A Two-Photon Fluorescent Probe for Imaging Endogenous ONOO

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A Two-Photon Fluorescent Probe for Imaging Endogenous ONOOnear NMDA Receptors in Neuronal Cells and Hippocampal Tissues Dayoung Lee, Chang Su Lim, Gyeongju Ko, Dayoung Kim, Myoung Ki Cho, Sang-Jip Nam, Hwan Myung Kim, and Juyoung Yoon Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b01960 • Publication Date (Web): 03 Jul 2018 Downloaded from http://pubs.acs.org on July 4, 2018

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Analytical Chemistry

A Two-Photon Fluorescent Probe for Imaging Endogenous ONOOnear NMDA Receptors in Neuronal Cells and Hippocampal Tissues Dayoung Lee,†,§ Chang Su Lim,‡, § Gyeongju Ko,†,§ Dayoung Kim,†, Myoung Ki Cho,‡ Sang-Jip Nam,† Hwan Myung Kim*,‡ and Juyoung Yoon*,† †

Department of Chemistry and Nano Science, Ewha Womans University, Seoul 120-750, Korea.

‡

Department of Energy Systems Research, Ajou University, Suwon 443-749, Korea.

*Correspondence : (J. Yoon) Email: [email protected], Fax: 82-2-3277-2385 (H. M. Kim) Email: [email protected], Fax: 82-31-219-1615. ABSTRACT: In this study, we developed a two-photon fluorescent probe for detection of peroxynitrite (ONOO-) near the N-methyl-D-aspartate (NMDA) receptor. This naphthalimide-based probe contains a boronic acid reactive group and an ifenprodil-like tail, which serves as a NMDA receptor targeting unit. The probe displays high sensitivity and selectivity, along with a fast response time in aqueous solution. More importantly, the probe can be employed along with twophoton fluorescence microscopy to detect endogenous ONOO- near NMDA receptors in neuronal cells as well as in hippocampal tissues. The results suggest that the probe has the potential of serving as a useful imaging tool for studying ONOO- related diseases in the nervous system.

Peroxynitrite (ONOO-) acts as a strong oxidant in various pathological and physiological processes and is produced by the diffusion-limited reaction of superoxide (O2·-) and nitric oxide (NO·).1-5 Many important biomolecules, such as proteins, lipids, nucleic acids and transition-metal enzyme centers, are oxidized and damaged by ONOO-. Also, it has been reported that abnormal levels of ONOOare associated with many diseases, including neurodegenerative, cardiovascular, or inflammatory disorders and cancer.6-9 The N-methyl-D-aspartate (NMDA) receptor is a glutamate receptor and a ligand-gated cationic channel widely expressed in nerve cells.10-12 This receptor plays an important role in controlling synaptic plasticity, excitatory neurotransmission and brain development related to memory.13 Also, reports have described the relationship that exists between the NMDA receptor and ONOO-.14,15 In addition, it has been demonstrated that generation of ONOO- in nerve cells is dependent on activation of the NMDA receptor,14 and that ONOOmight contribute to modification and regulation of the function of the NMDA receptor.15 Moreover, ONOO- acts as a mediator of neurodegenerative disorders such as

Parkinson’s disease, AIDS-related dementia, stroke, Huntington’s disease, and Alzheimer’s disease.16,17 The combined observation demonstrates that the development of novel imaging tools, which can monitor the ONOO- near the NMDA receptor, is highly desirable goal so that more precise information can be acquired about the role(s) ONOO- plays in the nervous system. Over the past several decades, two-photon microscopy (TPM) has attracted special attention because it employs two photons of low energy, near-infrared light to excite a fluorescent dye. As a result, photobleaching and photodamage can be avoided.18-24 Recently, a small number of two-photon fluorescent probes have been developed for imaging ONOO- in living cells and tissues.22,25,26 However, no fluorescent probe for specific detection of ONOO- near NMDA receptors has been described thus far. Owing to these issues, in the current study we designed, synthesized and explored the utility of the new twophoton fluorescence probe 1 for monitoring ONOOlocated near the NMDA receptors (Scheme 1). This probe contains a naphthalimide group as a two-photon

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fluorophore, a boronic acid moiety as the reactive group for sensing ONOO-, and an ifenprodil-like tail as a moiety for targeting the NMDA receptor. Importantly, it is known that ifenprodil acts as an inhibitor and antagonist of the NMDA receptor.12,27-30 In this effort, we observed that 1 displays high water solubility, a fast response time and high selectivity and sensitivity toward ONOO-. We also demonstrated that the new probe can be employed to detect ONOO- near NMDA receptors in living cells and tissues.

Scheme 1. The structures of probe 1 and the product of its reaction with ONOO .

EXPERIMENTAL SECTION Reagents and Materials. Unless otherwise noted, chemicals were obtained from commercial suppliers and were used without purification. Flash chromatography was carried out on silica gel (230-400 mesh), 1H NMR and 13 C NMR spectra were recorded by Bruker 300 MHz. UV absorption spectra were obtained using an Evolution 201 spectrometer at 25 oC. Fluorescence emission spectra were obtained using RF-5301/PC (Shimadzu) fluorescence spectrophotometer at 25 oC. Cell Culture. SH-SY5Y (human bone marrow neuroblastoma) cells were obtained from Korean Cell Line Bank (Seoul, Korea). Cells were cultured in MEM (Eagle's Minimum Essential Medium) supplemented with 100 U/mL penicillin and 100 U/mL streptomycin heatinactivated 10% fetal bovine serum. All cells were kept in 5% CO2 at 37 oC. Confocal microscope imaging. Cells were seeded in 35mm glass bottomed dishes at a density of 3 × 105 cells per dish in culture media. After 24 h, cells were incubated with 10 μM probe 1 for 30 min, then washed with DPBS and treated with ONOO- (0, 100 μM) for 60 min. Fluorescence images were the acquired by using confocal laser scanning microscopy (FV1200, Olympus, Japan). To acquire fluorescence images, cells were excited with 473 nm laser using a 490-590 nm emission filter nm. Cytotoxicity test. Cells were seeded in a 96-well plate with culture media. After overnight culture, cells were incubated with each concentration of sample for 24 h. To identify cell viability, reagents were removed and 0.5 mg/ml of MTT (Sigma) media was added to the cells and incubated for 4 hr at 37 oC CO2 incubator and the produced formazan was dissolved in 0.1 ml of dimethylsulfoxide (DMSO) and read at OD 650 nm with a Spectramax Microwell plate reader. Absorbance was

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determined and the mean cell viability was calculated as a percentage of the mean vehicle control and experiments were carried out in 3 independent tests. Measurement of two-photon cross section. The twophoton cross section (δ) was calculated by using a previously described femtosecond (fs) fluorescence measurement technique.31 Probe 1 was dissolved in 10 mM PBS buffer (containing 1% DMSO, pH 7.4) at a concentrations of 1.0 × 10-5 M and then the two-photon induced fluorescence intensity was measured upon twophoton excitation at 720−880 nm and Rhodamine 6G used as the reference.31 To measure the two-photon cross section (δ) of the product formed by reaction of 1 (1.0 × 105 M) with ONOO- (100 μM), the mixture was incubated at RT for 1 h before the measurement was conducted. The fluorescence intensities of the reference and sample were determined at the same two-photon excitation wavelength. The two-photon cross section was calculated by using the following equation: δ = δr(SsФrφrcr)/(SrФsφscs), where r and s stand for the reference and sample molecules, S is the intensity of the signal measured by a CCD, Φ is the fluorescence quantum yield, φ is the overall fluorescence collection efficiency according to the experimental apparatus, c is concentration in solution, and δr is the reported two-photon cross section value of the reference material. Two-photon fluorescence microscopy. TPM imaging of probe 1-labeled cells and tissues were performed with spectral confocal and multiphoton microscopes (Leica TCS SP8 MP) with ×10 dry (NAs: 0.30) and ×40 oil (NAs: 1.30) objectives. The images were collected by using a mode-locked titanium-sapphire laser source (Mai Tai HP; Spectra Physics, 80 MHz pulse frequency, 100 fs pulse width) after setting the wavelength of 750 nm and output laser power of 2670 mW used, which corresponds approximately to 15 mW at the focal plane. TPM images were captured in the 500-600 nm range, internal PMTs were used to acquire the signals under condition of 8 bit unsigned 512 × 512 pixels upon 400 Hz scan speed mode. Preparation and staining of fresh rat Hippocampal slices. 2-week-old rat (SD) were sacrificed for hippocampal slices preparation. 400 μm-thick coronal slices were prepared by using a vibrating-blade microtome with artificial cerebrospinal fluid (ACSF; 124 mM NaCl, 3 mM KCl, 26 mM NaHCO3, 1.25 mM NaH2PO4, 10 mM D-glucose, 2.4 mM CaCl2, and 1.3 mM MgSO4). The slices were incubated with 20 μM probe 1 in ACSF, previously bubbled under condition of 5% CO2 and 95% O2 for 50 min at 37 °C , then after washed with ACSF repeatedly, probe 1-labelled slice were transferred to imaging dish (glass-bottomed dish, MatTek) and observed in a spectral confocal multiphoton microscope. To assess the effects of SIN-1, ifenprodil, and ebselen, the slices were treated with 50 μM SIN-1, 100 μM ifenprodil, and 150 μM ebselen for 20, 30, and 50 min, respectively before being treated with 1.


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RESULTS AND DISCUSSION Synthesis. Probe 1 was synthesized by using the route shown in Scheme 2, which begins with Suzuki coupling of 4-bromo-1,8-naphthalic anhydride and bis(pinacolato)diboron to form boronate 3. Treatment of 3 with β-alanine yields carboxylic acid 4. The ifenprodil derivative 2, synthesized by using the previously described method,12,19 is reacted with 4 in the presence of HOBt/EDC to produce 1. The structures of probe 1 and all synthetic intermediates were characterized by using 1H NMR and 13C NMR spectroscopy, and ESI mass spectrometry (see ESI).

(a) 1.0

Absorbance

0.8

0.6

Only probe1, probe1 + H2O2, NO•, OCl , •OH, ROO•, t-ROOH

0.4 -

Probe 1 + ONOO 0.2

0.0 300

400

500

600

Wavelength (nm)

(b) 300 250

Fluorescent Intensity

-

Probe 1 + ONOO 200

150

Only probe 1, probe 1 + H2O2, NO•, OCl ,

100

•OH, ROO•, t-ROOH 50

0 500

550

600

650

700

Wavelength (nm)

GM at 750 nm (Figure 3). This result shows that a 4.0-fold increase in the two-photon excited fluorescence (TPEF) intensity occurs when 1 reacts with ONOO-. Figure 1. (a) UV/Vis absorption spectra and (b) fluorescence spectra of probe 1 (10 μM) with various ROS and RNS (100 μM) in PBS solution (pH 7.4, containing 1% DMSO). (λex= 450 nm, slits 3 × 3 nm).

Scheme 2. Route for synthesis of probe 1.

Optical properties. The UV/Vis absorption and fluorescence changes of a phosphate-buffer saline solution (pH 7.4, 0.1 M PBS, containing 1% DMSO) of probe 1 (10 μM) upon addition of various reactive oxygen (ROS) and nitrogen species (RNS) (100 μM), including ONOO-, H2O2, NO·, OCl-, ·OH, ROO·, tert-butyl hyperoxide (TBHP), were determined (Figure 1). As shown in Figure 1, probe 1 displays a UV/Vis absorption maximum at 350 nm and weak fluorescence with a maximum at 550 nm (excitation at 450 nm). Addition of ONOO- causes a red shift of the absorbance peak from 350 to 450 nm and a marked increase in the intensity of fluorescence at 550 nm. Importantly, probe 1 displays a high selectivity for ONOO- over other ROS and RNS and has a detection limit for ONOO- of 1.84 × 10-7 M (Figure S11). Furthermore, the two-photon (TP) action spectra of 1 and the product of reaction of 1 with ONOO- in PBS buffer solution (pH 7.4, 10 mM, containing 1% DMSO) were also determined. The two-photon action cross section (Φδ) value of 1 was calculated to be ca. 1.0 GM at 750 nm. In contrast, the reaction product has a Φδ value of ca. 4.0

300

250

Fluorescence Intensity

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


200

-

150

10 eq. ONOO

100 -

0 eq. ONOO 50

0 500

550

600

650

700

Wavelength (nm)

Figure 2. Fluorescence titration of probe 1 (10 μM) upon addition of ONOO (0-10 eq.) in PBS solution (pH 7.4, containing 1% DMSO). (λex= 450 nm, slits 3 × 3 nm).



4

δφ /GM

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

3

1 + ONOO 1

-

2 1 0 720 740 760 780 800 820 840 860 880

Wavelength/ nm Figure 3. Two-photon action spectra of probe 1 (10 μM) before (black) and after (red) addition of ONOO (10 eq.) in PBS buffer (10 mM, containing 1% DMSO, pH 7.4). The measurement uncertainties for the two-photon action crosssection values (Φδ) are approximately ±15%.

The proposed mechanism for reaction of probe with ONOO-, based on previous reports is shown in Scheme S1.32-35 The path begins with ONOO- addition to the boronate group and is followed by hydrolysis to form the corresponding phenol. Evidence for this proposal was supported by FAB-MS data after reaction of 1 with ONOO- (Figure S14). The peaks at m/z= 691. 3857 for [M+H]+ and m/z=713.3723 for [M+Na]+ were observed, which match the molecular weight of predicted product after reaction. It is reported that boronate group reacts with ONOO- much faster than with other oxidation species.36,37 The rate constant of oxidation of boronate group by ONOO- has been calculated as ~106M-1S-1. This high reactivity makes probe 1 as a selective fluorescent probe for ONOO-. One-photon fluorescence imaging in living cells. The utility of probe 1 for imaging ONOO- in live neuroblastoma cells (SH-SY5Y) was evaluated. As shown in Figure 4, weak fluorescence emanates from the membrane when SH-SY5Y cells are incubated with probe 1 (10 μM) for 30 min. Furthermore, when cells are treated with an additional 100 μM ONOO- for 60 min, the fluorescence intensity of probe 1 in the cellular membranes is significantly enhanced. These results indicate that the 1 can be used to detect ONOO- near NMDA receptors in cellular membranes. To examine the cytotoxicity of the 1, SH-SY5Y cells were incubated with various concentrations of 1 for 24 h, then the cell viability was measured by MTT assays. As shown in Figure S15, more than 97 % of SH-SY5Y cells survive after treatment with 50 μM of 1 for 24 h, suggesting that 1 has extremely negligible cytotoxicity. These results show that probe 1 can be used for imaging intracellular ONOO-.

Figure 4. Confocal microscope images. SH-SY5Y cells were incubated with probe 1 (10 μM) for 30 min and washed with DPBS. Cells were treated with (a) 0 and (b) 100 μM ONOO for 60 min. The fluorescence images were obtained at 490590 nm upon excitation at 473 nm.

Two-photon fluorescence imaging in living cells and tissues. We also evaluated the use of probe 1 for detecting ONOO- near NMDA receptors in live cells using TPM. TPM image of probe 1 (10 µM) labelled primary cortical neuronal cells shows weak fluorescence intensity (Figure 5a). The TPEF intensity of the image is markedly increased when the cells are pretreated with 300 µM ONOO- (Figure 5b). Moreover, the expanded image clearly shows the existence of bright spots and their heterogeneous distribution through the dendrites and axons in the neuron (Figure 5h). Probe 1 was then used to measure endogenous ONOO- in the region around the NMDA receptor. Treatment of neurons with 50 ng/mL IFN-γ and 500 ng/mL LPS leads to an enhancement of the intensity of TPEF images (Figure 5c). Similar increases in the intensities of the images occur when 3morpholinosydnonimine (SIN-1), a well-known ONOOdonor, is added (Figure 5d). The fluorescence intensities through the dendrites and axons decrease when the neurons are pretreated with 10 µM ifenprodil, which is an antagonist of NMDA receptors (specifically the NR2B receptor) (Figure 5e).12 In addition, when the cells are pretreated with 100 µM ebselen, a well-known ONOOscavenger, the fluorescence intensities of the images effectively decrease to the basal levels (Figure 5f). These data confirm that probe 1 is suitable for detecting ONOOnear the NMDA receptors in live neurons. We also tried to determine whether probe 1 was capable of measuring ONOO- near NMDA receptors in living tissues. TPM images of a portion of 1-labeled fresh rat hippocampal slice were investigated. The accumulated image of 50 sections at depths of 90-180 μm in the CA3 regions shows overall dim signal (Figure 6a), however, the


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TPEF intensity arise when the tissues are pre-treated with 50 µM SIN-1 (Figure 6b) as observed in studies with cultured neuronal cells. The images collected at a higher magnification clearly displayed the ONOO- levels in the individual cells (Figure 6c-f). In addition, the TPEF intensity decreased upon treatments with ifenprodil and ebselen (Figure 6e-g). The combined results demonstrated that probe 1 in conjunction with TPM can be successfully employed to measure ONOO- levels near the NMDA receptor in living tissues.

implemented by combining images in the z-direction, which correspond to depths of 90-180 μm and detected in the (a) absence and (b) presence of 50 μM SIN-1. (c-f) Enlarged images show a white box part of a and b at a depth of 120 μm, and were acquired (c) before and (d) after the addition of SIN-1 (50 μM) for 20 min, or (e) ifenprodil (100 μM) for 30 min, or (f) 150 μM ebselen with 50 μM SIN-1 for 40 min. (g) Average TPEF intensity in (c–f). Images were acquired at the range of 500–600 nm upon excitation at 750 nm. Scale bar: (a) 300 and (c) 50 μm, respectively.

CONCLUSION In conclusion, the two-photon fluorescent probe 1 for detecting ONOO- near the NMDA receptor was successfully developed in this investigation. Probe 1 exhibits high sensitivity and selectivity for detection of ONOO-. We also demonstrated that 1 has a low cytotoxicity and that it can be used along with TPM to monitor ONOO- levels near NMDA receptors in living neuronal cells and tissues. The results of this effort suggest that 1 can be employed to study cellular functions related to ONOO- near NMDA receptors and, importantly, that this information could be essential for the diagnosis of diseases related to ONOO- in nervous system.

ASSOCIATED CONTENT -

Figure 5. TPM images of exogenous ONOO in primary cortical neuronal cells. Cells were incubated with (a) probe 1 (10 μM) and (b) pretreated with ONOO (300 μM) for 20 min, (c) 50 ng/mL IFN-γ and 500 ng/mL LPS for 4 h, (d) SIN-1 (20 μM) for 10 min, (e) ifenprodil (10 μM) for 30 min, and (f) ebselen (100 μM) + ONOO (300 μM ) for 20 min. (g-l) Expanded images of dendritic spine region (white box in a-f). (m) TPEF intensities in a-f. The TPEF intensities were analyzed at the range of 500–600 nm upon excitation at 750 nm with fs pulses. All TPM images are representative images from five times replicate experiments. Scale bars: (a-f) 60 μm and (g-l) 15 μm, respectively.

Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1

13

Synthetic procedures, H NMR and C NMR analyses, MS, HRMS, generation of ROS and RNS, fluorescence, and UV data.

AUTHOR INFORMATION Corresponding Author *Juyoung Yoon: [email protected]; Fax: 82-2-3277-2385. *Hwan Myung Kim: [email protected]; Fax: 82-31-219-

1615. Author Contributions §

These authors contributed equally to this work.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT

Figure 6. TPM rat hippocampal slices images were acquired after incubation of 20 μM probe 1 for 1 h, and obtained at ×10 (a, b) and ×40 (c-f) magnification. (a, b) The TPM images are

This study was supported financially by a National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2012R1A3A2048814 for J. Yoon and No. 2016R1E1A1A02920873 for H. M. Kim). The Korea Basic Science Institute (Western Seoul) is acknowledged for the LC/MS data. FAB mass spectral data were obtained from the Korea Basic Science Institute (Daegu) on a Jeol JMS 700 high resolution mass spectrometer.


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A Two-Photon Fluorescent Probe for Imaging Endogenous ONOO

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