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

• Published in: Neurological research (New York) 2019-07, Vol.41 (7), p.594-608
• Main Authors: Mostafa, Dalia G., Khaleel, Eman F., Badi, Rehab M., Abdel-Aleem, Ghada A., Abdeen, Hanaa M.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; bcl-2-Associated X Protein - metabolism; brain; Brain - drug effects; Brain - metabolism; Cadmium chloride; Cadmium Chloride - antagonists & inhibitors; Cadmium Chloride - toxicity; Caspase 3 - metabolism; Cytochromes c - metabolism; endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Male; Membrane Potential, Mitochondrial - physiology; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Membrane Transport Proteins - metabolism; Oxidative Stress - drug effects; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Rutin - pharmacology; rutin hydrate
• ISSN: 0161-6412; 1743-1328
• DOI: 10.1080/01616412.2019.1596206

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), CdCl 2 (5 mg/kg), and CdCl 2 + RH. All treatments were administered orally for 30 days, on daily basis. Brain homogenates from CdCl 2 -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, CdCl 2 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 CdCl 2 -treated rats. Interestingly, in brain homogenates of CdCl 2 -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; [Ca 2+ ]i: intracellular free Ca 2+ concentration; Cd: cadmium; CdCl 2 : 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;