On the therapeutic targets and pharmacological treatments for pain relief following spinal cord injury: A mechanistic review

Fakhri, Sajad; Abbaszadeh, Fatemeh; Jorjani, Masoumeh

doi:10.1016/j.biopha.2021.111563

Cited by 21 publications

(21 citation statements)

References 450 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, the nuclear factor-κB (NF-κB) is a key regulator of molecules and pathways important for inflammation and pain [ 64 , 65 , 66 ]. NF-κB can exist as homo or heterodimers composed of the Rel family proteins (the p65/p50 subunits in humans) and is bound to the κB inhibitor (IκBα) in the cytoplasm, when in an inactive state.…”

Section: Apoptosis Pathways As Mediators Of Pain Formationmentioning

confidence: 99%

“…Upon activation by proinflammatory cytokines and growth factors, among others, the IκB kinase (IKK) phosphorylates IκBα, targeting its degradation in the UPP. As a result, IκBα releases the p65/p50 complex, which subsequently translocates to the nucleus and initiates the transcription of several genes, including inflammatory genes such as TNFα, IL-1β, and cyclooxogenase-2 (COX-2) that directly or indirectly influence pain [ 64 , 65 , 66 ]. Thus, targeting the NF-kB pathway, namely by inhibiting the IkB degradation in the UPP could be a new therapeutic approach to treating pain [ 43 , 64 , 65 ].…”

Section: Apoptosis Pathways As Mediators Of Pain Formationmentioning

confidence: 99%

See 1 more Smart Citation

Apoptosis and (in) Pain—Potential Clinical Implications

et al. 2022

View full text Add to dashboard Cite

The deregulation of apoptosis is involved in the development of several pathologies, and recent evidence suggests that apoptosis may be involved in chronic pain, namely in neuropathic pain. Neuropathic pain is a chronic pain state caused by primary damage or dysfunction of the nervous system; however, the details of the molecular mechanisms have not yet been fully elucidated. Recently, it was found that nerve endings contain transient receptor potential (TRP) channels that sense and detect signals released by injured tissues and respond to these damage signals. TRP channels are similar to the voltage-gated potassium channels or nucleotide-gated channels that participate in calcium and magnesium homeostasis. TRP channels allowing calcium to penetrate into nerve terminals can activate apoptosis, leading to nerve terminal destruction. Further, some TRPs are activated by acid and reactive oxygen species (ROS). ROS are mainly produced in the mitochondrial respiratory chain, and an increase in ROS production and/or a decrease in the antioxidant network may induce oxidative stress (OS). Depending on the OS levels, they can promote cellular proliferation and/or cell degeneration or death. Previous studies have indicated that proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), play an important role in the peripheral mediation of neuropathic pain. This article aims to perform a review of the involvement of apoptosis in pain, particularly the role of OS and neuroinflammation, and the clinical relevance of this knowledge. The potential discovery of new biomarkers and therapeutic targets can result in the development of more effective and targeted drugs to treat chronic pain, namely neuropathic pain. Highlights: Oxidative stress and neuroinflammation can activate cell signaling pathways that can lead to nerve terminal destruction by apoptosis. These could constitute potential new pain biomarkers and targets for therapy in neuropathic pain.

show abstract

Section: Apoptosis Pathways As Mediators Of Pain Formationmentioning

confidence: 99%

Section: Apoptosis Pathways As Mediators Of Pain Formationmentioning

confidence: 99%

Apoptosis and (in) Pain—Potential Clinical Implications

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The previous studies have indicated that increased expressions of TNF-α and IL-1β were associated with pain-related behaviors in a rat model of SCI (Detloff et al, 2008 ). The proinflammatory factor could induce SCI rat hyperalgesia via upregulating the excitability of superficial dorsal horn neurons (Fakhri et al, 2021 ). RIPK3 is a key kinase in regulating inflammatory factors (Yabal et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Receptor-Interacting Protein Kinase 3 Inhibition Relieves Mechanical Allodynia and Suppresses NLRP3 Inflammasome and NF-κB in a Rat Model of Spinal Cord Injury

Xue

Cao

Wang

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

BackgroundNeuroinflammation is critical in developing and maintaining neuropathic pain after spinal cord injury (SCI). The receptor-interacting protein kinase 3 (RIPK3) has been shown to promote inflammatory response by exerting its non-necroptotic functions. In this study, we explored the involvement of RIPK3 in neuropathic pain after SCI.MethodsThoracic (T10) SCI rat model was conducted, and the mechanical threshold in rats was measured. The expressions of RIPK3, nod-like receptor family pyrin domain-containing protein 3 (NLRP3), caspase-1, and nuclear factor-κB (NF-κB) were measured with western blotting analysis or quantitative real-time polymerase chain reaction (qRT-PCR). Double immunofluorescence staining was used to explore the colabeled NLRP3 with NeuN, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adapter molecule 1 (IBA1). In addition, enzyme-linked immunosorbent assay (ELISA) was applied to analyze the levels of proinflammatory factors interleukin 1 beta (IL-1β), interleukin 18 (IL-18), and tumor necrosis factor alpha (TNF-α).ResultsThe expression of RIPK3 was elevated from postoperative days 7–21, which was consistent with the development of mechanical allodynia. Intrathecal administration of RIPK3 inhibitor GSK872 could alleviate the mechanical allodynia in SCI rats and reduce the expression levels of RIPK3. The activation of NLRP3 inflammasome and NF-κB was attenuated by GSK872 treatment. Furthermore, immunofluorescence suggested that NLRP3 had colocalization with glial cells and neurons in the L4–L6 spinal dorsal horns. In addition, GSK872 treatment reduced the production of inflammatory cytokines.ConclusionOur findings indicated that RIPK3 was an important facilitated factor for SCI-induced mechanical allodynia. RIPK3 inhibition might relieve mechanical allodynia by inhibiting NLRP3 inflammasome, NF-κB, and the associated inflammation.

show abstract

“… 3 , 4 SCI triggers a sequential set of pathophysiological processes that can be classified as primary and secondary injury. 5 Acute primary injury commonly occurs due to the mechanical insult, which can be caused by laceration, contusion, compression, or transection. 6 , 7 These events severely disrupt neuronal pathways and axonal networks, cause hemorrhage, and compromise the blood-spinal cord barrier (BSCB).…”

Section: Introductionmentioning

confidence: 99%

Regulatory Role of Mesenchymal Stem Cells on Secondary Inflammation in Spinal Cord Injury

QM¹,

Sy²,

SP³

et al. 2022

JIR

View full text Add to dashboard Cite

Spinal cord injury (SCI) is a catastrophic condition with high morbidity and mortality that still lacks effective therapeutic strategies. It is well known that the most important stage in SCI pathogenesis is secondary injury, and among the involved mechanisms, the inflammatory cascade is the main contributor and directly influences neurological function recovery. In recent years, increasing evidence has shown that mesenchymal stem cells (MSCs) transplantation is a promising immunomodulatory strategy. Transplanted MSCs can regulate macrophage-, astrocyte-, and T lymphocyte-mediated neuroinflammation and help create a microenvironment that facilitates tissue repair and regeneration. This review focuses on the effects of different types of immune cells and MSCs, specifically the immunoregulatory capacity of MSCs in SCI and repair. We will also discuss how to exploit MSCs transplantation to regulate immune cells and develop novel therapeutic strategies for SCI.

show abstract

On the therapeutic targets and pharmacological treatments for pain relief following spinal cord injury: A mechanistic review

Cited by 21 publications

References 450 publications

Apoptosis and (in) Pain—Potential Clinical Implications

Apoptosis and (in) Pain—Potential Clinical Implications

Receptor-Interacting Protein Kinase 3 Inhibition Relieves Mechanical Allodynia and Suppresses NLRP3 Inflammasome and NF-κB in a Rat Model of Spinal Cord Injury

Regulatory Role of Mesenchymal Stem Cells on Secondary Inflammation in Spinal Cord Injury

Contact Info

Product

Resources

About