Scutellariae Radix constitutes a vital Chinese medicinal substance derived from the root of Scutellaria baicalensis Georgi. Traditionally employed in clinical settings, it addresses diverse inflammatory and immune-related maladies, as well as bacterial and viral infections affecting the respiratory and gastrointestinal tracts. Wogonoside (WG, CAS No. 51059-44-0; C22H20O11) emerges as a notable active compound extracted from Scutellariae Radix, classified within the flavonoid category based on its chemical structure. WG encompasses various pharmacological properties, with a primary emphasis on its anti-inflammatory effects (Liao et al., 2021). Recent investigations have elucidated the neuroprotective attributes and potential mechanisms of action of flavonoids in neurodegenerative disorders and central nervous system (CNS) injuries (Ullah et al., 2020; Wang et al., 2021).

With an enhanced comprehension of CNS diseases pathogenesis, the role of neuroinflammation in the progression of various ailments has garnered increasing attention, particularly in the context of spinal cord injury (SCI). SCI represents a severe event with heightened morbidity and significant complications, and its incidence continues to rise annually (Quadri et al., 2020). Upon injury, pattern recognition receptors on microglia are promptly activated, originally quiescent around the lesion site, in response to cell debris, intracellular proteins, DNA, and RNA released from damaged cells (Amarante-Mendes et al., 2018). This activation triggers elevated production of various cytokines, chemokines, and metalloproteinases, culminating in heightened vascular permeability and disruption of the blood-spinal cord barrier (BSCB). The active microglia, debris, and various molecules mentioned above collectively constituted an inflammatory microenvironment at the lesion site. Subsequently, astrocytes in CNS are also activated and peripheral immune cells are recruited. Various chemokines and pro-inflammatory cytokines are secreted by the above cells, exacerbating inflammatory microenvironment's deterioration at the lesion site. The above events together lead to hematoma, edema, as well as extensive death of neurons and gliocytes. The deleterious microenvironment accelerates injury progression and the consequent vicious circle continuously extends extent and degree of injury, hastening neurological and locomotor dysfunction (Ahuja et al., 2017; Wu et al., 2021). In this process, neuroinflammation plays a key role in driving disease progression. Therefore, therapeutic interventions or drugs targeting neuroinflammation hold promise for SCI treatment.

In clinical practice, alongside traditional procedures for spine fixation and spinal cord decompression, a high dose of methylprednisolone is frequently employed as a pharmacotherapeutic measure during the acute phase. Nevertheless, the narrow therapeutic window and substantial side effects have prompted considerable debate surrounding its utility (Ahuja et al., 2017). Consequently, there is a pronounced emphasis on exploring alternative anti-inflammatory pharmaceuticals in the realm of spinal cord injury (SCI) treatment.

Considering the aforementioned considerations, a comprehensive exploration into the anti-neuroinflammatory potential of WG in SCI, along with its targets and underlying mechanisms, becomes pertinent. Hence, this study aims to investigate the impact of WG on microglia-mediated neuroinflammation after SCI, utilizing lipopolysaccharide (LPS)-stimulated BV2 microglia cells and an SCI mouse model. Based on the results of in silico prediction and network pharmacology, particular attention will be directed towards toll-like receptor 4 (TLR4)/MyD88/NF-κB signaling axis. Furthermore, this investigation will encompass an evaluation of the indirect influence of WG on reactive astrocytes activated by microglial stimuli, thereby offering a more comprehensive understanding of WG's influence on the inflammatory microenvironment after SCI.