Epigallocatechin-3-gallate Enhances Cognitive and Memory Performance and Protects Against Brain Injury in Methionine-induced Hyperhomocysteinemia Through Interdependent Molecular Pathways.

Brain injury and cognitive impairment are major health issues associated with neurodegenerative diseases in young and aged persons worldwide. Epigallocatechin-3-gallate (EGCG) was studied for its ability to protect against methionine (Met)-induced brain damage and cognitive dysfunction. Male mice were given Met-supplemented in drinking water to produce hyperhomocysteinemia (HHcy)-induced animals. EGCG was administered daily concurrently with Met by gavage. EGCG attenuated the rise in homocysteine levels in the plasma and the formation of amyloid-ß and tau protein in the brain. Cognitive and memory impairment in HHcy-induced mice were significantly improved by EGCG administration. These results were associated with improvement in glutamate and gamma-aminobutyric acid levels in the brain. EGCG maintained the levels of glutathione and the activity of antioxidant enzymes in the brain. As a result of the reduction of oxidative stress, EGCG protected against DNA damage in Met-treated mice. Moreover, maintaining the redox balance significantly ameliorated neuroinflammation evidenced by the normalization of IL-1ß, IL-6, tumor necrosis factor α, C-reactive protein, and IL-13 in the same animals. The decreases in both oxidative stress and inflammatory cytokines were significantly associated with upregulation of the antiapoptotic Bcl-2 protein and downregulation of the proapoptotic protein Bax, caspases 3 and 9, and p53 compared with Met-treated animals, indicating a diminution of neuronal apoptosis. These effects reflect and explain the improvement in histopathological alterations in the hippocampus of Met-treated mice. In conclusion, the beneficial effects of EGCG may be due to interconnecting pathways, including modulation of redox balance, amelioration of inflammation, and regulation of antiapoptotic proteins.

Punicalagin ameliorates the elevation of plasma homocysteine, amyloid-ß, TNF-α and apoptosis by advocating antioxidants and modulating apoptotic mediator proteins in brain.

The present study investigated the neuroprotective role of punicalagin, a major polyphenolic compound of pomegranate on methionine-induced brain injury. Hyperhomocysteinemia (HHcy) was induced in two months old male BALB c mice by methionine supplementation in drinking water (1 g/kg body weight) for 30 days. Punicalagin (1 mg/kg) was injected i.p every other day concurrently with methionine. Punicalagin significantly prevented the rise in the levels of homocysteine, amyloid-ß and TNF-α. HHcy is associated with a decrease in the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (PGx) and glutathione reductase (GR) and glutathione (GSH) levels in the brains of methionine-treated mice while these antioxidants are increased by punicalagin supplementation. The treatment with punicalagin significantly decreased oxidative stress as indicated by decreased malondialdehyde and protein carbonyl formation in the brain. Compared with methionine-treated animals, mice that treated with methionine and punicalagin remarkably displayed less apoptosis, indicated by the lower level of proapoptotic protein (Bax, caspases- 3, 9 and p53) and higher levels of antiapoptotic Bcl-2 protein than those in hyperhomocysteinemic mice. The potent bioactivity of punicalagin extends to protect neuronal DNA as evidenced by the inhibition of the increase of comet parameters compared to the methionine-treated mice. In conclusion, punicalagin protected from methionine-induced HHcy and brain damage with an ability to repress apoptosis by modulating apoptotic mediators and maintaining DNA integrity in the brain of mice.