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Rutin hydrate inhibits apoptosis in the brains of cadmium chloride-treated rats via preserving the mitochondrial integrity and inhibiting endoplasmic reticulum stress

Dalia G Mostafa, Eman F Khaleel, Rehab M Badi, Ghada A Abdel-Aleem, Hanaa M Abdeen
Neurological Research 2019 April 11, : 1-15
Recent evidence has suggested that cadmium (Cd) ions-induced neurotoxicity is associated with increased oxidative stress and mitochondrial-dependent and endoplasmic reticulum (ER) stress-induced apoptosis. This study aimed to investigate if rutin hydrate (RH), a well-reported neuroprotective and an antioxidant flavonoid, can ameliorate cadmium chloride (CdCl2)-induced neurotoxicity by inhibiting the resultant ER stress. Rats were divided into 4 groups (n = 16/group) of control, control + RH (100 mg/kg), CdCl2 (5 mg/kg), and CdCl2 + RH. All treatments were administered orally for 30 days, on daily basis. Brain homogenates from CdCl2 -treated rats showed increased oxidative stress and induced activation of ER stress characterized by increasing mRNA and protein levels of GRP78, ATF-6, CHOP and Xbp-1 and protein levels of p-elF2α, p-JNK1/2 and cleaved caspase-12. Also, CdCl2 significantly reduced Bcl-2, enhanced Bax translocation to the mitochondrial membrane, increased cytoplasmic levels of cytochrome-C and caspase-3, and reduced mitochondrial membrane potential (Δψm) (increased Vmax and reduced time to Vmax). In contrast, RH significantly enhanced levels GSH and activities of SOD, GSH-Px, decreased levels of MDA and inhibited mitochondrial permeability transition pore (mtPTP) in the brains of both control and CdCl2 -treated rats. Interestingly, in brain homogenates of CdCl2 -treated rats only, RH reduced all markers of ER stress, increased Bcl-2, reduced mitochondrial Bax translocation and improved mitochondrial coupling. It also reduced cytosolic levels of cytochrome-C, cleaved caspase-3, and cleaved caspase-12. Overall, these findings support the efficiency of RH to inhibit ER stress in brains CdCl2-treated rats which is added to its existing mechanisms of neuroprotection. Abbreviations: ATF-6: activating transcription factor-6; Bax: Bcl-associated x; BBB: blood-brain barrier; Bcl-2: B-cell lymphoma 2; BiP: immunoglobulin heavy-chain-binding protein; [Ca2+ ]i: intracellular free Ca2+ concentration; Cd: cadmium; CdCl2 : cadmium chloride; CHOP: CCAAT/enhancer-binding protein-homologous protein; CMC: carboxymethyl cellulose; Δψm: mitochondrial membrane potential; elF2α: phospho-eukaryotic translation initiation factor 2-alpha; ER: endoplasmic reticulum; ERAD: ER-associated protein degradation; ERK1/2: extracellular signal-regulated kinases 1 and 2; GADD 153: growth arrest and DNA damage-inducible protein 153; GRP78, 78 kDa glucose-regulated protein; GSH: reduced glutathione; GSH: reduced glutathione; GSH-Px: glutathione peroxidase; GSSG: glutathione disulfide (oxidized glutathione); IRE-1: inositol-requiring enzyme-1; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; MDA: malondialdehyde; mTOR: Akt/mammalian target of rapamycin; mtPTP: mitochondrial permeability transition pore; ONOO- : peroxynitrite; PCR: polymerase chain reaction; PERK: protein kinase RNA-like ER kinase; p-JNK: phospho-JNK; qPCR: quantitative PCR; RCR: respiratory control ratio; RH: rutin hydrate; RHoGDI: Rho-GDP-dissociation inhibitor; ROS: reactive oxygen species; SOD: superoxide dismutase; UPR: unfolded protein response; VDAC: voltage-dependent anion channel; Vmax: maximal rate of pore opening; Xbp-1: X-box binding protein 1.


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