RESUMO
Background: Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian brain and is a non-proteinogenic amino acid. Doxorubcin (DOX) or adriamycin is one of the most potent chemotherapy drugs for breast cancer. Purpose: This study focused on diminishing the brain injury and neurotoxicity of doxorubicin (DOX) by GABA administration. Methods: Rats were randomly divided into four groups (8 rats each), which were the control group, DOX group (3 mg/kg for 4 weeks, then 2 mg/kg for 2 weeks), GABA group (2 mg/kg for 21 days), and DOX + GABA group (treated as the second and third groups). Neurotoxicity and brain injury were assessed by determining CSF biomarkers, serum inflammatory markers, and histopathological evaluation of the cerebral cortex. Results: DOX treatment significantly increased the levels of all CSF biomarkers (S100B, IL-1ß, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), glial fibrillary acidic protein (GFAP), spectrin breakdown products (SBDP145), and C-C motif chemokine ligand 2 (CCL2) and all inflammatory markers (IL-6, TNF-α, and IFN-γ), causing extensive neutrophilic infiltration and great alteration in the cerebral cortex architecture as evidence of neurotoxicity. The oral administration of GABA significantly reduced the levels of all CSF biomarkers and inflammatory markers and restored the normal architecture of the cerebral cortex, with observed ameliorations in neutrophilic infiltration. Conclusion: GABA administration can ameliorate neurotoxicity and protect the brain against the negative effects of DOX treatment.
RESUMO
BACKGROUND: Cardiorenal crosstalk has gained growing scientific curiosity recently. Clinical observations have approved that heart and kidney performances are intimately interrelated; acute or chronic dysfunction of either is inevitably mirrored on the other. This coexistence usually has the poor prognosis and worsened outcome. METHODS: We designed this study to explore therapeutic potentials of combined Vitis vinifera and Silymarin extracts on histopathological alterations of experimentally induced cardiorenal injury model. Moreover, to examine the pertinent role of Nrf2 in their bio-molecular actions. Sixty adult male Wistar albino rats were utilized, further subdivided into control, doxorubicin (DXR), DXR + Silymarin, DXR + Aqueous Vitis, DXR + Ethanolic Vitis, DXR + Ethanolic Vitis + Silymarin. Left ventricle and renal cortex sections from all groups were processed for histopathological examination, biochemical estimation of serum Urea, Creatinine, BUN, lipid profile and hs-CRP and real-time PCR of Nrf2 expression in cardiac and renal tissue homogenate were performed. RESULTS: Our results proved that combined ethanolic extract of Vitis vinifera and Silymarin restored normal renal and cardiac histomorphology. Significant improvement of Creatinine, BUN, lipid profile and hs-CRP cardiac and renal biochemical indicators confirmed our results. Moreover, significant elevation of mRNA expression levels of Nrf2 proved that combined Vitis vinifera and Silymarin action was directly related to the redox-sensitive regulator pathway. CONCLUSIONS: We concluded that synergistic therapeutic effect of Vitis vinifera extract and Silymarin on experimental cardiorenal injury model owes principally to promoting activation of the Keap1/Nrf2 signaling pathway.
