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Electrically Controlled Neurochemical Delivery from Microelectrodes for Focal and Transient Modulation of Cellular Behavior.

ABSTRACT: Electrically controlled drug delivery of neurochemicals and biomolecules from conducting polymer microelectrode coatings hold great potentials in dissecting neural circuit or treating neurological disorders with high spatial and temporal resolution. The direct doping of a drug into a conducting polymer often results in low loading capacity, and the type of molecule that can be released is limited. Poly(3,4-ethylenedioxythiophene) (PEDOT) doped with sulfonated silica nanoparticles (SNP) has been developed as a more versatile platform for drug delivery. In this work, we demonstrate that neurochemicals with different surface charge, e.g., glutamate (GLU), gamma-Aminobutyric acid (GABA), dopamine (DA), 6,7-Dinitroquinoxaline- 2,3-dione (DNQX) and bicuculline, can be, respectively, incorporated into the SNP and electrically triggered to release repeatedly. The drug loaded SNPs were incorporated in PEDOT via electrochemical deposition on platinum microelectrodes. After PEDOT/SNP(drug) coating, the charge storage capacity (CSC) increased 10-fold to 55 ± 3 mC/cm², and the impedance at 1 kHz was also reduced approximately 6-fold. With the aid of a porous SNP, the loading capacity and number of releases of GLU was increased >4-fold and 66-fold, respectively, in comparison to the direct doping of PEDOT with GLU (PEDOT/GLU). The focal release of GLU and GABA from a PEDOT/SNP (drug) coated microelectrode were tested in cultured neurons using Ca imaging. The change in fluo-4 fluorescence intensity after electrically triggered GLU (+6.7 ± 2.9%) or GABA (-6.8 ± 1.6%) release indicated the successful modulation of neural activities by neurotransmitter release. In addition to activating neural activities, glutamate can also act on endothelial cells to stimulate nitric oxide (NO) release. A dual functional device with two adjacent sensing and releasing electrodes was constructed and we tested this mechanism in endothelial cell cultures. In endothelial cells, approximately 7.6 ± 0.6 nM NO was detected in the vicinity of the NO sensor within 6.2 ± 0.5 s of GLU release. The rise time of NO signal, T_0-100, was 14.5 ± 2.2 s. In summary, our work has demonstrated (1) a platform that is capable of loading and releasing drugs with different charges; (2) proof of concept demonstrations of how focal release of drugs can be used as a pharmacological manipulation to study neural circuitry or NO's effect on endothelial cells.

SUBMITTER: Tan C

PROVIDER: S-EPMC8467485 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Dermatosis often as a chronic disease requires effective long-term treatment; a comprehensive evaluation of mental health of dermatology drug does not receive enough attention. An interaction between dermatology and psychiatry has been increasingly described. Substantial evidence has accumulated that psychological stress can be associated with pigmentation, endocrine and immune systems in skin to create the optimal responses against pathogens and other physicochemical stressors to maintain or restore internal homeostasis. Additionally, given the common ectodermal origin shared by the brain and skin, we are interested in assessing how disruption of skin systems (pigmentary, endocrine and immune systems) may play a key role in brain functions. Thus, we selected three drugs (hydroquinone, isotretinoin, tacrolimus) with percutaneous excessive delivery to respectively intervene in these systems and then evaluate the potential neurotoxic effects. Firstly, C57BL/6 mice were administrated a dermal dose of hydroquinone cream, isotretinoin gel or tacrolimus ointment (2%, 0.05%, 0.1%, respectively, 5 times of the clinical dose). Behavioral testing was performed and levels of proteins were measured in the hippocampus. It was found that mice treated with isotretinoin or tacrolimus, presented a lower activity in open-field test and obvious depressive-like behavior in tail suspension test. Besides, they damaged cytoarchitecture, reduced the level of 5-HT-5-HT1A/1B system and increased the expression of apoptosis-related proteins in the hippocampus. To enable sensitive monitoring the dose-response characteristics of the consecutive neurobehavioral disorders, mice received gradient concentrations of hydroquinone (2%, 4%, 6%). Subsequently, hydroquinone induced behavioral disorders and hippocampal dysfunction in a dose-dependent response. When doses were high as 6% which was 3 times higher than 2% dose, then 100% of mice exhibited depressive-like behavior. Certainly, 6% hydroquinone exposure elicited the most serious impairment of hippocampal structure and survival. The fact that higher doses of hydroquinone are associated with a greater risk of depression is further indication that hydroquinone is responsible for the development of depression. These above data demonstrated that chronic administration of different dermatology drugs contributed into common mental distress. This surprising discovery of chemical stressors stimulating the hippocampal dysfunction, paves the way for exciting areas of study on the cross-talk between the skin and the brain, as well as is suggesting how to develop effective and safe usage of dermatological drugs in daily practice.

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Electrically Controlled Neurochemical Delivery from Microelectrodes for Focal and Transient Modulation of Cellular Behavior.

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