Novel NSAID-Derived Drugs for the Potential Treatment of Alzheimer's Disease.

Ivana Cacciatore, Lisa Marinelli, Erika Fornasari, Laura S Cerasa, Piera Eusepi et al.

Other International journal of molecular sciences 2016 29 citazioni

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Study Design

Tipo di studio: In Vitro
Popolazione: In vitro (Alzheimer's drug development)

Intervento: Novel NSAID-Derived Drugs for the Potential Treatment of Alzheimer's Disease. novel NSAID derivatives
Comparatore: parent NSAIDs
Esito primario: amyloid-beta aggregation and COX inhibition
Direzione dell'effetto: Mixed
Rischio di bias: Unclear

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested for the potential treatment of neurodegenerative diseases, such as Alzheimer's disease (AD). Prolonged use of NSAIDs, however, produces gastrointestinal (GI) toxicity. To overcome this serious limitation, the aim of this study was to develop novel NSAID-derived drug conjugates (Anti-inflammatory-Lipoyl derivatives, AL4-9) that preserve the beneficial effects of NSAIDS without causing GI problems. As such, we conjugated selected well-known NSAIDs, such as (S)-naproxen and (R)-flurbiprofen, with (R)-α-lipoic acid (LA) through alkylene diamine linkers. The selection of the antioxidant LA was based on the proposed role of oxidative stress in the development and/or progression of AD. Our exploratory studies revealed that AL7 containing the diaminoethylene linker between (R)-flurbiprofen and LA had the most favorable chemical and in vitro enzymatic stability profiles among the synthesized compounds. Upon pretreatment, this compound exhibited excellent antioxidant activity in phorbol 12-miristate 13-acetate (PMA)-stimulated U937 cells (lymphoblast lung from human) and Aβ(25-35)-treated THP-1 cells (leukemic monocytes). Furthermore, AL7 also modulated the expression of COX-2, IL-1β and TNF-α in these cell lines, suggesting anti-inflammatory activity. Taken together, AL7 has emerged as a potential lead worthy of further characterization and testing in suitable in vivo models of AD.

TL;DR

Novel NSAID-derived drug conjugates are developed that preserve the beneficial effects of NSAIDS without causing GI problems and AL7 containing the diaminoethylene linker between (R)-flurbiprofen and LA had the most favorable chemical and in vitro enzymatic stability profiles among the synthesized compounds.

Full Text

Supplementary Materials: Novel NSAID-Derived Drugs for the Potential Treatment of Alzheimer’s Disease

Ivana Cacciatore, Lisa Marinelli, Erika Fornasari, Laura S. Cerasa, Piera Eusepi, Hasan Türkez, Cristina Pomilio, Marcella Reale, Chiara D’Angelo, Erica Costantini and Antonio Di Stefano

Figure S1. (A,B) Cellular vitality evaluated by MTT assay on THP-1 cell line for AL1–9.

Figure S2. (A,B) Cellular vitality evaluated by MTT assay on U937 cell line for AL1–9.

(B)

Figure S3. (A) 1H- and (B) 13C-NMR spectra of AL4.

Figure S4. HR-MS spectra of AL4.

(B)

Figure S5. (A) 1H- and (B) 13C-NMR spectra of AL5.

Figure S6. Expanded 13C-NMR spectra of AL5.

Figure S7. HR-MS spectra of AL5.

Figure S8. (A) 1H- and (B) 13C-NMR spectra of AL6.

Figure S9. Expanded 13C-NMR spectra of AL6.

Figure S10. HR-MS spectra of AL6.

Figure S12. HR-MS spectra of AL7.

(A)

Figure S13. Cont.

Figure S13. (A) 1H- and (B)13C-NMR spectra of AL8.

Figure S14. Expanded 13C-NMR spectra of AL8.

Figure S15. HR-MS spectra of AL8.

(A)

Figure S16. Cont.

Figure S16. (A)1H- and (B) 13C-NMR spectra of AL9.

Figure S17. HR-MS spectra of AL9.

Table S1. Experimental conditions HR-MS.

Instrument Method: Uni_CH

Wednesday, 18 May 2016, 09:30:36; Page 1 of 4 Program for Dionex Chromatography MS Link Column Oven. Temp Ctrl = On Column Oven. Temperature. Nominal = 40.0 °C Column Oven. Temperature. Lower Limit = 5.0 °C Column Oven. Temperature. Upper Limit = 80.0 °C Equilibration Time = None Column Oven. Ready Temp Delta = 3.0 °C Sampler. Temp Ctrl = Off Pressure. Lower Limit = 10 bar Pressure. Upper Limit = 468 bar Maximum Flow Ramp Down = 0.250 mL/min² Maximum Flow Ramp Up = 0.250 mL/min²

%A. Equate = “%A”
%B. Equate = “%B”
%C. Equate = “%C”
%D. Equate = “%D” Draw Speed = 5.000 μL/s Draw Delay = 3000 ms Disp Speed = 20.000 μL/s Dispense Delay = 0 ms Waste Speed = 32.000 μL/s Sample Height = 2.000 mm Inject Wash = No Wash Loop Wash Factor = 2.000 Puncture Offset = 0.0 mm Pump Device = “Pump” Inject Mode = Normal Response Time = 2.000 s UV_VIS_1.Wavelength = 280.0 nm UV_VIS_1.Band width = 1 nm UV_VIS_1.Ref Wavelength = Off UV_VIS_1.Ref Band width = 1 nm 0.000 Wait UV. Ready and Pump. Ready and Column Oven. Ready and Sampler. Ready and Pump Module. Ready Chromeleon sets this property to signal to Xcalibur that it is ready to start a run. Ready To Run = 1 Xcalibur sets this property to start the run or injection. Wait StartRun Autozero Flow = 0.200 mL/min

%B = 0.0%
%C = 20.0%
%D = 80.0% Curve = 5 Wait UV. Ready and Pump. Ready and Column Oven. Ready and Sampler. Ready and Pump Module. Ready Inject Inject Response = 1 Chromeleon sets this property to signal the injection to Xcalibur.

Depending on your system configuration it might be necessary to manually insert a “Relay” command below in order to send the start signal to the MS. Instrument Method: Uni_CH

Wednesday, 18 May 2016, 09:30:36; Page 2 of 4 Typical syntaxes: Pump_Relay_1. Closed Duration = 2.00 UM3PUMP_Relay1. On Duration = 2.00 UV_VIS_1.AcqOn Flow = 0.200 mL/min
Wednesday, 18 May 2016, 09:30:36; Page 3 of 4 Method of Q Exactive Overall method settings Global Settings use lock masses best Lock mass injection― Chrom. peak width (FWHM) 30 s Time Method duration 25.00 min Customized Tolerances (+/−) Inclusion Exclusion Neutral Loss Mass Tags Dynamic Exclusion

Experiment Full MS—SIM General Runtime 0 to 25 min Polarity Positive In-source CID 0.0 eV Full MS—SIM Microscans 1 Resolution 140,000 AGC target 5 e 5 Maximum IT 200 ms Number of scan ranges 1 Scan range 250 to 750 m/z Spectrum data type Profile Setup Tunefiles General Switch Count 0 Base Tunefile C:\Xcalibur\TSDev\Method\cal mix.mstune Contact Closure General Used False Start in Closed True Switch Count 0 Syringe General Instrument Method: Uni_CH
Wednesday, 18 May 2016, 09:30:36; Page 4 of 4 Used False Start in OFF True Stop at end of run False Switch Count 0 Pump setup Syringe type Hamilton Flow rate 3.000 μL/min Inner diameter 2.303 mm Volume 250 μL

Divert Valve A General Used False Start in 1-2 True Switch Count 0
Divert Valve B General Used False Start in 1-2 True Switch Count 0 Lock Masses 1 entry Mass Polarity Start End Comment

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Figures

Figure 1

Chemical structures and synthetic schemes for novel NSAID-derived compounds designed as potential Alzheimer's disease therapeutics. The molecular modifications aim to enhance neuroprotective properties while retaining anti-inflammatory activity.

Figure 2

Figure 3

Figure 4

Figure 5

Biological activity data for NSAID-derived compounds tested against Alzheimer's disease targets. The evaluation includes assessments of anti-inflammatory, antioxidant, or cholinesterase inhibitory properties.

Novel NSAID-Derived Drugs for the Potential Treatment of Alzheimer's Disease.

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Study Design

Abstract

TL;DR

Full Text

Supplementary Materials: Novel NSAID-Derived Drugs for the Potential Treatment of Alzheimer’s Disease

Ivana Cacciatore, Lisa Marinelli, Erika Fornasari, Laura S. Cerasa, Piera Eusepi, Hasan Türkez, Cristina Pomilio, Marcella Reale, Chiara D’Angelo, Erica Costantini and Antonio Di Stefano

Figure S2. (A,B) Cellular vitality evaluated by MTT assay on U937 cell line for AL1–9.

(B)

Figure S4. HR-MS spectra of AL4.

(B)

(A)

(A)

Figures

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