Hepatic encephalopathy (HE) is characterised by varying range of neurological complications including cognitive and motor impairment in individuals with acute/chronic hepatic diseases (DeMorrow et al., 2021). Existing studies have reported that the neurological consequences of HE are fatal, leading to coma or death in 60–80% of individuals with hepatic cirrhosis (DeMorrow et al., 2021; Hadjihambi et al., 2018; Jalan and Rose, 2022). Different mechanisms of pathogenicity like hyperammonemia, oxidative stress and inflammation have been reported to play pivotal roles in the development of HE. While a well-accepted major pathological manifestation of hepatic encephalopathy is classically characterised by hyperammonemia resulting from impaired ammonia detoxification (Braissant et al., 2019; Saleh et al., 2021). Ammonia is highly neurotoxic and can directly infiltrate the brain and affect the neural and glial cell communications, leading towards astrocyte swelling and the activation of microglial cells, which in turn potentiates neuroinflammation (Braissant et al., 2019; Claeys et al., 2023).

On the other end, the induced systemic inflammatory cytokines potentially disrupt the blood-brain barrier (BBB), triggering neuroinflammation via the liver-to-brain axis (Azhari and Swain, 2018; Cabrera-Pastor et al., 2019). Previous reports have demonstrated that mitogen-activated protein kinases (MAPK) and nuclear factor (NF)-κB signalling play an additional role in the pathogenesis of ammonia-induced neuroinflammation in diverse pre-clinical and clinical studies (Balzano et al., 2020; Huang et al., 2021; Khalil et al., 2021). In another instance, Franca et al. reported the activation of MAPK/NF-κB signalling in rats with liver injury induced by thioacetamide (TAA) (França et al., 2019). Furthermore, activated microglial cells express toll-like receptors (TLRs), which can activate inflammatory signalling, including NLRP3 inflammasome complex (Lünemann et al., 2021; Xu et al., 2018). The activated NLRP3 inflammasome moderates the maturation of interleukin-(IL)-1β, via the cleavage of caspase-1, a most widely targeted pro-inflammatory cytokine during disease states (Broderick and Hoffman, 2022). Given the vital importance of inflammatory signalling in HE, it is imperative to identify targets and develop strategies for its reversal to enhance the effectiveness of HE treatment.

The International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) has enlisted various animal models to induce neurological damage in hepatic encephalopathy (HE) (DeMorrow et al., 2021). Among these models, TAA has been extensively used to develop HE, as the model generated using TAA, exhibits clinical aspects of liver injury involving neurobehavioral impairment (Jia et al., 2020; Saleh et al., 2021).

Phytoconstituents isolated from plants have attracted the scientific community for their credible role in treating various diseases, presenting an alternative approach in clinical medicine (Ali et al., 2021a; Najmi et al., 2022). Tinospora cordifolia (TC) Miers, also known as guduchi, is an Indian medicinal herb that exhibits diverse pharmacological properties, including antioxidant and anti-inflammatory effects. The decoction of TC stem has been widely used in India to treat fever, including cerebral fever, since ancient times (Ninama et al., 2022). TC contains chemical constituents such as glycosides, alkaloids, steroids, phenolics etc. (Sharma et al., 2019). TC is reported to inhibit inflammation by reducing TNF-α, IL-12 and IL-1β, provide protection to liver by inhibiting LPO and oxidative stress and exert immunomodulatory effects by promoting cell-mediated and humoral immunity (B and T-cell subsets) (Baskaran et al., 2018; Birla et al., 2019; Tiwari et al., 2023). Moreover, the aqueous extract of TC showed anti-diabetic activity by modulating PI3K and AMPK in L6 myotubes and C57BL/KsJ-db/db mice (Mishra et al., 2023). Based on this, we hypothesized that TC might mitigate HE by inhibiting glial cell activation and neuroinflammation. Therefore, this study was aimed to examine the beneficial effects of TC aqueous extract in TAA-induced HE in rats.