Sophocarpine alleviates chronic itch in mouse atopic dermatitis by inhibiting spinal astrocyte reactivity and pro-inflammatory signaling

Abstract

Chronic itch is a debilitating symptom of atopic dermatitis (AD). Current therapeutic approaches for managing this condition include topical and systemic pharmacological agents with inconsistent efficacy and potential adverse effects. Sophocarpine (SPC) is a quinolizidine alkaloid derived from Sophora flavescens and has a wide range of bioactive activities, including anticancer, anti-inflammatory, antiviral, and analgesic effects. Recent research has shown that SPC exerts anti-inflammatory, anti-pruritic, and analgesic effects primarily through the inhibition of TRPA1 and TRPV1 channels. In this study, we investigated the antipruritic effects of SPC in an AD mouse model of chronic itch. AD-like chronic itch was induced in mice by topical application of MC903 solution (2 nmol in ethanol) on the shaved nape skin once daily for 14 consecutive days. Spontaneous scratching behaviors were recorded on D8, D10, D12, and D14. AD mice were administered SPC (1, 5, 10, and 20 mg·kg^-1·d^-1, i.p.) from D8 to D14. SPC (500 ng/10 μL) was also intrathecally injected once a day for 7 days. We showed that SPC treatment dose-dependently mitigated scratching behavior and suppressed spinal astrocyte reactivity in AD mice. Histological and imaging analyses revealed that SPC treatment reversed epidermal thickening and attenuated dermal vasodilation. In LPS-stimulated astrocytes in vitro, SPC (20, 80 μM) dose-dependently downregulated the mRNA levels of the proinflammatory factors Tnf, Cxcl1, Ccl2, Il1b, Il6, and Lcn2. In IP3R2 knockout mice, disruption of spinal astrocytic calcium signaling also reduced chronic itch, thereby supporting the involvement of astroglial pathways. Collectively, these results demonstrate that SPC effectively alleviates chronic itch in the AD mouse model by suppressing astrocyte reactivity, likely through modulation of neuroinflammatory and calcium signaling pathways, supporting its potential as a promising therapeutic candidate for the treatment of AD-associated chronic itch. Schematic summary of the main findings illustrating that SPC alleviates chronic itch in AD by inhibiting spinal astrocyte reactivity and pro-inflammatory signaling. Specifically, SPC suppresses the activation of spinal astrocytes in the dorsal horn, reduces the expression of pro-inflammatory mediators, and thereby decreases scratching behavior in AD mice.

Keywords: astrocyte reactivity; atopic dermatitis; calcium signaling; chronic itch; sophocarpine; spinal cord.