Synthetic β-hydroxy ketone derivative inhibits cholinesterases, rescues oxidative stress and ameliorates cognitive deficits in 5XFAD mice model of AD

Ahmad, Samia; Ali, Gowhar; Tahir, Muhammad; Ullah, Rahim; Umar, Muhammad Naveed; Hashmi, Aisha Nasir

doi:10.1007/s11033-020-05997-0

Cited by 16 publications

(10 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For immunofluorescence staining, the spinal cord tissue samples (lumbar region) were blocked in 4% (v/v) paraformaldehyde in 1 M PBS and stored at 4°C as previously described ( Ikram et al, 2019 ; Ahmad et al, 2020 ). On the day of staining, tissue samples were washed 2× with 0.3% polyvinyl alcohol in 1× PBS (PBS-PVA).…”

Section: Methodsmentioning

confidence: 99%

Selected Thiadiazine-Thione Derivatives Attenuate Neuroinflammation in Chronic Constriction Injury Induced Neuropathy

Qureshi

Ali

Idrees

et al. 2021

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

Neuropathic pain refers to a lesion or disease of peripheral and/or central somatosensory neurons and is an important body response to actual or potential nerve damage. We investigated the therapeutic potential of two thiadiazine-thione [TDT] derivatives, 2-(5-propyl-6-thioxo-1, 3, 5-thiadiazinan-3-yl) acetic acid [TDT1] and 2-(5-propyl-2-thioxo-1, 3, 5-thiadiazinan-3-yl) acetic acid [TDT2] against CCI (chronic constriction injury)-induced neuroinflammation and neuropathic pain. Mice were used for assessment of acute toxicity of TDT derivatives and no major toxic/bizarre responses were observed. Anti-inflammatory activity was assessed using the carrageenan test, and both TDT1 and TDT2 significantly reduced carrageenan-induced inflammation. We also used rats for the induction of CCI and performed allodynia and hyperalgesia-related behavioral tests followed by biochemical and morphological analysis using RT-qPCR, immunoblotting, immunohistochemistry and immunofluorescence. Our findings revealed that CCI induced clear-cut allodynia and hyperalgesia which was reversed by TDT1 and TDT2. To determine the function of TDT1 and TDT2 in glia-mediated neuroinflammation, Iba1 mRNA and protein levels were measured in spinal cord tissue sections from various experimental groups. Interestingly, TDT1 and TDT2 substantially reduced the mRNA expression and protein level of Iba1, implying that TDT1 and TDT2 may mitigate CCI-induced astrogliosis. In silico molecular docking studies predicted that both compounds had an effective binding affinity for TNF-α and COX-2. The compounds interactions with the proteins were dominated by both hydrogen bonding and van der Waals interactions. Overall, these results suggest that TDT1 and TDT2 exert their neuroprotective and analgesic potentials by ameliorating CCI-induced allodynia, hyperalgesia, neuroinflammation and neuronal degeneration in a dose-dependent manner.

show abstract

Section: Methodsmentioning

confidence: 99%

Selected Thiadiazine-Thione Derivatives Attenuate Neuroinflammation in Chronic Constriction Injury Induced Neuropathy

Qureshi

Ali

Idrees

et al. 2021

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The animal failed to enter into the close arm within 120 s, manually guided to enter into the close arm. The above procedure was repeated after 24 h to examine the withholding of memory [28].…”

Section: Elevated Plus Maze (Epm)mentioning

confidence: 99%

“…Paddling Y-maze was performed for the analysis of spatial learning and memory [28].In the paddling Y-Maze test, escape latency time was determined for each group of animals for five consecutive days. The results showed that the 5xFAD group exhibited an increase in the latency time as compared to the WT-group (p < 0.001).…”

Section: Effect Of 2ncp In the Y-maze (Paddling) Testmentioning

confidence: 99%

“…Ketone bodies have the potential to ameliorate AD, amyotrophic lateral sclerosis, stroke, traumatic brain injury, and Parkinson's disease [25][26]. β-hydroxy ketone derivatives; 2-(hydroxyl-3-nitrophenyl) methyl)cyclopentanone and 2-(hydroxyl-(4-nitrophenyl)methyl)cyclopentanone were tested in our lab, finding of these studies showed significant inhibition of cholinesterases, oxidative stress, reduced plaques in the HC and FC, and improved memory in 5xFAD mice [27][28]. There is no effective drug in the market to treat AD, hence, across the globe research is going on to find out therapeutically effective drugs for this disease.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Attenuation of spatial memory in 5xFAD mice by targeting cholinesterases, oxidative stress and inflammatory signaling using 2-(hydroxyl-(2-nitrophenyl)methyl)cyclopentanone

Ullah

Ali

Subhan

et al. 2021

International Immunopharmacology

Self Cite

View full text Add to dashboard Cite

“…Indeed, the real promise of metabolic/ketogenic approaches is that by altering cellular energetics, oxidative stress, and inflammation, ketogenic (and possible 3NCP) have the potential to do more than provide symptomatic relief but also have the potential to alter disease trajectory. The cyclopentanone derivatives including 3NCP that were tested in our lab exhibited anti-cholinesterase, anti-oxidant, and anti-neuroinflammatory potential [23,24]. The 3NCP has a nitrophenyl group, and the literature studies revealed that compounds containing nitrophenyl group have the potential to inhibit AChE, BChE, MAO-B, and relieve oxidative stress [25].…”

Section: Introductionmentioning

confidence: 95%

Cyclopentanone Derivative Attenuates Memory Impairment by Inhibiting Amyloid Plaques Formation in the 5xFAD Mice

Ullah

Ali

Khan

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder. This study was designed to investigate the effects of cyclopentanone derivative i.e., 2-(hydroxyl-(3-nitrophenyl)methyl)cyclopentanone (3NCP) on behavior, amyloid β (Aβ) plaque deposition, and βAPP cleaving enzyme-1 (BACE-1) expression in the 5xFAD mouse brain. In this study, computational studies were conducted to predict the binding mode of the 3NCP with target sites of the β-secretase. In vivo studies were performed on the 5xFAD mice model of AD using different behavioral test models like light/dark box, elevated plus maze (EPM), and the Barnes maze tests for the assessment of anxiety, spatial learning and memory. The thioflavin-S staining, immunohistochemistry (IHC), and RT-PCR studies were carried out to find the effect of the 3NCP on the β-amyloid plaques formation and BACE-1 expression. The results of the computational studies showed that the 3NCP has excellent binding affinities for beta-secretase. The light/dark box study depicted that the 3NCP does not cause anxiety. The 3NCP treatment effects in the EPM and Barnes maze tests showed a significant effect on learning and memory. Furthermore, the results of the thioflavin staining and IHC revealed that the 3NCP significantly reduced the formation of the beta-amyloid plaques in brain tissues. Moreover, the RT-PCR study showed that 3NCP significantly reduced the BACE-1 expression in the brain. Conclusively, the results of the current study demonstrate that the 3NCP may be a potential candidate for AD treatment in the future.

show abstract

Synthetic β-hydroxy ketone derivative inhibits cholinesterases, rescues oxidative stress and ameliorates cognitive deficits in 5XFAD mice model of AD

Cited by 16 publications

References 48 publications

Selected Thiadiazine-Thione Derivatives Attenuate Neuroinflammation in Chronic Constriction Injury Induced Neuropathy

Selected Thiadiazine-Thione Derivatives Attenuate Neuroinflammation in Chronic Constriction Injury Induced Neuropathy

Attenuation of spatial memory in 5xFAD mice by targeting cholinesterases, oxidative stress and inflammatory signaling using 2-(hydroxyl-(2-nitrophenyl)methyl)cyclopentanone

Cyclopentanone Derivative Attenuates Memory Impairment by Inhibiting Amyloid Plaques Formation in the 5xFAD Mice

Contact Info

Product

Resources

About