Background Ketamine can act as a multifunctional neuroprotective agent by inhibiting oxidative stress, cellular dysfunction, and apoptosis. Although it has been proven to be effective in various neurologic disorders, the mechanism of the treatment of traumatic brain injury (TBI) is not fully understood. The aim of this study was to investigate the neuroprotective function of ketamine in models of TBI and the potential role of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in this putative protective effect. Materials and methods Wild-type male mice were randomly assigned to five groups: Sham group, Sham + ketamine group, TBI group, TBI + vehicle group, and TBI + ketamine group. Marmarou's weight drop model in mice was used to induce TBI, after which either ketamine or vehicle was administered via intraperitoneal injection. After 24 h, the brain samples were collected for analysis. Results Ketamine significantly ameliorated secondary brain injury induced by TBI, including neurological deficits, brain water content, and neuronal apoptosis. In addition, the levels of malondialdehyde (MDA), glutathione peroxidase (GPx), and superoxide dismutase (SOD) were restored by the ketamine treatment. Western blotting and immunohistochemistry showed that ketamine significantly increased the level of Nrf2. Furthermore, administration of ketamine also induced the expression of Nrf2 pathway-related downstream factors, including hemeoxygenase-1 and quinine oxidoreductase-1, at the pre- and post-transcriptional levels. Conclusion Ketamine exhibits neuroprotective effects by attenuating oxidative stress and apoptosis after TBI. Therefore, ketamine could be an effective therapeutic agent for the treatment of TBI.

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Ketamine ameliorates oxidative stress-induced apoptosis in experimental traumatic brain injury via the Nrf2 pathway

Parkinson's disease (PD) is a highly prevalent neurodegenerative disorder, often associated with oxidative stress-induced transcriptional changes in dopaminergic neurons. Phenolic antioxidants, oleuropein (OLE) and rutin (RUT) have attracted a great interest due to their potential to counteract oxidative protein aggregation and toxicity. This study aimed at examining the effects of OLE and RUT against 6-OHDA-induced stress response in rat pheochromocytoma cells. When differentiated PC12 cells were exposed to oxidative stress composer 6-OHDA (100 μM, 8 h), a decreased mitochondrial membrane potential (ΔΨm) was observed along with a significant loss of cell viability and apoptotic nuclear changes. Exposure to 6-OHDA resulted in unfolded protein response (UPR) in differentiated PC12 cells as evidenced by an increased level of endoplasmic reticulum (ER)-localized transmembrane signal transducer IRE1α, adaptive response proteins ATF-4 and proapoptotic transcription factor CHOP. OLE or RUT pretreatment (24 h) at low doses (1-50 μM) protected the differentiated PC12 cells from 6-OHDA-induced cytotoxicity as assessed by increased viability, improved ΔΨm and inhibited apoptosis, whereas relatively high doses of OLE or RUT (>50 μM) inhibited cell growth and proliferation, indicating a typical hormetic effect. In hormetic doses, OLE and RUT up-regulated 6-OHDA-induced increase in IRE1α, ATF-4 and inhibited CHOP, PERK, BIP and PDI. 6-OHDA-activated XBP1 splicing was also inhibited by OLE or RUT. The presented results suggest that neuroprotection against 6-OHDA-induced oxidative toxicity may be attributable to neurohormetic effects of OLE or RUT at low doses through regulating mitochondrial functions, controlling persistent protein misfolding, activating and/or amplificating the adaptive response-related signaling pathways, leading to UPR prosurvival output.

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Oleuropein and rutin protect against 6-OHDA-induced neurotoxicity in PC12 cells through modulation of mitochondrial function and unfolded protein response

Background: Neurovascular dysfunction caused by traumatic brain injury (TBI) is characterized by cerebralvascular damage, blood–brain barrier (BBB) breakdown, brain edema, etc. This study was desig...

Troxerutin cerebroprotein hydrolysate injection ameliorates neurovascular injury induced by traumatic brain injury - via endothelial nitric oxide synthase pathway regulation.

ABT-737 is a BH-3 mimetic that inhibits Bcl-2 and induces apoptosis of cancer cells, which has potential for anticancer therapies. Studies have shown that Bcl-2 expression in human osteosarcoma (OS) cells plays a significant role in tumor progression; however, its effects on OS cell apoptosis are still unknown. Therefore, we examined whether ABT-737 was effective in eliminating human U-2OS cells, either alone or in combination with the chemotherapy drug cisplatin [cis-diamminedichloroplatinum (II); DDP]. Furthermore, we studied the molecular mechanisms of ABT-737 in combination with DDP to induce apoptosis. To analyze the role of ABT-737 and/or DDP on osteosarcoma progression, CCK-8 viability assay, flow cytometry, Hoechst 33258 staining, and western blots were performed. Combined use of ABT-737 and DDP synergistically suppressed cell viability and induced apoptosis in human U-2OS cells when compared with either compound treated alone at low doses. We found that the combination of ABT-737 and DDP upregulated the expression of the pro-apoptotic protein Bax and downregulated the expression of the pro-survival protein Bcl-2, resulting in a change in the Bax/Bcl-2 ratio, release of cytochrome c, and activation of the mitochondrial apoptotic pathway, which resulted in caspase-9 and caspase-3 activation and PARP cleavage. Our results demonstrated that ABT-737 alone has a nominal influence on human U-2OS cells when treated within the clinically administered range, but when combined with DDP, it can inhibit the proliferation of human U-2OS cells by inducing apoptosis via the mitochondrial apoptotic pathway.

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ABT-737 potentiates cisplatin-induced apoptosis in human osteosarcoma cells via the mitochondrial apoptotic pathway

Background Sinomenine (SIN) has been shown to have protective effects against brain damage following traumatic brain injury (TBI). However, the mechanisms and its role in these effects remain unclear. This study was conducted to investigate the potential mechanisms of the protective effects of SIN. Methods The weight-drop model of TBI in Institute of Cancer Research (ICR) mice were treated with SIN or a vehicle via intraperitoneal administration 30 min after TBI. All mice were euthanized 24 h after TBI and after neurological scoring, a series of tests were performed, including brain water content and neuronal cell death in the cerebral cortex. Results The level of cytochrome c (Cyt c), malondialdehyde (MDA), glutathione peroxidase (GPx) and superoxide dismutase 1 (SOD) were restored to some degree following the SIN treatment. The SIN treatment significantly decreased caspase-3 expression and reduced the number of positive cells by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and improved the survival of neuronal cells. Additionally, the pretreatment levels of MDA were restored, while Bax translocation to mitochondria and Cyt c release into the cytosol were reduced by the SIN treatment. Conclusion SIN protected neuronal cells by protecting them against apoptosis via mechanisms that involve the mitochondria following TBI.

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Sinomenine reduces neuronal cell apoptosis in mice after traumatic brain injury via its effect on mitochondrial pathway.

Rutin reportedly conveys many beneficial effects, including neuroprotection in brain injury. However, the mechanisms underlying these effects are still not well understood. This study investigates the effect of rutin on potential mechanisms for neuroprotective effects, using the weight-drop model of traumatic brain injury (TBI) in male mice treated either with rutin or a vehicle via intraperitoneal injection 30 min after TBI. After euthanasia and 24 h after TBI, all mice were examined by tests, including neurologic scores, blood-brain barrier permeability, brain water content and neuronal cell death in the cerebral cortex. Results indicate that the levels of cytochrome c, malondialdehyde (MDA) and superoxide dismutase (SOD) were restored by rutin treatment. Rutin treatment resulted in the downregulation of caspase-3 expression in a reduced number of positive cells under terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and also the improved survival of neurons. Furthermore, pretreatment levels of MDA were restored, while Bcl-2-associated X protein translocation to mitochondria and cytochrome c release into cytosol were reduced by rutin treatment. Our results demonstrate that rutin improves neurological outcome by protecting neural cells against apoptosis via mechanisms that involve the mitochondria following TBI.

Fayin Li

Papers

Rutin Acid Ameliorates Neural Apoptosis Induced by Traumatic Brain Injury via Mitochondrial Pathways in Mice.