Current pharmaceutical design · 2026
Diindolylmethane Pretreatment Attenuated Thioacetamide-Induced Acute Liver Failure and its Associated Brain Injury in Rats.
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Reddy Dontiboina Harikrishna, Tuyishime Honnete Samuel, Yadava Srikanth, P Y Srikari Lakshmi, Bommadevara Moni Saswitha, Doddavajjulla Lakshmi Amrutha, Guntupalli Chakravarthi, Kakarla Ramakrishna, Kundnani Nilima Rajpal
Аннотация
INTRODUCTION: Acute liver failure (ALF) is a life-threatening condition associated with hepatic encephalopathy (HE), characterised by neurological impairments, hyperammonemia, oxidative stress, and inflammation. Diindolylmethane (DIM), a bioactive compound derived from cruciferous vegetables, has shown potential hepatoprotective and neuroprotective effects via its antioxidant and anti-inflammatory properties. Despite beneficial effects, its protective effects have not been investigated against HE. The present study evaluated the hepatoprotective and neuroprotective effects of DIM in a rat model of thioacetamide (TAA)- induced ALF and HE.
METHODS: ALF was induced using thioacetamide (TAA; 300 mg/kg, i.p.). DIM at doses of 12.5, 25, and 50 mg/kg, p.o., was administered for 7 days prior to TAA injection. Behavioral assessments, including the open field test and Y-maze, were performed to evaluate motor and cognitive functions. Biochemical parameters (AST, ALT, ALP, and LDH), ammonia levels, oxidative stress markers (MDA, NRF2, SOD, GSH, and catalase), inflammatory cytokines (IL-6, TNF-α, and IL-10), and apoptotic markers (cytochrome c, caspase 9, and caspase 3) were analysed. Histopathological examinations of the liver, cortex, and hippocampus were conducted using hematoxylin and eosin staining.
RESULTS: DIM pretreatment significantly reduced liver enzyme levels (AST, ALT, ALP, and LDH), normalised organ weight ratios, and decreased ammonia levels in blood, liver, and brain. DIM attenuated oxidative stress by reducing MDA levels and enhancing NRF2, SOD, GSH, and catalase activity, suggesting its antioxidant potential. Further, DIM reduced IL-6 and TNF-α levels and increased IL-10 levels, indicating its antiinflammatory effects. Furthermore, DIM reduced the apoptotic markers, including cytochrome c, caspase 9, and caspase 3, suggesting attenuation of apoptosis. Additionally, DIM improved motor activity and spatial memory and exhibited an anxiolytic effect. DIM mitigated the TAA-induced liver, hippocampal, and cortical tissue abnormalities.
DISCUSSION: The findings suggest that DIM exerts protective effects against ALF-induced HE by modulating key pathological mechanisms, including oxidative stress, neuroinflammation, and apoptosis. The reduction in hyperammonemia and restoration of biochemical and behavioral parameters indicate its potential role in preserving liver and brain function.
CONCLUSION: DIM demonstrates significant hepatoprotective and neuroprotective effects in TAA-induced ALF and HE. These effects are mediated through multiple mechanisms, suggesting DIM as a potential therapeutic candidate for managing ALF-associated neurological complications. Future studies require investigating the in-depth mechanism of DIM against HE.
METHODS: ALF was induced using thioacetamide (TAA; 300 mg/kg, i.p.). DIM at doses of 12.5, 25, and 50 mg/kg, p.o., was administered for 7 days prior to TAA injection. Behavioral assessments, including the open field test and Y-maze, were performed to evaluate motor and cognitive functions. Biochemical parameters (AST, ALT, ALP, and LDH), ammonia levels, oxidative stress markers (MDA, NRF2, SOD, GSH, and catalase), inflammatory cytokines (IL-6, TNF-α, and IL-10), and apoptotic markers (cytochrome c, caspase 9, and caspase 3) were analysed. Histopathological examinations of the liver, cortex, and hippocampus were conducted using hematoxylin and eosin staining.
RESULTS: DIM pretreatment significantly reduced liver enzyme levels (AST, ALT, ALP, and LDH), normalised organ weight ratios, and decreased ammonia levels in blood, liver, and brain. DIM attenuated oxidative stress by reducing MDA levels and enhancing NRF2, SOD, GSH, and catalase activity, suggesting its antioxidant potential. Further, DIM reduced IL-6 and TNF-α levels and increased IL-10 levels, indicating its antiinflammatory effects. Furthermore, DIM reduced the apoptotic markers, including cytochrome c, caspase 9, and caspase 3, suggesting attenuation of apoptosis. Additionally, DIM improved motor activity and spatial memory and exhibited an anxiolytic effect. DIM mitigated the TAA-induced liver, hippocampal, and cortical tissue abnormalities.
DISCUSSION: The findings suggest that DIM exerts protective effects against ALF-induced HE by modulating key pathological mechanisms, including oxidative stress, neuroinflammation, and apoptosis. The reduction in hyperammonemia and restoration of biochemical and behavioral parameters indicate its potential role in preserving liver and brain function.
CONCLUSION: DIM demonstrates significant hepatoprotective and neuroprotective effects in TAA-induced ALF and HE. These effects are mediated through multiple mechanisms, suggesting DIM as a potential therapeutic candidate for managing ALF-associated neurological complications. Future studies require investigating the in-depth mechanism of DIM against HE.