Analgesic drugs and antidepressants are frequently ineffective, and opioids may induce side effects, including hyperalgesia. Recent results on brainstem pain modulatory circuits may explain those clinical challenges. The dual action of noradrenergic (NA) modulation was demonstrated in animal models of neuropathic pain. Besides the well-established antinociception due to spinal effects, the NA system may induce pronociception by directly acting on brainstem pain modulatory circuits, namely, at the locus coeruleus (LC) and medullary dorsal reticular nucleus (DRt). The serotoninergic system also has a dual action depending on the targeted spinal receptor, with an exacerbated activity of the excitatory 5-hydroxytryptamine 3 (5-HT3) receptors in neuropathic pain models. Opioids are involved in the modulation of descending modulatory circuits. During neuropathic pain, the opioidergic modulation of brainstem pain control areas is altered, with the release of enhanced local opioids along with reduced expression and desensitization of μ-opioid receptors (MOR). In the DRt, the installation of neuropathic pain increases the levels of enkephalins (ENKs) and induces desensitization of MOR, which may enhance descending facilitation (DF) from the DRt and impact the efficacy of exogenous opioids. On the whole, the data discussed in this review indicate the high plasticity of brainstem pain control circuits involving monoaminergic and opioidergic control. The data from studies of these neurochemical systems in neuropathic models indicate the importance of designing drugs that target multiple neurochemical systems, namely, maximizing the antinociceptive effects of antidepressants that inhibit the reuptake of serotonin and noradrenaline and preventing desensitization and tolerance of MOR at the brainstem.

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