Background & Aims

Diabetic neuropathy (DN) is a common complications of diabetes mellitus. Patients with DN exhibit abnormal sensory perception such as allodynia and hyperalgesia that contributes to poor quality of life. However, no effective therapy is available. Lysophosphatidic acid (LPA) is known as a lipid mediator that causes neuropathic pain (NP) through one of its receptors, LPA1 receptor (LPA1R). Previous reports have shown that LPA levels in the cerebrospinal fluid in patients with NP were elevated and associated with pain intensity. Schwann cell-specific deletion of LPA1R occurs recovery from allodynia in a NP mice model. However, there is no LPA1R antagonist which achieve a high enough peripheral nerve concentration. Hence, we identified a novel LPA1R antagonist UD-039, which shows high transferability to peripheral nerve, and UD-059Na, a prodrug with improved oral bioavailability of UD-039. We evaluated recovery effects of UD-059Na in Streptozotocin (STZ)-induced rats as model of DN.

Methods

Diabetic neuropathy was induced by a single intraperitoneal injection of 50 mg/kg STZ to male Wistar rats. Two weeks after STZ injection, rats were orally administered with UD-059Na at 0.1, 1, 10 mg/kg daily for 2 weeks. To measure allodynia, 50% paw withdrawal threshold (PWT) was determined using von Frey filaments, based on the up-down method. PWT was assessed at 60 and 150 minutes after the first dose and thereafter weekly from 1 to 3 week. At the end of the experimental period, STZ rats were measured nerve conduction velocity (NCV) of the sciatic nerve using electromyography under isoflurane anesthesia. STZ rats were euthanized, the skin tissue was collected, and intraepidermal nerve fiber (IENF) density was evaluated based on immunohistochemistry using PGP9.5 antibody.

Results

We evaluated anti-neuropathic effects of UD-059Na in a STZ-induced rat model. In STZ rats, UD-059Na significantly improved mechanical allodynia in a dose-dependent manner at 60 and 150 minutes after the first dose. Chronic administration of UD-059Na showed that PWT gradually recovered over time and recovered to the same level as normal on 4 weeks after STZ injection, while other LPA1R antagonist with less transfer to the peripheral nerves showed no recovery effects. Whereas UD-059Na did not affect plasma glucose level or body weight. Interestingly, these recovery efficacies of UD-059Na continued after one-week treatment discontinuation, although plasma concentrations of UD-039, active form of UD-059Na, were undetectable. In addition, UD-059Na also reversed the slowing of NCV and reduction of IENF density.

Conclusions

This study showed that UD-059Na, a prodrug of UD-039, has significant anti-neuropathic effects and these effects persist even after discontinuation of administration. It has been suggested that LPA induced neuropathy via LPA1R and inhibition of LPA1R in peripheral nerve might lead to therapeutic effects on diabetic neuropathy. Therefore, UD-059Na may appear to be a novel therapeutic approach for neuropathic pain, which is different from current therapy.

References

Kuwajima K, Sumitani M, Kurano M, Kano K, et al. Lysophosphatidic acid is associated with neuropathic pain intensity in humans: An exploratory study. PLoS One. 2018;13:e0207310.
Rivera RR, Lin ME, Bornhop EC, et al. Conditional Lpar1 gene targeting identifies cell types mediating neuropathic pain. FASEB J. 2020;34:8833-8842.

Presenting Author

Sayaka Ogi

Poster Authors

Sayaka Ogi

MSc

UBE Corporation

Lead Author

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Kenji Nishikawa

UBE Corporation; Yamaguchi University Graduate School of Medicine

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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Hidenori Suzuki

MD

Yamaguchi University Graduate School of Medicine

Lead Author

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Yasuhiro Aga

PhD

UBE Corporation

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Topics

  • Models: Chronic Pain - Neuropathic