Biology subjects

Iseppon, F.

Publications and source records attributed to Iseppon, F..

4 recordsLinked to original sources

bioRxiv2026

E-Selectin Orchestrates IL-1B-Dependent Neuroinflammation via NLRP3 in Vincristine-Induced Neuropathy

Vincristine-induced peripheral neuropathy (VIPN) is a frequent and dose-limiting complication of cancer therapy, yet the upstream mechanisms coupling vascular activation to neuroinflammation remain poorly defined. Here we identify E-selectin as a critical orchestrator of vincristine-induced neuropathy. Systematic interrogation of endothelial adhesion molecules in a murine model of VIPN revealed that blockade of E-selectin, but not ICAM-1, PECAM-1 or P-selectin, completely prevented mechanical hypersensitivity and markedly reduced F4/80 immune cell accumulation in dorsal root ganglia and peripheral nerves. Genetic deletion of E-selectin conferred equivalent protection, despite the absence of structural loss of intraepidermal or myelinated fibres, indicating a predominantly functional neuroimmune pathology. Spatial transcriptomics demonstrated that vincristine induces a conserved stress and neuroinflammation-associated transcriptional programme in dorsal root ganglia, with immune and stromal populations acting as dominant signalling hubs. Genetic or pharmacological perturbation of E-selectin did not abolish injury-associated pathways but redistributed cell-cell communication networks, reducing immune-cell dominance and reshaping interferon and metabolic signalling states without inducing Sele expression. Mechanistically, E-selectin exerted non-canonical effects beyond endothelial adhesion. Local E-selectin administration was sufficient to induce macrophage-dependent mechanical hypersensitivity that was abolished in Fut4/7-deficient mice and following phagocyte depletion. In macrophages, E-selectin enhanced vincristine-driven NF-{kappa}B activation, NLRP3 inflammasome assembly and IL-1{beta} release. Together, these findings position E-selectin as an upstream regulator of IL-1{beta}-dependent neuroinflammation in VIPN and identify selective targeting of E-selectin-mediated immune-neuron interactions as a therapeutic strategy for chemotherapy-induced neuropathy.

neuroscience↗

bioRxiv2024

Novel therapies for cancer-induced bone pain

1.Cancer pain is a growing problem, especially with the substantial increase in cancer survival. Reports indicate that bone metastasis, whose primary symptom is bone pain, occurs in 65-75% of patients with advanced breast or prostate cancer. We optimized a preclinical in vivo model of cancer-induced bone pain (CIBP) involving the injection of Lewis Lung Carcinoma cells into the intramedullary space of the femur of C57BL/6 mice or transgenic mice on a C57BL/6 background. Mice gradually reduce the use of the affected limb, leading to altered weight bearing. Symptoms of secondary cutaneous heat sensitivity also manifest themselves. Following optimization, three potential analgesic treatments were assessed; 1) single ion channel targets (targeting the voltage-gated sodium channels NaV1.7, NaV1.8, or acid-sensing ion channels), 2) silencing {micro}-opioid receptor-expressing neurons by modified botulinum compounds, and 3) targeting two inflammatory mediators simultaneously (nerve growth factor (NGF) and tumor necrosis factor (TNF)). Unlike global NaV1.8 knockout mice which do not show any reduction in CIBP-related behavior, embryonic conditional NaV1.7 knockout mice in sensory neurons exhibit a mild reduction in CIBP-linked behavior. Modified botulinum compounds also failed to cause a detectable analgesic effect. In contrast, inhibition of NGF and/or TNF resulted in a significant reduction in CIBP-driven weight-bearing alterations and prevented the development of secondary cutaneous heat hyperalgesia. Our results support the inhibition of these inflammatory mediators; and more strongly their dual inhibition to treat CIBP, given the superiority of combination therapies in extending the time needed to reach limb use score zero in our CIBP model.

neuroscience↗

bioRxiv2024

Analgesic targets identified in mouse sensory neuron somata and terminal pain translatomes

The relationship between transcription and protein expression is complex. We identified polysome-associated RNA transcripts in the somata and central terminals of mouse sensory neurons in control, painful (+ Nerve Growth Factor (NGF)) and pain-free conditions (Nav1.7 null mice). The majority (98%) of translated transcripts are shared between male and female mice in both the somata and terminals. Some transcripts are highly enriched in the somata or terminals. Changes in the translatome in painful and pain-free conditions include novel and known regulators of pain pathways. Antisense knockdown of selected somatic and terminal polysome-associated transcripts that correlate with pain states diminished pain behaviour. Terminal-enriched transcripts encoding synaptic proteins (e.g. Synaptotagmin), non-coding RNAs, transcription factors (e.g. Znf431), proteins associated with trans-synaptic trafficking (HoxC9), GABA generating enzymes (Gad1 and Gad2) and neuropeptides (Penk). Thus, central terminal translation may well be a significant regulatory locus for peripheral input from sensory neurons.

neuroscience↗

bioRxiv2022

Pregabalin silences oxaliplatin-activated sensory neurons to relieve cold allodynia

Oxaliplatin is a platinum-based chemotherapeutic agent that causes cold and mechanical allodynia in up to 90% of patients. Silent NaV1.8-positive nociceptive cold sensors have been shown to be unmasked by oxaliplatin and other neuropathic insults. This event has been causally linked to the development of cold and mechanical allodynia. Pregabalin is an anti-epileptic and analgesic drug that acts through a calcium channel 2{delta}-1 subunit to lower neurotransmitter release. Recent data also suggest pregabalin can act on NMDA receptors and other proteins, but the site of analgesic action has been considered to be the central nervous system. We examined the effects of pregabalin on oxaliplatin-evoked unmasking of cold sensitive neurons using mice expressing GCaMP-3 driven by a Pirt promoter in all sensory neurons. We found that in mice treated with oxaliplatin, intravenous injection of pregabalin significantly decreased cold allodynia. Interestingly, pregabalin also decreased the number of sensory neurons responding to cold nociceptive stimuli by altering their excitability and their temperature thresholds. These silenced neurons are medium/large cells responding to both painful mechanical and cold stimuli, corresponding to the "silent" cold sensors that become active in numerous neuropathic pain models. Deletion of 2{delta}-1 subunits abolished the effects of pregabalin on both cold allodynia and the silencing of sensory neuron unmasked by oxaliplatin. Taken together, these results define a novel, peripheral inhibitory effect of pregabalin on the excitability of silent cold-sensing neurons in a model of oxaliplatin-dependent cold allodynia. Abbreviated SummaryIseppon et al. report a novel, peripheral effect of pregabalin on oxaliplatin-dependent cold allodynia. The drug exerts its effect by silencing a specific sub-population of neurons responding to cold and mechanical stimuli in the dorsal root ganglion, and this effect is dependent on the 2{delta}-1 subunit of voltage-gated calcium channels.

neuroscience↗