Background & Aims

Neuropathic pain is a complex chronic pain state with a prevalence of almost 10% in the general population. In patients with neuropathic pain, lysophosphatidic acid (LPA) levels are elevated in the cerebrospinal fluid and correlate well with severity. Furthermore, several reports have shown that LPA is associated with demyelination and the development of behavioral allodynia via LPA1 receptors. However, the mechanisms of LPA-induced nerve injury remain unclear. Here, we evaluated anti-demyelination and anti-inflammation effects of LPA1 antagonism and investigated the underlying mechanisms, using our newly identified LPA1 antagonist, UD-039.

Methods

To clarify the effects of LPA on peripheral nerves, 5 µL of 2% LPA in saline was injected into the sciatic nerve of rats under deep anesthesia. We then measured paw withdrawal thresholds with von Frey filaments and evaluated histopathologically the extent demyelination and neuroinflammation. Next, we investigated the detailed underlying mechanism of LPA-induced demyelination and neuroinflammation using IFRS1 cells, a rat Schwann cell line, and primary human Schwann cells. To obtain mature Schwann cells, Both Schwann cells were treated with 250 nM 8-CPT-cAMP for 72hr.

Results

In a rat intraneural injection model, LPA induced severe demyelination and infiltration of inflammatory cells, leading to a significant reduction in pain threshold. Therefore, to analyze the mechanism of LPA-induced injuries, we focused on Schwann cells. In IFRS1 cells, the LPA1 receptor was predominantly expressed compared with other LPA receptors, and LPA increased intracellular Ca influx. In differentiated IFRS1 cells, LPA induced immature cell-like morphological changes, decreased the expression of the maturation markers MBP and PMP22, and increased the expression of the immature marker p75. These results indicates that LPA induced dedifferentiation of mature Schwann cells into immature Schwann cells. LPA induced similar changes in primary human Schwann cells. Additionally, LPA increased the expression of the chemokine CCL2 in a concentration-dependent manner in IFRS1 cells. UD-039, a newly identified LPA1 antagonist, strongly inhibited these LPA-induced effects.

Conclusions

It has been suggested that LPA is involved in pain by acting directly on Schwann cells via the LPA1 receptor to induce demyelination and neuroinflammation. UD-039 is a newly identified small molecule LPA1 antagonist that strongly inhibits LPA-induced demyelination and neuroinflammation in vitro and in vivo. Therefore, UD-039 may be a promising treatment for neuropathic pain.

References

Kuwajima K., Sumitani M., Kurano M., et al. Lysophosphatidic acid is associated with neuropathic pain intensity in humans: An exploratory study. PLoS One. 2018;13: e0207310.

Inoue M., Rashid M.H., Fujita R., et al. Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. Nat Med. 2004;10:712-718.

Rivera R.R., Lin M, Bornhop E.C., Chun J. Conditional Lpar1 gene targeting identifies cell types mediating neuropathic pain. FASEB J. 2020;34:8833-8842.

Presenting Author

Kenji Nishikawa

Poster Authors

Kenji Nishikawa

PhD

UBE Corporation; Yamaguchi University Graduate School of Medicine

Lead Author

E-mail

Sayaka Ogi

UBE Corporation

Lead Author

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Kosei Matsumoto

UBE Corporation

Lead Author

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Eiji Okanari

UBE Corporation

Lead Author

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Yasuhiro Aga

PhD

UBE Corporation

Lead Author

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Topics

  • Mechanisms: Biological-Molecular and Cell Biology