Resveratrol Delivery from Implanted Cyclodextrin Polymers Provides Sustained Antioxidant Effect on Implanted Neural Probes

Haley, Rebecca M; Zuckerman, Sean T.; Dakhlallah, Hassan; Capadona, Jeffery R; Recum, Horst A. von; Ereifej, Evon S.

doi:10.3390/ijms21103579

Cited by 22 publications

(23 citation statements)

References 91 publications

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“…Iba-1 and 4HNE, stains for microglia and lipid peroxidation, respectively, also validate MT's known anti-inflammatory and antioxidative properties [48,53,54]. MT reduced the number of microglia surrounding the implants, as indicated by the significant decrease in Iba-1 staining as compared to the control tissue.…”

Section: Discussionsupporting

confidence: 55%

Melatonin Decreases Acute Inflammatory Response to Neural Probe Insertion

Krahe¹,

Woeppel²,

Yang³

et al. 2022

Preprint

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Neural electrode insertion trauma impedes the recording and stimulation capabilities of numerous diagnostic and treatment avenues. Implantation leads to the activation of inflammatory markers and cell types, which is detrimental to neural tissue health and recording capabilities. Oxidative stress and inflammation at the implant site have been shown to decrease with chronic administration of antioxidant melatonin at week 16, but its effects on the acute landscape have not been studied. To assess the effect of melatonin administration in the acute phase, specifically the first week post-implantation, we utilized histological and q-PCR methods to quantify cellular and molecular indicators of inflammation and oxidative stress as well as two-photon microscopy to track the microglial responses in real-time. Histological results indicate that melatonin effectively maintained neuron density surrounding the electrode, inhibited accumulation and activation of microglia, astrocytes, and reduced oxidative tissue damage. The expression of the pro-inflammatory cytokines, TNF-α and IL-6, were significantly reduced in melatonin-treated animals. Additionally, microglia encapsulation of the implant surface was inhibited by melatonin as compared to control animals following implantation. Our results combined with previous research suggest that melatonin is a particularly suitable drug for modulating inflammatory activity around neural electrode implants both acutely and chronically, translating to more stable and reliable interfaces.

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Section: Discussionsupporting

confidence: 55%

Melatonin Decreases Acute Inflammatory Response to Neural Probe Insertion

Krahe¹,

Woeppel²,

Yang³

et al. 2022

Preprint

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“…In addition, as 7KC induces major organelle dysfunction (mitochondria, peroxisome), targeting of these organelles by functionalized nanoparticles could also be considered (Targeted Organelle Nano therapy: TORN therapy) to oppose the toxicity of 7KC [ 30 , 101 ]. Currently, there are several lines of evidence that new nanoformulations of polyphenols (RSV, QCT) strongly improve the bioavailability of these polyphenols in vivo [ 118 , 119 ] and this makes it possible to envisage therapeutic applications with these molecules. Using iron nanoparticles, this would have the advantage of implementing targeted therapies.…”

Section: Discussionmentioning

confidence: 99%

Prevention by Dietary Polyphenols (Resveratrol, Quercetin, Apigenin) Against 7-Ketocholesterol-Induced Oxiapoptophagy in Neuronal N2a Cells: Potential Interest for the Treatment of Neurodegenerative and Age-Related Diseases

Yammine

Zarrouk

Nury

et al. 2020

Cells

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The Mediterranean diet is associated with health benefits due to bioactive compounds such as polyphenols. The biological activities of three polyphenols (quercetin (QCT), resveratrol (RSV), apigenin (API)) were evaluated in mouse neuronal N2a cells in the presence of 7-ketocholesterol (7KC), a major cholesterol oxidation product increased in patients with age-related diseases, including neurodegenerative disorders. In N2a cells, 7KC (50 µM; 48 h) induces cytotoxic effects characterized by an induction of cell death. When associated with RSV, QCT and API (3.125; 6.25 µM), 7KC-induced toxicity was reduced. The ability of QCT, RSV and API to prevent 7KC-induced oxidative stress was characterized by a decrease in reactive oxygen species (ROS) production in whole cells and at the mitochondrial level; by an attenuation of the increase in the level and activity of catalase; by attenuating the decrease in the expression, level and activity of glutathione peroxidase 1 (GPx1); by normalizing the expression, level and activity of superoxide dismutases 1 and 2 (SOD1, SOD2); and by reducing the decrease in the expression of nuclear erythroid 2-like factor 2 (Nrf2) which regulates antioxidant genes. QCT, RSV and API also prevented mitochondrial dysfunction in 7KC-treated cells by counteracting the loss of mitochondrial membrane potential (ΨΔm) and attenuating the decreased gene expression and/or protein level of AMP-activated protein kinase α (AMPKα), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) implicated in mitochondrial biogenesis. At the peroxisomal level, QCT, RSV and API prevented the impact of 7KC by counteracting the decrease in ATP binding cassette subfamily D member (ABCD)3 (a peroxisomal mass marker) at the protein and mRNA levels, as well as the decreased expresssion of genes associated with peroxisomal biogenesis (Pex13, Pex14) and peroxisomal β-oxidation (Abcd1, Acox1, Mfp2, Thiolase A). The 7KC-induced decrease in ABCD1 and multifunctional enzyme type 2 (MFP2), two proteins involved in peroxisomal β-oxidation, was also attenuated by RSV, QCT and API. 7KC-induced cell death, which has characteristics of apoptosis (cells with fragmented and/or condensed nuclei; cleaved caspase-3; Poly(ADP-ribose) polymerase (PARP) fragmentation) and autophagy (cells with monodansyl cadaverine positive vacuoles; activation of microtubule associated protein 1 light chain 3–I (LC3-I) to LC3-II, was also strongly attenuated by RSV, QCT and API. Thus, in N2a cells, 7KC induces a mode of cell death by oxiapoptophagy, including criteria of OXIdative stress, APOPTOsis and autoPHAGY, associated with mitochondrial and peroxisomal dysfunction, which is counteracted by RSV, QCT, and API reinforcing the interest for these polyphenols in prevention of diseases associated with increased 7KC levels.

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“…The extracts of the blank tissue samples were used to generate standard curves by spiking known amounts of resveratrol standard. The extracts of the experimental tissue samples were then evaluated based on the standard curve generated as previously described [49].…”

Section: Liquid Chromatography-mass Spectrometry (Lc-ms) Analysismentioning

confidence: 99%

Investigation of the Feasibility of Ventricular Delivery of Resveratrol to the Microelectrode Tissue Interface

et al. 2021

Self Cite

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(1) Background: Intracortical microelectrodes (IMEs) are essential to basic brain research and clinical brain–machine interfacing applications. However, the foreign body response to IMEs results in chronic inflammation and an increase in levels of reactive oxygen and nitrogen species (ROS/RNS). The current study builds on our previous work, by testing a new delivery method of a promising antioxidant as a means of extending intracortical microelectrodes performance. While resveratrol has shown efficacy in improving tissue response, chronic delivery has proven difficult because of its low solubility in water and low bioavailability due to extensive first pass metabolism. (2) Methods: Investigation of an intraventricular delivery of resveratrol in rats was performed herein to circumvent bioavailability hurdles of resveratrol delivery to the brain. (3) Results: Intraventricular delivery of resveratrol in rats delivered resveratrol to the electrode interface. However, intraventricular delivery did not have a significant impact on electrophysiological recordings over the six-week study. Histological findings indicated that rats receiving intraventricular delivery of resveratrol had a decrease of oxidative stress, yet other biomarkers of inflammation were found to be not significantly different from control groups. However, investigation of the bioavailability of resveratrol indicated a decrease in resveratrol accumulation in the brain with time coupled with inconsistent drug elution from the cannulas. Further inspection showed that there may be tissue or cellular debris clogging the cannulas, resulting in variable elution, which may have impacted the results of the study. (4) Conclusions: These results indicate that the intraventricular delivery approach described herein needs further optimization, or may not be well suited for this application.

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Resveratrol Delivery from Implanted Cyclodextrin Polymers Provides Sustained Antioxidant Effect on Implanted Neural Probes

Cited by 22 publications

References 91 publications

Melatonin Decreases Acute Inflammatory Response to Neural Probe Insertion

Melatonin Decreases Acute Inflammatory Response to Neural Probe Insertion

Prevention by Dietary Polyphenols (Resveratrol, Quercetin, Apigenin) Against 7-Ketocholesterol-Induced Oxiapoptophagy in Neuronal N2a Cells: Potential Interest for the Treatment of Neurodegenerative and Age-Related Diseases

Investigation of the Feasibility of Ventricular Delivery of Resveratrol to the Microelectrode Tissue Interface

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