FSC231 can alleviate paclitaxel-induced neuralgia by inhibiting PICK1 and affecting related factors

doi:10.1016/j.neulet.2020.135471

Neuroscience Letters

Volume 741, 10 January 2021, 135471

https://doi.org/10.1016/j.neulet.2020.135471 Get rights and content

Highlights

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The treatment of FSC231 could alleviate the shortened foot contraction reflex time.
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The treatment of FSC231 could reduced inhibition rate caused by paclitaxel.
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This may be achieved by inhibiting PICK1 and affecting the secretion of substance P.

Abstract

Aim

To explore the inhibitory effect of FSC231, a PDZ domain inhibitor of protein interacting with C kinase 1 (PICK1), on paclitaxel induced neuralgia and its possible pathways.

Methods

Forty C57BL/6 mice were randomly divided into four groups (n = 10): the control group (CON), the FSC231 group (FSC), the paclitaxel group (PTL) and the FSC231 add paclitaxel group (F + P). Behavioral indictors of mice including the mechanical pain threshold, foot contraction reflex and inhibition rate were evaluated. ELISA, RT-qPCR and Western Blot were performed to determine the expression levels of IL-1β, IL-10, substance P and PICK1.

Results

Compared with the control group, the foot contraction reflex time, mechanical pain threshold and IL-10 levels were significantly reduced in the PTL group, and IL-1β, substance P and PICK1 levels were significantly increased (P < 0.05). Compared with the PTL group, the foot contraction reflex time, mechanical pain threshold and IL-10 level were significantly increased, while IL-1β, SP and PICK1 levels were significantly decreased in the F + P group (P < 0.05).

Conclusion

FSC231 could alleviate paclitaxel-induced neuralgia by inhibiting PICK1 and affecting the secretion of inflammatory factors and substance P. The results of this study provide experimental basis for FSC231 to treat neuralgia caused by chemotherapy.

Introduction

Paclitaxel (Taxol) is a member of taxanes. As a first-line clinical anti-tumor drug [1], paclitaxel has significant therapeutic effects on various malignant tumors and has been widely used in cancer patients. However, dose-dependent neurotoxicity is shown in the treatment process, the most common of which is neuropathic peripheral neuropathic pain [2]. Neuropathic pain is the pain sensation directly caused by the injury or pain of the sensory nervous system of the body, which can persist for months or even years after treatment [3]. At present, the mechanism of Taxol neuropathy pain has not been reported there are clear, and the analgesic drugs currently used are not sensitive to the lack of effective treatments, further influence tumor treatment effect and the quality of life of patients with [4], limits the clinical application of Taxol, therefore, to explore paclitaxel induced pathogenesis and look for effective treatment of neuropathic pain has profound clinical significance.

FSC231, a PDZ domain inhibitor of protein interacting with C kinase 1 (PICK1), has been shown to have analgesic effects. Studies have shown that FSC231 can inhibit synaptic long term enhancement (LTP) and long term suppression (LTD) in hippocampus by inhibiting PICK1's role in GluR2 transport [5]. FSC231 can inhibit the production and maintenance of LTP in rat hippocampus by inhibiting PICK1 [6].

Dorsal root ganglions (DRG) are primary neurons for sensory transmission and, as the first level neurons for pain, play an extremely important role in the peripheral pathogenesis of pain. In this study, we try to confirmed FSC231 has inhibitory effect on the neuropathic pain induced by paclitaxel on dorsal root ganglia in mice, and try to find the possible mechanism.

Section snippets

Animals and drugs

Wild-type male C57BL/6 mice weighted 23−26 g were obtained from Experimental Animal Center of Peking University. The mice were housed under the following conditions: Temperature, 21 °C; humidity, 40–60 %; 12 h light/dark cycle and free access to food and water. Forty C57BL/6 mice aged 8–10 weeks were randomly divided into four groups (n = 10): the control group (CON, intraperitoneal injection of normal saline), the FSC231 group (FSC, intraperitoneal injection of FSC231), the paclitaxel group

Behavioral tests and weight records in each group

The results of foot contraction reflex tests and inhibition rates in mice were shown in Fig. 1 (A) and (B). Compared with the CON group, foot contraction reflex time of other groups’ mice were significantly different (P < 0.05). Among them, FSC group and F + P group mice foot contraction reflex time significantly longer than the CON group (P < 0.05), and the reflex time of foot contraction in PTL group was significantly shorter than that in CON group (P < 0.05). Compared with the PTL group, the

Discussion

Protein interacting with C Kinase 1 (PICK1), a PDZ domain-containing scaffolding protein, interacts with multiple different proteins in the mammalian nervous system and is believed to play important roles in diverse physiological and pathological conditions. PICK1 appears to be required for peripheral nerve injury-induced neuropathic pain development and to be a potential biochemical target for treating this disorder [7]. A study has suggested a critical involvement of protein: PICK1 associated

Conclusion

FSC231, an inhibitor in the PDZ region of PICK1, may have an inhibitory effect on paclitaxel induced peripheral neuralgia, possibly by regulating inflammatory response and the secretion of substance P.

Funding

This study was supported by Natural Science Foundation of Hubei Province (2018CFB275).

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Dysregulation of glutamatergic synapses plays an important role in the pathogenesis of neurological diseases. In addition to mediating excitatory synaptic transmission, postsynaptic glutamate receptors interact with various membrane and intracellular proteins. They form structural and/or signaling synaptic protein complexes and thereby play diverse postsynaptic functions. Recently, several postsynaptic protein complexes have been associated with various neurological diseases and hence, have been characterized as important therapeutic targets. Moreover, novel small molecules and therapeutic peptides targeting and modulating the activities of these protein complexes have been discovered, some of which have advanced through preclinical translational research and/or clinical studies. This article describes the recent investigation of eight key protein complexes associated with the postsynaptic ionotropic and metabotropic glutamate receptors as therapeutic targets for central nervous system diseases.
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View full text

FSC231 can alleviate paclitaxel-induced neuralgia by inhibiting PICK1 and affecting related factors

Highlights

Abstract

Aim

Methods

Results

Conclusion

Introduction

Section snippets

Animals and drugs

Behavioral tests and weight records in each group

Discussion

Conclusion

Funding

Pain

Pain

Pain

Mol. Cell. Neurosci.

Pain

Biochimie

Clinical pharmacokinetics of paclitaxel monotherapy: an updated literature review

Clin. Pharmacokinet.

Identification of a small-molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD

Proc. Natl. Acad. Sci. U. S. A.

The effect of PICK1 PDZ domain inhibitor FSC231 on long-term potentiation of hippocampus in rat

Acta Pharmacol. Sin.