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

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

doi:10.3390/ijms21103579

Abstract

Intracortical microelectrodes are valuable tools used to study and treat neurological diseases. Due in large part to the oxidative stress and inflammatory response occurring after electrode implantation, the signal quality of these electrodes decreases over time. To alleviate this response, resveratrol, a natural antioxidant which elicits neuroprotective effects through reduction of oxidative stress, was utilized. This work compares traditional systemic delivery of resveratrol to the novel cyclodextrin polymer (pCD) local delivery approach presented herein, both in vitro and in vivo. The pCD displayed an extended resveratrol release for 100 days, as well as 60 days of free radical scavenging activity in vitro. In vivo results indicated that our pCD delivery system successfully delivered resveratrol to the brain with a sustained release for the entire short-duration study (up to 7 days). Interestingly, significantly greater concentrations of resveratrol metabolites were found at the intracortical probe implantation site compared to the systemic administration of resveratrol. Together, our pilot results provide support for the possibility of improving the delivery of resveratrol in an attempt to stabilize long-term neural interfacing applications.

Highlights

Intracortical microelectrodes (IME) are a neuroscience tool that can be utilized for studying the functions of the nervous system [1]
Oxidative stress demonstrated by the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS) by glial cells, has been identified as a factor contributing to the failure of IMEs [6,7,8,9]
Significance is defined to be a p-value < 0.05. The objective of this pilot study was to present a proof of concept approach to locally deliver resveratrol to the neural probe implantation site, utilizing a novel polymerized cyclodextrin disk loaded with resveratrol

Summary

Introduction

Intracortical microelectrodes (IME) are a neuroscience tool that can be utilized for studying the functions of the nervous system [1]. The signal quality from electrophysiology recordings has been shown to decrease over time, in part due to the inflammatory and oxidative stress responses around the electrode. During implantation, breaching of the blood–brain barrier occurs, resulting in the infiltration of neurotoxic factors and myeloid cells contributing to the inflammatory response [3]. Oxidative stress demonstrated by the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS) by glial cells, has been identified as a factor contributing to the failure of IMEs [6,7,8,9]. Oxidative stress leads to neuronal death, exacerbation of the inflammatory response, and corrosion of the electrode [8,9,10,11]. Neurons have low antioxidant activity levels and high methyl ions, resulting in a vulnerability to the damage of cellular lipids, proteins, and DNA [12,13]

Methods

Findings

Discussion

Conclusion