Dipeptidyl peptidase 4(DPP4) inhibitors stride up the management of Parkinson's disease

Maanvi,; Kumari, Shilpa; Deshmukh, Rahul

doi:10.1016/j.ejphar.2022.175426

Cited by 4 publications

(3 citation statements)

References 75 publications

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“…As well, metformin has a neuroprotective role against PD neuropathology through different mechanisms including autophagy upregulation, degradation of pathological α‐synuclein and regulation of mitochondrial functions 149 . Furthermore, DPP4 inhibitors which are used in the management of T2DM can attenuate neuroinflammation and degeneration of dopaminergic neurons in the SN by inhibiting NF‐κB and the NLRP3 inflammasome signaling pathways 146,150 . Therefore, inhibition of NF‐κB and the NLRP3 inflammasome signaling pathways by antidiabetic agents' metformin and DPP4 inhibitors could be a potential therapeutic perspectives to prevent the development of PD in T2DM patients.…”

Section: Future Therapeutic Perspectivesmentioning

confidence: 99%

“… 149 Furthermore, DPP4 inhibitors which are used in the management of T2DM can attenuate neuroinflammation and degeneration of dopaminergic neurons in the SN by inhibiting NF‐κB and the NLRP3 inflammasome signaling pathways. 146 , 150 Therefore, inhibition of NF‐κB and the NLRP3 inflammasome signaling pathways by antidiabetic agents' metformin and DPP4 inhibitors could be a potential therapeutic perspectives to prevent the development of PD in T2DM patients.…”

Section: Future Therapeutic Perspectivesmentioning

confidence: 99%

See 1 more Smart Citation

NF‐κB/NLRP3 inflammasome axis and risk of Parkinson's disease in Type 2 diabetes mellitus: A narrative review and new perspective

Alrouji

Al-Kuraishy

Al-Gareeb

et al. 2023

J Cellular Molecular Medi

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Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). Genetic predisposition and immune dysfunction are involved in the pathogenesis of PD. Notably, peripheral inflammatory disorders and neuroinflammation are associated with PD neuropathology. Type 2 diabetes mellitus (T2DM) is associated with inflammatory disorders due to hyperglycaemia-induced oxidative stress and the release of pro-inflammatory cytokines. Particularly, insulin resistance (IR) in T2DM promotes the degeneration of dopaminergic neurons in the substantia nigra (SN). Thus, T2DM-induced inflammatory disorders predispose to the development and progression of PD, and their targeting may reduce PD risk in T2DM.

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Section: Future Therapeutic Perspectivesmentioning

confidence: 99%

Section: Future Therapeutic Perspectivesmentioning

confidence: 99%

NF‐κB/NLRP3 inflammasome axis and risk of Parkinson's disease in Type 2 diabetes mellitus: A narrative review and new perspective

Alrouji

Al-Kuraishy

Al-Gareeb

et al. 2023

J Cellular Molecular Medi

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“…DPP4 inhibitors are considered viable agents for the treatment of neurodegenerative diseases, such as Parkinson's disease, which neuroprotective and therapeutic potential is provided by leveling dopaminergic degeneration, promoting neuronal regeneration [13,14]. Figure 1 shows the scheme of pharmacologically determined and potential therapeutic use of DPP4 inhibitors.…”

Section: ■ Introductionmentioning

confidence: 99%

The Theoretical Substantiation of the Targeted Search for New DPP4 Inhibitors. Computational Studies of Potential Candidates

Suleiman,

Semenets,

Kobzar

et al. 2024

J. Org. Pharm. Chem.

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Growing evidence suggests that dipeptidyl peptidase 4 (DPP4) inhibitors, in addition to their role in improving glycemic control, help to reduce endothelial dysfunction and have hypolipidemic, anti-atherosclerotic, antitumor, antiviral, and neurotropic properties. This multi-target property may be one of the reasons for repurposing therapeutic treatment strategies with existing agents and the basis for finding new agents to inhibit this target. Based on the structural prerequisites and the evolutionary path of creating DPP4 inhibitors, an inhibitory (R)-β-aminoamide base was used as the basis for constructing potential candidates. It contained a substituted piperazine-2-one derivative and (S)-pyrrolidine-2-carbonitrile fragment, as well as phenyl and diphenyl rings, which were additionally saturated with substituents of various electronic structures, in position 4 of the β-aminoamide chain. The construction of the molecules was carried out taking into account the correspondence of chiral centers to combinations of chiral chains at the DPP4 binding site to possibly prevent a decrease in the inhibitory activity. In silico assessment of the “drug-likeness” and pharmacokinetic profile of the group of compounds studied showed that it had favorable characteristics and could be recommended for further molecular docking in order to predict the likely inhibition of the catalytic activity of DPP4. According to the results of docking, molecules with a moderate and high affinity were found. A detailed analysis of the resulting complexes showed that only nine compounds had a binding mode similar to classical inhibitors. According to the calculated array of values and analysis of the results of docking among the derivatives tested, a hit compound was found as a promising DPP4 inhibitor.

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DPP-4 inhibitors sitagliptin and PF-00734,200 mitigate dopaminergic neurodegeneration, neuroinflammation and behavioral impairment in the rat 6-OHDA model of Parkinson’s disease

Yu,

Wang,

Shen

et al. 2024

GeroScience

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Epidemiological studies report an elevated risk of Parkinson's disease (PD) in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed dipeptidyl peptidase 4 (DPP-4) inhibitors. With an objective to characterize clinically translatable doses of DPP-4 inhibitors (gliptins) in a well-characterized PD rodent model, sitagliptin, PF-00734,200 or vehicle were orally administered to rats initiated either 7-days before or 7-days after unilateral medial forebrain bundle 6-hydroxydopamine (6-OHDA) lesioning. Measures of dopaminergic cell viability, dopamine content, neuroinflammation and neurogenesis were evaluated thereafter in ipsi- and contralateral brain. Plasma and brain incretin and DPP-4 activity levels were quantified. Furthermore, brain incretin receptor levels were age-dependently evaluated in rodents, in 6-OHDA challenged animals and human subjects with/without PD. Cellular studies evaluated neurotrophic/neuroprotective actions of combined incretin administration. Pre-treatment with oral sitagliptin or PF-00734,200 reduced methamphetamine (meth)-induced rotation post-lesioning and dopaminergic degeneration in lesioned substantia nigra pars compacta (SNc) and striatum. Direct intracerebroventricular gliptin administration lacked neuroprotective actions, indicating that systemic incretin-mediated mechanisms underpin gliptin-induced favorable brain effects. Post-treatment with a threefold higher oral gliptin dose, likewise, mitigated meth-induced rotation, dopaminergic neurodegeneration and neuroinflammation, and augmented neurogenesis. These gliptin-induced actions associated with 70–80% plasma and 20–30% brain DPP-4 inhibition, and elevated plasma and brain incretin levels. Brain incretin receptor protein levels were age-dependently maintained in rodents, preserved in rats challenged with 6-OHDA, and in humans with PD. Combined GLP-1 and GIP receptor activation in neuronal cultures resulted in neurotrophic/neuroprotective actions superior to single agonists alone. In conclusion, these studies support further evaluation of the repurposing of clinically approved gliptins as a treatment strategy for PD.

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Dipeptidyl peptidase 4(DPP4) inhibitors stride up the management of Parkinson's disease

Cited by 4 publications

References 75 publications

NF‐κB/NLRP3 inflammasome axis and risk of Parkinson's disease in Type 2 diabetes mellitus: A narrative review and new perspective

NF‐κB/NLRP3 inflammasome axis and risk of Parkinson's disease in Type 2 diabetes mellitus: A narrative review and new perspective

The Theoretical Substantiation of the Targeted Search for New DPP4 Inhibitors. Computational Studies of Potential Candidates

DPP-4 inhibitors sitagliptin and PF-00734,200 mitigate dopaminergic neurodegeneration, neuroinflammation and behavioral impairment in the rat 6-OHDA model of Parkinson’s disease

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