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Inhibiting IB Kinase- Downregulates Inflammatory Cytokines in Injured Discs and Neuropeptides in Dorsal Root Ganglia Innervating Injured Discs in Rats

Kobori, Sayako*; Miyagi, Masayuki MD, PhD; Orita, Sumihisa MD, PhD; Gemba, Takefumi PhD‡,§; Ishikawa, Tetsuhiro MD, PhD; Kamoda, Hiroto MD, PhD; Suzuki, Miyako MD; Hishiya, Takatoshi*; Yamada, Toshihide*; Eguchi, Yawara MD, PhD*; Arai, Gen MD*; Sakuma, Yoshihiro MD; Oikawa, Yasuhiro MD*; Aoki, Yasuchika MD, PhD; Toyone, Tomoaki MD, PhD; Takahashi, Kazuhisa MD, PhD; Inoue, Gen MD, PhD; Ohtori, Seiji MD, PhD

Spine:
doi: 10.1097/BRS.0000000000000374
Basic Science
Abstract

Study Design. Quantitative and immunohistological analysis of the efficacy of an IκB kinase-β (IKKβ) inhibitor in an injured intervertebral disc (IVD) model.

Objective. To elucidate the efficacy of an IKKβ inhibitor on inflammatory cytokine levels in injured IVDs or on neuropeptide levels in the dorsal root ganglia (DRG) neurons innervating injured IVDs in rats.

Summary of Background Data. Multiple studies have suggested that upregulation of inflammatory cytokines in damaged IVDs causes discogenic low back pain. The efficacy of blocking individual inflammatory cytokines is limited; however, inflammatory cytokine stimuli often require IKKβ to activate nuclear factor-k B.

Methods. Sprague-Dawley rats were divided into 3 groups: sham, saline (disc-injury plus saline), and IKKβ (disc-injury plus anti-IKKβ). To induce injury, IVDs were repeatedly punctured.

Experiment 1: Four, 7, and 14 days postinjury, coccygeal (Co) 5/6, Co6/7, and Co7/8 IVDs were resected and tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 levels were quantified by enzyme-linked immunosorbent assay. Experiment 2: The neurotracer Fluoro-Gold was injected into injured L5–L6 IVDs and uninjured sham group IVDs to detect DRG neurons. One week postsurgery, L1–L6 DRGs were immunolabeled with the neuropeptide calcitonin gene-related peptide. The proportions of Fluoro-Gold-labeled calcitonin gene-related peptide-immunoreactive DRG neurons were assessed.

Results. Experiment 1: IVD levels of tumor necrosis factor-α (through 2 wk), IL-1β (at 4 d), and IL-6 (at 4 d) were significantly higher in the saline group than in the sham group, and significantly lower in the IKKβ group than in the saline group (P < 0.05). Experiment 2: The percentage of calcitonin gene-related peptide-immunoreactive Fluoro-Gold-labeled DRG neurons was significantly higher in the saline group than in the sham group, and significantly lower in the IKKβ group than in the saline group (P < 0.05).

Conclusion. Injury-induced upregulation of inflammatory cytokines within IVDs and increased levels of neuropeptides within DRG neurons can be suppressed by inhibiting IKKβ.

Level of Evidence: N/A

In Brief

Injury-induced upregulation of inflammatory cytokines within intervertebral discs and upregulation of dorsal root ganglia neuron-associated neuropeptides can be suppressed by inhibiting I&amp;#x03BA;B kinase (IKK) &amp;#x03B2;. This finding helps elucidate the mechanism by which IKK&amp;#x03B2; inhibitors alleviate discogenic low back pain.

Author Information

*School of Medicine, Chiba University, Chiba, Japan

Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan

IMMD Inc., Tokyo, Japan

§Chiralgen Ltd., Chiba, Japan

Department of Orthopaedic Surgery, Toho University Sakura Medical Center, Sakura, Japan

Department of Orthopaedic Surgery, Teikyo University Chiba Medical Center, Chiba, Japan.

Address correspondence and reprint requests to Masayuki Miyagi, MD, PhD, Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan; E-mail address: masayuki008@aol.com

Acknowledgment date: May 5, 2013. First revision date: August 5, 2013. Second revision date: November 26, 2013. Third revision date: January 19, 2014. Acceptance date: March 31, 2014.

The manuscript submitted does not contain information about medical device(s)/drug(s).

No funds were received in support of this work.

No relevant financial activities outside the submitted work.

© 2014 by Lippincott Williams & Wilkins