NeuropharmacologyResearch PaperDistribution and tumor necrosis factor-alpha isoform binding specificity of locally administered etanercept into injured and uninjured rat sciatic nerve
Section snippets
Animals and anesthesia
A total of 52 Adult female Sprague–Dawley rats (Harlan Laboratories, Indianapolis, IN, USA) weighing 200–250 g were used. Rats were housed in pairs with a 12-h light/dark cycle with free access to food and water. The experimental protocols were approved by the VA Healthcare System Committee on Animal Research, and conform to the NIH Guidelines for Animal Use. All efforts were made to minimize animal suffering and to reduce the number of animals used. The animals were anesthetized with 4%
Immunohistochemistry for etanercept in uninjured nerve
To stain for etanercept itself in the nerve tissue, we developed a method using anti-human IgG antibody that detects its Fc portion of human IgG (Fig. 1A). All the sections from the normal nerve without application of etanercept yielded negative staining with anti-human IgG antibody (Fig. 1B). At 1 h after intraneurial injection of etanercept into rat sciatic nerve, widespread distribution of the etanercept–human IgG immunoreactivity was observed in the endoneurial space of the nerve (Fig. 1B).
Discussion
Etanercept has great promise in managing the progression of inflammatory diseases, and it has been used experimentally in painful neuropathy. Locally administered etanercept has potential as a targeted immunomodulating agent to treat local pathogenesis in neuropathic pain after peripheral nerve injury and might therefore minimize potential systemic adverse effects of etanercept administration (Tobinick and Britschgi-Davoodifar 2003, Tobinick 2009). This is perhaps the more appropriate method
Conclusion
In conclusion, locally administered etanercept reaches the endoneurial space in the injured nerve and preferentially binds to transmembrane and bioactive trimer TNF isoforms. We speculate that locally administered etanercept after nerve injury may exert more specific therapeutic effects in local lesions and minimize side effects compared with systemically administered etanercept.
Acknowledgments
The authors gratefully acknowledge Jennifer Dolkas for expert technical assistance. This work was supported by the Veteran Affairs Rehabilitation R&D Program. Disclosure statements: The devices and drugs that are the subject of this manuscript are not FDA approved for this indication. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.
References (46)
- et al.
Regulation of VCAM-1 expression and involvement in cell adhesion to murine microvascular endothelium
Cell Immunol
(1993) - et al.
Quantitative assessment of tactile allodynia in the rat paw
J Neurosci Methods
(1994) Intrathecal toxicity studies with benzyl alcohol
Toxicol Appl Pharmacol
(1973)- et al.
Serial determination of tumor necrosis factor-a content in rat sciatic nerve after chronic constriction injury
Exp Neurol
(1999) - et al.
Wallerian degeneration after crush injury of rat sciatic nerve increases endo- and epineurial tumor necrosis factor-alpha protein
Neurosci Lett
(2004) - et al.
The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor
Cell
(1995) - et al.
The benefit/risk profile of TNF-blocking agents: findings of a consensus panel
Semin Arthritis Rheum
(2005) - et al.
A comparison of chronic pain behavior following local application of tumor necrosis factor alpha to the normal and mechanically compressed lumbar ganglia in the rat
Pain
(2002) - et al.
Effect of different tumor necrosis factor (TNF) reactive agents on reverse signaling of membrane integrated TNF in monocytes
Cytokine
(2004) - et al.
MMPs initiate Schwann cell-mediated MBP degradation and mechanical nociception after nerve damage
Mol Cell Neurosci
(2008)
Antibody pharmacokinetics and pharmacodynamics
J Pharmacol Sci
Proximodistal gradient in endoneurial fluid pressure
Exp Neurol
The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets
Drug Discov Today
Upregulation and interaction of TNFalpha and gelatinases A and B in painful peripheral nerve injury
Brain Res
TNF alpha-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve
Mol Cell Neurosci
Tumor necrosis factor-alpha in immune-mediated demyelination and wallerian degeneration of the rat peripheral nervous system
J Neuroimmunol
Perispinal etanercept for neuroinflammatory disorders
Drug Discov Today
Tumor necrosis factor antagonist mechanisms of action: a comprehensive review
Pharmacol Ther
Schwann cells produce TNF-alpha: expression in injured and non-injured nerves
Neuroscience
Perineural permeability increases during wallerian degeneration
Brain Res
Perineurial permeability to sodium during wallerian degeneration in rat sciatic nerve
Brain Res
Changes in tactile stimuli-induced behavior and c-Fos expression in the superficial dorsal horn and in parabrachial nuclei after sciatic nerve crush
J Comp Neurol
Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and metal-analysis of rare harmful effects in randomized controlled trials
JAMA
Cited by (25)
Peripheral-to-central immune communication at the area postrema glial-barrier following bleomycin-induced sterile lung injury in adult rats
2020, Brain, Behavior, and ImmunityCitation Excerpt :Negative controls for TNF-α and IL-6 consisted only of primary antibody exclusion. These antibodies were selected based on the literature, which supported their use: i) throughout the CNS/PNS, ii) with pre-absorption (TNF-α: (Wei et al., 2008; Kato et al., 2009; Fuchs et al., 2013); IL-6: (Leibinger et al., 2013; Wei et al., 2013b; Chen et al., 2018)), or iii) for neutralization (TNF-α (Nadeau and Rivest, 2000; Wei et al., 2008; Wang et al., 2019); IL-6 (Faustino et al., 2011; Shrivastava et al., 2017; Sun et al., 2017; Wang et al., 2019)). In co-localization studies, we took precautions to minimize potential cross-reactivity between antibodies by utilizing a serial protocol (Guo et al., 2007; Wei et al., 2008; Jones et al., 2019).
Nuclear factor erythroid 2-related factor 2 antibody attenuates thermal hyperalgesia in the dorsal root ganglion: Neurochemical changes and behavioral studies after sciatic nerve-pinch injury
2016, InjuryCitation Excerpt :Bester and colleagues reported that a rat sciatic nerve pinch for 30 s resulted in an inconsistent, but marked tactile allodynia manifesting first at 3 weeks and persisting for up to 52 weeks [6]. Kato and co-workers reported that a rat sciatic nerve pinch for 5 s induced mechanical hyperalgesia that was evident for a time period of 12 days [5]. These models showed a transient mechanical hypoalgesia that usually develops for a brief period and then is replaced by mechanical hyperalgesia that persists for weeks.
Cellular and molecular insights into neuropathy-induced pain hypersensitivity for mechanism-based treatment approaches
2011, Brain Research ReviewsCitation Excerpt :Besides prevention of the activation of pro-inflammatory cytokines, the cytokines themselves can be blocked. Blocking can be achieved by several pharmacological approaches of which the (soluble) TNF decoy receptor etanercept (which traps TNF-α) and IL-1β receptor antagonists (Kato et al., 2009; Schafers et al., 2003b; Sweitzer et al., 2001a) are most described and (alone or in combination) are effective in experimental treatment of neuropathy-induced pain hypersensitivity. Also a clinical phase I and phase II trial have recently been completed on the use of epidural etanercept in treatment of peripheral neuropathic pain (sciatica) (see http://clinicaltrials.gov/).
Platelet-rich plasma and cytokines in neuropathic pain: A narrative review and a clinical perspective
2022, European Journal of Pain (United Kingdom)