title: Investigation of SAFit2 as a potential treatment option for nerve injury- and chemotherapy-induced neuropathic pain
Creators: name: Wedel, Saskia
Publisher: name: UNSPECIFIED
Year: 2023

description: Neuropathic pain describes a pathological and often chronic pain state that affects around 10% of the world population. The pathological pain arises after nerve lesions which are caused by diverse etiologies, encompassing diseases, medical conditions, and interventions. However, current and recommended treatment strategies carry a high risk of adverse effects and are inefficient in many cases. Consequently, the demand of novel targets and drug candidates for neuropathic pain emerges. In line with this, the focus of this thesis is set on the investigation of SAFit2, a selective FKBP51 inhibitor, as novel treatment option for nerve injury- and chemotherapy-induced neuropathic pain.
In the first part of this thesis, the influence of SAFit2 on nerve injury-induced neuropathic pain and the underlying mechanisms was assessed in a spared nerve injury mouse model. The results showed that SAFit2 ameliorates mechanical hypersensitivity as it diminishes excessive neuroinflammation after nerve injury. More specifically, SAFit2 counteracted an enhanced NF-κB activation and thereby reduced immune cell infiltration as well as pro-inflammatory cytokine and chemokine levels in dorsal root ganglia and spinal cord of nerve injured mice. However, SAFit2 did not impair the immune cell distribution and resolution of inflammation at the site of injury, the sciatic nerve. Besides this, SAFit2 desensitized the pain-mediating ion channel TRPV1 in primary sensory neurons by enhancing the activity of calcineurin, resulting in a reduction of TRPV1-mediated calcium transients. In consequence, SAFit2 decreased the release of the pro-inflammatory neuropeptide calcitonin gene-related peptide (CGRP) as downstream event, leading to a reduction of exacerbated pain transmission and neuroinflammation after nerve injury.
In the second part of this thesis, the impact of SAFit2 on lipid distribution was assessed in a spared nerve injury mouse model, since lipids represent crucial mediators in pain. Interestingly, SAFit2 restored lipid levels after nerve injury, especially levels of the C16 dihydroceramide in dorsal root ganglia. Like SAFit2, C16 dihydroceramide desensitized the pain-mediating ion channel TRPV1 in primary sensory neurons as well as reduced the CGRP release from primary sensory neurons. In line with this, C16 dihydroceramide alleviated acute thermal hypersensitivity in a capsaicin mouse model, indicating its anti-nociceptive properties.
In the third part of this thesis, the effect of SAFit2 on chemotherapy-induced neuropathic pain, especially paclitaxel-induced neuropathic pain, was evaluated in a multiple low dose mouse model. The data demonstrated that SAFit2 efficiently ameliorates paclitaxel-induced mechanical hypersensitivity. Moreover, SAFit2 counteracted paclitaxel-mediated spinal cord gliosis since it reduced the activation of astrocytes and microglia, as well as the levels of pain-mediating chemokines in the spinal cord. Beside the immunological component, the analysis of lipids revealed that SAFit2 increases anti-inflammatory and pro-resolving oxylipin levels in dorsal root ganglia and spinal cord after paclitaxel treatment. These results crucially expand our mechanistic understandings as well as identify how SAFit2 alleviates paclitaxel-induced neuropathic pain and decreases pain contributing processes.
In summary, these insights reveal promising analgesic properties of SAFit2 in the context of nerve injury- and paclitaxel-induced neuropathic pain. Furthermore, SAFit2 mediated a neuropathic pain relief by restoring injury-altered lipid levels and addressing several underlying neuroinflammatory mechanisms. However, the bioavailability and selectivity of SAFit2 has to be improved for preclinical and clinical usage. Based on this, SAFit2 constitutes as novel and promising lead compound and drug precursor for the treatment of nerve injury- and paclitaxel-induced neuropathic pain.