Tetrandrine Alleviates Nociception in a Rat Model of Migraine via Suppressing S100B and p-ERK Activation in Satellite Glial Cells of the Trigeminal Ganglia

Abstract

Sensitization and activation of the trigeminal ganglia have been implicated in the pathology of migraine. Satellite glial cells (SGCs), a specialized type of glial cells that ensheathe trigeminal neurons, may be critical for peripheral nociceptive sensitization. Tetrandrine (TET), an alkaloid extracted from a traditional Chinese herb, exerts an inhibitory effect on glial activation in vitro and has been used in various neurologic diseases. The current study investigated the effect of TET on nitroglycerin (NTG)-induced trigeminal sensitization and examined potential signaling pathways related to SGC activation in the model of migraine. We measured trigeminal nociceptive thresholds using electronic von Frey rigid tips before and after NTG injection in control rats and rats pretreated with TET, while expression and subcellular location of the inflammatory mediators S100B and activated phosphorylation extracellular signal-regulated kinase (p-ERK) were measured using real-time quantitative polymerase chain reaction, Western blotting, and double immunofluorescence staining. Pretreatment with TET caused a dose-dependent reversal of the trigeminal nociceptive hypersensitivity induced by NTG. In addition, TET pretreatment blocked the activation of S100B and p-ERK in trigeminal ganglion SGCs of NTG-treated rats. Reduced p-ERK activity can suppress the inflammation that leads to hyperexcitability of trigeminal ganglion neurons. Administration of TET may therefore be a safe and effective therapeutic treatment for the hyperalgesic symptoms of migraine.

The S100B story: from biomarker to active factor in neural injury

“…More recently, even extracts from traditional remedies have been used in an attempt to block the protein (Qin et al . ). The identification of molecules able to inactivate S100B, thereby offering a common therapeutic tool to combat apparently heterogeneous disorders of the nervous system, could be the next step in the story of this intriguing protein.…”

“…It may be relevant in this respect that the search for additional similarly useful molecules is being actively pursued via a structure-based approach (Cavalier et al 2016). More recently, even extracts from traditional remedies have been used in an attempt to block the protein (Qin et al 2018). The identification of molecules able to inactivate S100B, thereby offering a common therapeutic tool to combat apparently heterogeneous disorders of the nervous system, could be the next step in the story of this intriguing protein.…”

The role of satellite glial cells in orofacial pain

“…Under physiological conditions, SGCs display low levels of GFAP, but the expression of this protein detected by immunohistochemistry greatly increases after nerve injury and/or inflammation, which are observed in various orofacial pain models, including tooth injury (Liu et al, ; Stephenson & Byers, ), temporomandibular joint (TMJ) inflammation (Villa, Ceruti, et al, ), pulpal inflammation (Matsuura et al, ), upper molar extraction (Gunjigake, Goto, Nakao, Kobayashi, & Yamaguchi, ), whisker pad inflammation (Takeda et al, ), chronic constriction injury of the infraorbital nerve (Donegan, Kernisant, Cua, Jasmin, & Ohara, ; Vit, Jasmin, Bhargava, & Ohara, ; Xu, Aita, & Chavkin, ), inferior alveolar nerve injury (Anderson, Bartheld, & Byers, ; Chudler, Anderson, & Byers, ), lingual nerve injury (Mikuzuki et al, ), lower gingival cancer pain (Hironaka et al, ), migraine (Qin et al, ), and chronic restraint stress model (Zhao et al, ). Such nerve injury and/or inflammation can cause a variety of changes in the gene expression in the TG neurons (Cairns, O'Brien, Dong, & Gazerani, ; Lukacs et al, ), and even activate resident macrophages in the TG (Villa, Ceruti, et al, ).…”

“…NO‐proton stimulation of orofacial tissues increases active ERK and p38 levels detected in neurons and SGCs (Freeman, Patil, & Durham, ). Upregulation of ERK phosphorylation in SGCs is demonstrated in the model of pulpal inflammation (Matsuura et al, ), local inflammation of the dura mater (Lukacs et al, ), lingual nerve injury (Mikuzuki et al, ), migraine (Qin et al, ), and TMJ inflammation (Bi et al, ). The phosphorylation of MAPKs in the TG is involved in SGC activation and peripheral sensitization.…”

Research Progress on Anti‐Inflammatory Effects and Mechanisms of Alkaloids from Chinese Medical Herbs

“…It has therapeutic effects on gout, osteoarthritis, and systemic lupus erythematosus. Tetrandrine can significantly inhibit rats' joint swelling caused by carrageenan or formaldehyde and increased vascular permeability in rats induced by histamine [16]. Intraperitoneal injection of 20 mg/kg of tetrandrine can significantly reduce the amount of hydrothorax, protein exudation, and leukocyte migration in rats with pleurisy caused by carrageenan [17].…”