Novel proresolving lipid mediator mimetic 3-oxa-PD1n-3 docosapentaenoic acid reduces acute and chronic itch by modulating excitatory and inhibitory synaptic transmission and astroglial secretion of lipocalin-2 in mice

Abstract

Specialized proresolving mediators (SPMs) have demonstrated potent analgesic actions in animal models of pathological pain. The actions of SPMs in acute and chronic itch are currently unknown. Recently, n-3 docosapentaenoic acid (DPA) was found to be a substrate for the biosynthesis of several novel families of SPMs and 3-oxa-PD1 n-3 DPA (3-oxa-PD1) is an oxidation-resistant metabolic stable analogue of the n-3 DPA-derived protectin D1 (PD1). In this article, we demonstrate that 3-oxa-PD1 effectively reduces both acute and chronic itch in mouse models. Intrathecal injection of 3-oxa-PD1 (100 ng) reduced acute itch induced by histamine, chloroquine, or morphine. Furthermore, intrathecal 3-oxa-PD1 effectively reduced chronic itch, induced by cutaneous Tcell lymphoma (CTCL), allergic contact dermatitis with dinitrofluorobenzene, and psoriasis by imiquimod. Intratumoral injection of 3oxa-PD1 also suppressed CTCL-induced chronic itch. Strikingly, the antipruritic effect lasted for several weeks after 1-week intrathecal 3-oxa-PD1 treatment. Whole-cell recordings revealed significant increase in excitatory postsynaptic currents in spinal dorsal horn (SDH) neurons of CTCL mice, but this increase was blocked by 3-oxa-PD1. 3-oxa-PD1 further increased inhibitory postsynaptic currents in SDH neurons of CTCL mice. Cutaneous T-cell lymphoma increased the spinal levels of lipocalin-2 (LCN2), an itch mediator produced by astrocytes. 3-oxa-PD1 suppressed LCN2 production in CTCL mice and LCN2 secretion in astrocytes. Finally, CTCL-induced anxiety was alleviated by intrathecal 3-oxa-PD1. Our findings suggest that 3-oxa-PD1 potently inhibits acute and chronic itch through the regulation of excitatory or inhibitory synaptic transmission and astroglial LCN2 production. Therefore, stable SPM analogs such as 3-oxa-PD1 could be useful to treat pruritus associated with different skin injuries.

Biology and Total Synthesis of n-3 Docosapentaenoic Acid-Derived Specialized Pro-Resolving Mediators

“…The biological evaluations of simpler chemical synthetic analogs of the 12 n-3 DPA-derived SPMs known will also be of future interest. Some studies have emerged recently [ 86 , 87 ]. However, success in such endeavors is dependent on stereoselective synthesis of the native SPMs highlighted herein, but also the synthesis of isomers [ 88 ] and analogs [ 86 ], in particular since SPMs are produced in nanogram amounts in living systems, making NMR studies for their exact structural elucidation impossible to perform [ 89 ].…”

“Next top” mouse models advancing CTCL research

“…The NOD SCID mouse model, formally designated as the NOD. CB17-Prkdc scid strain, is valuable in CTCL research as recipient mice due to its lack of mature T and B cells, making it suitable not only for studying pruritus—a hallmark symptom of CTCL ( Prochazka et al, 1992 ) —but also for investigating tumor growth and early symptoms ( Chen et al, 2023 ; Furutani et al, 2023 ). Employing the NOD SCID mice for the CTCL model, LW-213 was found to significantly inhibit CTCL tumor growth and enhance survival rates ( Yu et al, 2021 ).…”

Annexin 1 Reduces Dermatitis-Induced Itch and Cholestatic Itch through Inhibiting Neuroinflammation and Iron Overload in the Spinal Dorsal Horn of Mice

“…Astrocytes that are involved in neuroinflammatory process and dorsal horn synaptic plasticity in the spinal cord are one of the most important contributors to the pathogenesis of persistent pruritus [7][8][9]. Biochemical experiments were employed to quantitatively measure spinal IL-17, IL-17R, GFAP, iron content and iron metabolism-related proteins (TfR1, IRP1 and DMT1).…”

“…Current research has recapitulated the important roles of astrocyte-coding neuroinflammation in the spinal cord neurocircuits for chronic itch pathogenesis, which is associated with excitatory pruriceptive synaptic plasticity and central itch-specific neuronal sensitization [7][8][9]. Specifically, the long-lasting existence of astrocyte activation is uncovered in the dorsal horn of the spinal cord in rodent animals undergoing atopic dermatitis and contact dermatitis [10].…”