SAFit2 reduces neuroinflammation and ameliorates nerve injury-induced neuropathic pain

Abstract

Background Neuropathic pain is experienced worldwide by patients suffering from nerve injuries, infectious or metabolic diseases or chemotherapy. However, the treatment options are still limited because of low efficacy and sometimes severe side effects. Recently, the deficiency of FKBP51 was shown to relieve chronic pain, revealing FKBP51 as a potential therapeutic target. However, a specific and potent FKBP51 inhibitor was not available until recently which hampered targeting of FKBP51. Methods In this study, we used the well-established and robust spared nerve injury model to analyze the effect of SAFit2 on nerve injury-induced neuropathic pain and to elucidate its pharmacodynamics profile. Therefore, the mice were treated with 10 mg/kg SAFit2 after surgery, the mice behavior was assessed over 21 days and biochemical analysis were performed after 14 and 21 days. Furthermore, the impact of SAFit2 on sensory neurons and macrophages was investigated in vitro. Results Here, we show that the FKBP51 inhibitor SAFit2 ameliorates nerve injury-induced neuropathic pain in vivo by reducing neuroinflammation. SAFit2 reduces the infiltration of immune cells into neuronal tissue and counteracts the increased NF-κB pathway activation which leads to reduced cytokine and chemokine levels in the DRGs and spinal cord. In addition, SAFit2 desensitizes the pain-relevant TRPV1 channel and subsequently reduces the release of pro-inflammatory neuropeptides from sensory neurons. Conclusions SAFit2 ameliorates neuroinflammation and counteracts enhanced neuronal activity after nerve injury leading to an amelioration of nerve injury-induced neuropathic pain. Based on these findings, SAFit2 constitutes as a novel and promising drug candidate for the treatment of nerve injury-induced neuropathic pain.

The FKBP51 Inhibitor SAFit2 Restores the Pain-Relieving C16 Dihydroceramide after Nerve Injury

“…Moreover, the highly potent FKBP51 inhibitor SAFit2 has been shown to pass the blood-brain barrier [7,8], indicating that SAFit2 is also able to pass the blood spinal cord barrier and can mediate analgesic effects in the central and peripheral nervous system. Likewise, we recently showed that SAFit2 ameliorates neuropathic pain in vivo as it counteracts the enhanced neuronal activity and reduces neuroinflammation after nerve injury [9]. These previous reports highlight the concept of FKBP51 inhibitors as a potential novel treatment approach for neuropathic pain.…”

“…Based on that, it might be beneficial to maintain the TRPV1 activity in a physiological state and to reduce its sensitization, which mainly occurs in inflammation-related pain states. In conclusion, the desensitizing effects of the C16 dihydroceramide further contribute to the analgesic effects of SAFit2, which are capable of mediating pain relief after neve injury [9].…”

“…However, a SAFit2 treatment was capable to restore the physiological level of DHA after SNI to a level comparable to sham mice. Since docosahexaenoic acid metabolites were identified as endogenous TRP inhibitors, which can contribute to the relief of inflammation and pain [33], these results indicate that SAFit2 can restore omega-3 polyunsaturated fatty acids as precursors for potentially antihyperalgesic lipids, thereby resolving mechanical hypersensitivity after SNI [9]. Nonetheless, synthesis, signaling, and occurrence of SPM in tissues have been the subject of controversies, because of the inability and inconsistency of their detection with analytical methods in biological samples [42].…”

“…Based on the previous findings that SAFit2 reduces mechanical hypersensitivity after nerve injury [9], we investigated the influence of the C16 dihydroceramide (d18:0/16:0), which is named as C16 or C16 dihydroceramide in the following, on pain-sensing calcium channels. Firstly, we characterized the impact of C16 on the TRPV1 channel, as it is the most important and most abundantly expressed pain-mediating, ligand-gated calcium channel in sensory neurons, and plays a crucial role in the development of various pain conditions, including neuropathic pain [26].…”

“…These previous reports highlight the concept of FKBP51 inhibitors as a potential novel treatment approach for neuropathic pain. Mechanistically, SAFit2 reduces the NF-κB pathway activation after nerve injury, potentially also modulating crucial target genes in the NF-κB downstream signaling [9]. NF-κB itself is a crucial transcription factor in lipid metabolism as it regulates the expression of various enzymes, such as cyclooxygenases, lipoxygenases, and phospholipases [10,11].…”