Amitriptyline Downregulates Chronic Inflammatory Response to Biomaterial in Mice

Scheuermann, Karina; Orellano, Laura Alejandra Ariza; Viana, Celso Tarso Rodrigues; Machado, Clara Tolentino; Lazari, Marcela Guimarães Takahashi de; Capettini, Luciano dos Santos Aggum; Andrade, Sílvia Passos; Campos, Paula Peixoto

doi:10.1007/s10753-020-01356-0

Cited by 8 publications

(10 citation statements)

References 42 publications

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“…The results presented in Figure 1g,h (inflammatory score) are consisted with the anti‐inflammatory effect of AM on chronic inflammation. These results are consistent with our previous work showing modulatory effects of AM on inflammatory parameters only in 14‐day‐old implants but not in 7‐day‐old implants 25 . Thus, in our experimental system, AM was effective only in late phases of the healing process in which angiogenesis and fibrogenesis involved in the formation of the fibrovascular tissue are prominent.…”

Section: Discussionsupporting

confidence: 93%

“…[19][20][21][22][23][24] Beyond its actions on the nervous system, AM has been shown to reduce the presence of inflammatory markers in a number of pathological conditions in human and in experimental animal models, including in our spongeinduced chronic inflammation. [25][26][27][28] Furthermore, modulatory activities of AM on angiogenesis and fibrogenesis have been reported. In the aortic ring model (ex vivo), AM impaired blood vessel formation and in vitro the drug suppressed endothelial tube formation, cell proliferation, and angiogenic signaling including endothelial nitric oxide synthase (eNOS), serine/threonine protein kinase (Akt), and extracellular regulated kinases 1/2 (Erk1/2) pathways.…”

Section: Introductionmentioning

confidence: 99%

“…Amitriptyline (AM) is a classical antidepressant tricyclic drug that has been also considered the treatment of choice for different types of chronic pain, including migraine and chronic myofascial pain 19–24 . Beyond its actions on the nervous system, AM has been shown to reduce the presence of inflammatory markers in a number of pathological conditions in human and in experimental animal models, including in our sponge‐induced chronic inflammation 25–28 . Furthermore, modulatory activities of AM on angiogenesis and fibrogenesis have been reported.…”

Section: Introductionmentioning

confidence: 99%

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Amitriptyline efficacy in decreasing implant‐induced foreign body reaction

et al. 2023

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Beyond its actions on the nervous system, amitriptyline (AM) has been shown to lower inflammatory, angiogenic, and fibrogenic markers in a few pathological conditions in human and in experimental animal models. However, its effects on foreign body reaction (FBR), a complex adverse healing process, after biomedical material implantation are not known. We have evaluated the effects of AM on the angiogenic and fibrogenic components on a model of implant‐induced FBR. Sponge disks were implanted subcutaneously in C57BL/6 mice, that were treated daily with oral administration of AM (5 mg/kg) for seven consecutive days in two protocols: treatment was started on the day of surgery and the implants were removed on the seventh day after implantation and treatment started 7 days after implantation and the implants removed 14 after implantation. None of the angiogenic (vessels, Vascular endothelial growth factor (VEGF), and interleukin‐1β (IL‐1β) or fibrogenic parameters (collagen, TGF‐β, and fibrous capsule) and giant cell numbers analyzed were attenuated by AM in 7‐day‐old implants. However, AM was able to downregulate angiogenesis and FBR in 14‐day‐old implants. The effects of AM described here expands its range of actions as a potential agent capable of attenuating fibroproliferative processes that may impair functionality of implantable devices.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Amitriptyline efficacy in decreasing implant‐induced foreign body reaction

et al. 2023

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“…It has been shown that amitriptyline modulates depressive-like behavior in a myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (MOG-EAE) model of MS in mice [ 51 ]. Moreover, amitriptyline showed anti-inflammatory effects in humans and experimental animal models of acute inflammation, as well as inhibiting the chronic inflammatory response to biomaterial in mice [ 52 ]. Amitriptyline led to a significant decrease in the activated rounded phagocytic type of microglia in our physiological M5 and pathological M30 co-cultures, confirming the inhibition of microglial activation and partially anti-inflammatory effects.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Microglial Activation by Amitriptyline and Doxepin in Interferon-β Pre-Treated Astrocyte–Microglia Co-Culture Model of Inflammation

et al. 2023

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Depression may occur in patients with multiple sclerosis, especially during interferon-β (IFN-β) treatment, and therapy with antidepressants may be necessary. Interactions of IFN-β with antidepressants concerning glia-mediated inflammation have not yet been studied. Primary rat co-cultures of astrocytes containing 5% (M5, consistent with “physiological” conditions) or 30% (M30, consistent with “pathological, inflammatory” conditions) of microglia were incubated with 10 ng/mL amitriptyline or doxepin for 2 h, or with 2000 U/mL IFN-β for 22 h. To investigate the effects of antidepressants on IFN-β treatment, amitriptyline or doxepin was added to IFN-β pre-treated co-cultures. An MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed to measure the glial cell viability, immunocytochemistry was performed to evaluate the microglial activation state, and ELISA was performed to measure pro-inflammatory TNF-α and IL-6 cytokine concentrations. Incubation of inflammatory astrocyte–microglia co-cultures with amitriptyline, doxepin or IFN-β alone, or co-incubation of IFN-β pre-treated co-cultures with both antidepressants, significantly reduced the extent of inflammation, with the inhibition of microglial activation. TNF-α and IL-6 levels were not affected. Accordingly, the two antidepressants did not interfere with the anti-inflammatory effect of IFN-β on astrocytes and microglia. Furthermore, no cytotoxic effects on glial cells were observed. This is the first in vitro study offering novel perspectives in IFN-β treatment and accompanying depression regarding glia.

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“…The other studies that described the effectiveness of antidepressants on CCL2 inhibition covered the use of these drugs in different diseases other than depressive disorders. Indeed, amitriptyline (tricyclic antidepressants, TCAs) used in a murine sepsis model decreased the level of CCL2 and CXCL1 in the serum of the tested animals [ 74 ], also reduced the same chemokines in chronic inflammation caused by the implantation of biomaterials [ 75 ]. In addition, our research also indicates the effectiveness of antidepressants, such as fluoxetine, imipramine (TCAs) and desipramine (SNRIs) in inhibiting the secretion of the CCL2 chemokine, both by LPS- or TNF-α/IFN-γ-activated keratinocytes and dendritic cells used as a cellular model of contact hypersensitivity (in press).…”

Section: Ccl2-ccr2 Axis In Antidepressant Therapy—experimental Studies and Clinical Trialsmentioning

confidence: 99%

Targeting the CCL2-CCR2 axis in depressive disorders

Curzytek

Leśkiewicz

2021

Pharmacol. Rep

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Since affective disorders are considered to be underlain by the immune system malfunction, an important role in their pathophysiology is assigned to the proinflammatory mediators. Recently, chemokines, the group of chemotactic cytokines, have become a focus for basic and clinical scientists in the context of the development and treatment of brain diseases. Among them, chemokine CCL2 and its main receptor CCR2 have become candidate mediators of abnormal brain-immune system dialogue in depression. Besides the chemotactic activity, the CCL2-CCR2 axis is involved in various neurobiological processes, neurogenesis, neurotransmission, neuroinflammation, neurodegeneration, as well as neuroregeneration. Given the range of immunomodulatory possibilities that the CCL2-CCR2 pair can exert on the nervous system, its proinflammatory properties were initially thought to be a major contributor to the development of depressive disorders. However, further research suggests that the malfunctions of the nervous system are rather associated with impaired homeostatic properties manifested by the CCL2-CCR2 dyad dysfunctions. This review aims to present literature data on the action of the CCL2-CCR2 axis in the central nervous system under physiological and pathological conditions, as well as the contribution of this ligand-receptor system to the processes underlying affective disorders. Additionally, this article draws attention to the importance of the CCL2-CRR2 pathway as a potential pharmacological target with antidepressant potential.

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Amitriptyline Downregulates Chronic Inflammatory Response to Biomaterial in Mice

Cited by 8 publications

References 42 publications

Amitriptyline efficacy in decreasing implant‐induced foreign body reaction

Amitriptyline efficacy in decreasing implant‐induced foreign body reaction

Inhibition of Microglial Activation by Amitriptyline and Doxepin in Interferon-β Pre-Treated Astrocyte–Microglia Co-Culture Model of Inflammation

Targeting the CCL2-CCR2 axis in depressive disorders

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