Targeting TRPC5 ameliorates acute migraine symptoms and chronic central sensitization by blocking the PI3K-Akt/P2X7R/IL-1β cascade
Abstract
Abstract Background Central sensitization is the core pathological mechanism underlying the onset and chronification of chronic migraine (CM). The transient receptor potential canonical 5 (TRPC5) channel is involved in multiple pain conditions and modulates central sensitization, yet its specific function and molecular mechanism in acute and chronic migraine remain unclear. This study aimed to investigate the role of TRPC5 and its downstream regulatory pathway in nitroglycerin (NTG)-induced migraine, so as to clarify the novel pathogenic mechanism of migraine. Methods Repetitive NTG injection was used to establish a mouse model of acute and chronic migraine. Migraine-like behaviors, including mechanical allodynia, thermal hyperalgesia and photophobia, were evaluated. qRT-PCR and Western blot were used to detect TRPC5 expression in the primary somatosensory (SSP) cortex. Immunofluorescence staining was performed to identify the cellular localization of TRPC5 and assess the activation status of neurons and microglia. Pharmacological interventions with TRPC5 antagonist AC1903 and PI3K-Akt inhibitor LY294002 were applied to verify the key signaling axis. The phosphorylation of PI3K-Akt and the expression of P2X7 receptor (P2X7R) and IL-1β were detected via Western blot. Result NTG-induced migraine mice exhibited obvious nociceptive hypersensitivity and neuronal hyperactivation in the SSP cortex. TRPC5 mRNA and protein levels were significantly upregulated, and elevated TRPC5 was…
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