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. 2019 Mar 25;4(2):e719.
doi: 10.1097/PR9.0000000000000719. eCollection 2019 Mar-Apr.

Sez6 levels are elevated in cerebrospinal fluid of patients with inflammatory pain-associated conditions

Maria Roitman  1 , Laura E Edgington-Mitchell  2   3   4 , Jon Mangum  5 , James Ziogas  5 , Alexios A Adamides  6 , Paul Myles  7 , Hearan Choo-Bunnett  8 , Nigel W Bunnett  8 , Jenny M Gunnersen  1
Affiliations

Sez6 levels are elevated in cerebrospinal fluid of patients with inflammatory pain-associated conditions

Maria Roitman et al. Pain Rep. .

Abstract

Introduction: Seizure-related protein 6 (Sez6) contributes to chronic pain development as sez6 knockout mice show attenuated pain behaviours after peripheral nerve injury, compared with control mice. The type I transmembrane isoform of Sez6 is cleaved by the β-amyloid precursor protein cleavage enzyme 1 (BACE1), resulting in Sez6 extracellular domain shedding from the neuron surface.

Objectives: To determine whether this BACE1-shed form of Sez6 can be detected in the cerebrospinal fluid (CSF) and whether Sez6 levels in the CSF are altered in neuropathic pain or chronic inflammatory pain (IP).

Methods: We analysed the CSF samples collected during surgery from patients with chronic neuropathic pain (n = 8) or IP (n = 33), comparing them to the CSF samples from patients with suspected subarachnoid haemorrhage that was subsequently excluded (nonsurgical group, n = 5). Western blots were used to determine the relative Sez6 levels in the CSF from the different patient and nonsurgical comparison groups.

Results: The results show that BACE1-shed Sez6 can be readily detected in the CSF by Western blot and that the levels of Sez6 are significantly higher in the IP group than in the nonsurgical comparison group.

Conclusion: The association between elevated Sez6 levels in the CSF and IP is further evidence for persistent alterations in central nervous system activity in chronic IP conditions.

Keywords: BACE1; CSF; Chronic pain; Inflammatory pain; Seizure-related protein 6.

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Conflict of interest statement

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Figures

Figure 1.
Figure 1.
Relative Sez6 levels in the CSF by condition. Example of (A) stain-free and (B) Chemi Hi-Resolution Western blots used for analysis of total protein and Sez6 protein levels, respectively. For each sample, 10 or 5 μL was loaded (left or right lanes of each pair, respectively). CSF, cerebrospinal fluid.
Figure 2.
Figure 2.
Cerebrospinal fluid Sez6 levels are significantly elevated in inflammatory, but not neuropathic, pain patients compared with samples from the nonsurgical comparison group. A significant increase in shed Sez6 levels in patients with inflammatory pain (n = 33, P < 0.05) was detected compared to samples from the nonsurgical comparison group (n = 5). No significant difference in patients with neuropathic pain (n = 8, p > 0.05) was observed compared to the control samples. CSF, cerebrospinal fluid.
Figure 3.
Figure 3.
Relative CSF Sez6 levels are not correlated with pain severity scores. (A) Heat maps of modified Brief Pain Inventory (mBPI) pain severity scores and relative Sez6 levels. (B) Linear regression of mBPI pain severity score in patients with neuropathic (y = −0.1115x + 1.703) and inflammatory (y = 0.1118x + 2.484) pain. Dark triangles represent patient outliers (1.5 × interquartile range) for relative Sez6 levels. Pain severity scores were not significantly correlated with CSF Sez6 levels (P > 0.05). CSF, cerebrospinal fluid.
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