Impact of vitamin E-blended UHMWPE wear particles on the osseous microenvironment in polyethylene particle-induced osteolysis.

Neuerburg C, Loer T, Mittlmeier L, Polan C, Farkas Z, Holdt LM, Utzschneider S, Schwiesau J, Grupp TM, Böcker W, Aszodi A, Wedemeyer C, Kammerlander C.

Int J Mol Med. 2016 Dec;38(6):1652-1660. doi: 10.3892/ijmm.2016.2780. Epub 2016 Oct 18.

Abstract

Aseptic loosening mediated by wear particle-induced osteolysis (PIO) remains the major cause of implant loosening in endoprosthetic surgery. The development of new vitamin E (α-tocopherol)-blended ultra-high molecular weight polyethylene (VE-UHMWPE) with increased oxidation resistance and improved mechanical properties has raised hopes. Furthermore, regenerative approaches may be opened, as vitamin E supplementation has shown neuroprotective characteristics mediated via calcitonin gene-related peptide (CGRP), which is known to affect bone remodeling in PIO. Therefore, the present study aimed to further clarify the impact of VE-UHMWPE wear particles on the osseous microenvironment and to identify the potential modulatory pathways involved. Using an established murine calvaria model, mice were subjected to sham operation (SHAM group), or treated with UHMWPE or VE-UHMWPE particles for different experimental durations (7, 14 and 28 days; n=6/group). Morphometric analysis by micro-computed tomography detected significant (p<0.01) and comparable signs of PIO in all particle-treated groups, whereas markers of inflammation [tumor necrosis factor (TNF)-α/tartrate resistant acid phosphatase (TRAP) staining] and bone remodeling [Dickkopf-related protein 1 (DKK-1)/osteoprotegerin (OPG)] were most affected in the early stages following surgery. Taking the present data into account, VE-UHMWPE appears to have a promising biocompatibility and increased ageing resistance. According to the α-CGRP serum levels and immunohistochemistry, the impact of vitamin E on neuropeptidergic signaling and its chance for regenerative approaches requires further investigation.

Finno CJ, Bordbari MH, Valberg SJ, Lee D, Herron J, Hines K, Monsour T, Scott E, Bannasch DL, Mickelson J, Xu L.

Free Radic Biol Med. 2016 Dec;101:261-271. doi: 10.1016/j.freeradbiomed.2016.10.009. Epub 2016 Oct 15.

Abstract

Specific spontaneous heritable neurodegenerative diseases have been associated with lower serum and cerebrospinal fluid α-tocopherol (α-TOH) concentrations. Equine neuroaxonal dystrophy (eNAD) has similar histologic lesions to human ataxia with vitamin E deficiency caused by mutations in the α-TOH transfer protein gene (TTPA). Mutations in TTPA are not present with eNAD and the molecular basis remains unknown. Given the neuropathologic phenotypic similarity of the conditions, we assessed the molecular basis of eNAD by global transcriptome sequencing of the cervical spinal cord. Differential gene expression analysis identified 157 significantly (FDR<0.05) dysregulated transcripts within the spinal cord of eNAD-affected horses. Statistical enrichment analysis identified significant downregulation of the ionotropic and metabotropic group III glutamate receptor, synaptic vesicle trafficking and cholesterol biosynthesis pathways. Gene co-expression analysis identified one module of upregulated genes significantly associated with the eNAD phenotype that included the liver X receptor (LXR) targets CYP7A1, APOE, PLTP and ABCA1. Validation of CYP7A1 and APOE dysregulation was performed in an independent biologic group and CYP7A1 was found to be additionally upregulated in the medulla oblongata of eNAD horses. Evidence of LXR activation supports a role for modulation of oxysterol-dependent LXR transcription factor activity by tocopherols. We hypothesize that the protective role of α-TOH in eNAD may reside in its ability to prevent oxysterol accumulation and subsequent activation of the LXR in order to decrease lipid peroxidation associated neurodegeneration.

An HM, Tan YL, Shi J, Wang Z, Lv MH, Soares JC, Zhou D, Yang F, Zhang XY.

Phytomedicine. 2016 Dec 1;23(13):1653-1660. doi: 10.1016/j.phymed.2016.10.009. Epub 2016 Oct 15.

Abstract

Tardive dyskinesia (TD) is a serious side effect of long-term administration of typical neuroleptics, such as haloperidol. The pathophysiology of TD remains unclear, but the experimental evidence suggests that free radical-induced neuronal apoptosis in the basal ganglia may play an important role. This study was to investigate changes in Bax and Bcl-2 expression levels in TD-associated brain regions and the effects of the antioxidant EGb761 on Bax and Bcl-2 levels in an animal model of TD. The results obtained demonstrate that long-term haloperidol administration may affect Bcl-2 protein family expression and promote neuronal apoptosis in the basal ganglia. In combination with their antioxidant capacity, EGb761 and alpha-tocopherol‘s antiapoptotic effects through Bcl-2 might account for the symptom improvement observed in haloperidol-induced TD rats.

Debbabi M, Nury T, Zarrouk A, Mekahli N, Bezine M, Sghaier R, Grégoire S, Martine L, Durand P, Camus E, Vejux A, Jabrane A, Bretillon L, Prost M, Moreau T, Ammou SB, Hammami M, Lizard G.

Int J Mol Sci. 2016 Nov 25;17(12). pii: E1973.

Abstract

Lipid peroxidation products, such as 7-ketocholesterol (7KC), may be increased in the body fluids and tissues of patients with neurodegenerative diseases and trigger microglial dysfunction involved in neurodegeneration. It is therefore important to identify synthetic and natural molecules able to impair the toxic effects of 7KC. We determined the impact of 7KC on murine microglial BV-2 cells, especially its ability to trigger mitochondrial and peroxisomal dysfunction, and evaluated the protective effects of α- and γ-tocopherol, Trolox, and oleic acid (OA). Multiple complementary chemical assays, flow cytometric and biochemical methods were used to evaluate the antioxidant and cytoprotective properties of these molecules. According to various complementary assays to estimate antioxidant activity, only α-, and γ-tocopherol, and Trolox had antioxidant properties. However, only α-tocopherol, γ-tocopherol and OA were able to impair 7KC-induced loss of mitochondrial transmembrane potential, which is associated with increased permeability to propidium iodide, an indicator of cell death. In addition, α-and γ-tocopherol, and OA were able to prevent the decrease in Abcd3 protein levels, which allows the measurement of peroxisomal mass, and in mRNA levels of Abcd1 and Abcd2, which encode for two transporters involved in peroxisomal β-oxidation. Thus, 7KC-induced side effects are associated with mitochondrial and peroxisomal dysfunction which can be inversed by natural compounds, thus supporting the hypothesis that the composition of the diet can act on the function of organelles involved in neurodegenerative diseases.

Galli F, Azzi A, Birringer M, Cook-Mills JM, Eggersdorfer M, Frank J, Cruciani G, Lorkowski S, Özer NK.

Free Radic Biol Med. 2016 Nov 2;102:16-36. doi: 10.1016/j.freeradbiomed.2016.09.017. [Epub ahead of print]

Abstract

The discovery of vitamin E will have its 100th anniversary in 2022, but we still have more questions than answers regarding the biological functions and the essentiality of vitamin E for human health. Discovered as a factor essential for rat fertility and soon after characterized for its properties of fat-soluble antioxidant, vitamin E was identified to have signaling and gene regulation effects in the 1980s. In the same years the cytochrome P-450 dependent metabolism of vitamin E was characterized and a first series of studies on short-chain carboxyethyl metabolites in the 1990s paved the way to the hypothesis of a biological role for this metabolism alternative to vitamin E catabolism. In the last decade other physiological metabolites of vitamin E have been identified, such as α-tocopheryl phosphate and the long-chain metabolites formed by the ω-hydroxylase activity of cytochrome P-450. Recent findings are consistent with gene regulation and homeostatic roles of these metabolites in different experimental models, such as inflammatory, neuronal and hepatic cells, and in vivo in animal models of acute inflammation. Molecular mechanisms underlying these responses are under investigation in several laboratories and side-glances to research on other fat soluble vitamins may help to move faster in this direction. Other emerging aspects presented in this review paper include novel insights on the mechanisms of reduction of the cardiovascular risk, immunomodulation and antiallergic effects, neuroprotection properties in models of glutamate excitotoxicity and spino-cerebellar damage, hepatoprotection and prevention of liver toxicity by different causes and even therapeutic applications in non-alcoholic steatohepatitis. We here discuss these topics with the aim of stimulating the interest of the scientific community and further research activities that may help to celebrate this anniversary of vitamin E with an in-depth knowledge of its action as vitamin.

Ibrahim NF, Yanagisawa D, Durani LW, Hamezah HS, Damanhuri HA, Wan Ngah WZ, Tsuji M, Kiuchi Y, Ono K, Tooyama I.

Alzheimers Dis. 2016 Nov 19;55(2):597-612.

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia. The cardinal neuropathological characteristic of AD is the accumulation of amyloid-β (Aβ) into extracellular plaques that ultimately disrupt neuronal function and lead to neurodegeneration. One possible therapeutic strategy therefore is to prevent Aβ aggregation. Previous studies have suggested that vitamin E analogs slow AD progression in humans. In the present study, we investigated the effects of the tocotrienol-rich fraction (TRF), a mixture of vitamin E analogs from palm oil, on amyloid pathology in vitro and in vivo. TRF treatment dose-dependently inhibited the formation of Aβ fibrils and Aβ oligomers in vitro. Moreover, daily TRF supplementation to AβPPswe/PS1dE9 double transgenic mice for 10 months attenuated Aβ immunoreactive depositions and thioflavin-S-positive fibrillar type plaques in the brain, and eventually improved cognitive function in the novel object recognition test compared with control AβPPswe/PS1dE9 mice. The present result indicates that TRF reduced amyloid pathology and improved cognitive functions, and suggests that TRF is a potential therapeutic agent for AD.

Prathipati P, Zhu J, Dong X.

Eur J Pharm Biopharm. 2016 Nov;108:126-135. doi: 10.1016/j.ejpb.2016.08.005. Epub 2016 Aug 12.

Abstract

Nerve Growth Factor (NGF) is one of the members of the neurotrophin family with multifaceted functions. However, clinical application of NGF is hurdled by the challenge on formulation development. The objective of this study was to develop novel high-density lipoproteins (HDL)-mimicking nanoparticles (NPs) coated with α-tocopherol to incorporate NGF by a self-assembly approach. The NPs were prepared by an optimized self-assembly method that is simple and scalable. The composition of HDL-mimicking NPs was optimized. The prototype of the HDL-mimicking α-tocopherol-coated NPs contained phosphatidylserine (a negative charged phospholipid) and d-α-Tocopheryl polyethylene glycol succinate (a source of vitamin E) to enhance the entrapment efficiency of apolipoprotein A-I in the NPs. The entrapment efficiency of apolipoprotein A-I was about 30%. The NPs had particle size about 200nm with a relatively narrow size distribution. Finally, cationic ion-pair agents were optimized to form ion-pairs with NGF to facilitate the incorporation of NGF into the NPs. Protamine sodium salt USP formed an optimal ion-pair complex with NGF. The results showed that the novel HDL-mimicking α-tocopherol-coated NPs successfully encapsulated NGF with over 65% entrapment efficiency by using this ion-pair strategy. In vitro release studies demonstrated a slow release of NGF from NGF NPs in PBS containing 5% BSA at 37°C for 72 h. Further biodistribution studies showed that intravenously injected NGF NPs significantly increased NGF concentration in plasma and decreased the uptake in liver, spleen and kidney, compared to free NGF in mice.

Grimm MO, Regner L, Mett J, Stahlmann CP, Schorr P, Nelke C, Streidenberger O, Stoetzel H, Winkler J, Zaidan SR, Thiel A, Endres K, Grimm HS, Volmer DA, Hartmann T.

Int J Mol Sci. 2016 Oct 29;17(11). pii: E1809.

Abstract

One of the characteristics of Alzheimer´s disease (AD) is an increased amyloid load and an enhanced level of reactive oxidative species (ROS). Vitamin E has known beneficial neuroprotective effects, and previously, some studies suggested that vitamin E is associated with a reduced risk of AD due to its antioxidative properties. However, epidemiological studies and nutritional approaches of vitamin E treatment are controversial. Here, we investigate the effect of α-tocotrienol, which belongs to the group of vitamin E, on AD-relevant processes in neuronal cell lines. In line with the literature, α-tocotrienol reduced the ROS level in SH-SY5Y cells. In the presence of tocotrienols, cholesterol and cholesterol esters, which have been shown to be risk factors in AD, were decreased. Besides the unambiguous positive effects of tocotrienol, amyloid-β (Aβ) levels were increased accompanied by an increase in the activity of enzymes responsible for Aβ production. Proteins and gene expression of the secretases and their components remained unchanged, whereas tocotrienol accelerates enzyme activity in cell-free assays. Besides enhanced Aβ production, tocotrienolsinhibited Aβ degradation in neuro 2a (N2a)-cells. Our results might help to understand the controversial findings of vitamin E studies and demonstrate that besides the known positive neuroprotective properties, tocotrienols also have negative characteristics with respect to AD.

Grimm MO, Mett J, Hartmann T.

Int J Mol Sci. 2016 Oct 26;17(11). pii: E1785. Review.

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population, currently affecting 46 million people worldwide. Histopathologically, the disease is characterized by the occurrence of extracellular amyloid plaques composed of aggregated amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles containing the microtubule-associated protein tau. Aβ peptides are derived from the sequential processing of the amyloid precursor protein (APP) by enzymes called secretases, which are strongly influenced by the lipid environment. Several vitamins have been reported to be reduced in the plasma/serum of AD-affected individuals indicating they have an impact on AD pathogenesis. In this review we focus on vitamin E and the other lipophilic vitamins A, D, and K, and summarize the current knowledge about their status in AD patients, their impact on cognitive functions and AD risk, as well as their influence on the molecular mechanisms of AD. The vitamins might affect the generation and clearance of Aβ both by direct effects and indirectly by altering the cellular lipid homeostasis. Additionally, vitamins A, D, E, and K are reported to influence further mechanisms discussed to be involved in AD pathogenesis, e.g., Aβ-aggregation, Aβ-induced neurotoxicity, oxidative stress, and inflammatory processes, as summarized in this article.]