Possible role of DPP4 inhibitors to promote hippocampal neurogenesis in Alzheimer’s disease

Chalichem, Nehru Sai Suresh; Pindiprolu, Sai Kiran S. S.; Basavan, Duraiswamy

doi:10.1080/1061186x.2018.1433682

Cited by 14 publications

(11 citation statements)

References 72 publications

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“…Various DPP-4 inhibitors showed a prominent effect in several pre-clinical and clinical trials for the treatment of neurodegenerative disorders [6][7][8]. One of the potent and selective DPP-4 inhibitors is Vildagliptin (Vilda) that is approved as an anti-hyperglycemic drug for the treatment of type-2 diabetes [9].…”

Section: Introductionmentioning

confidence: 99%

Vildagliptin Attenuates Huntington's Disease through Activation of GLP-1 Receptor/PI3K/Akt/BDNF Pathway in 3-Nitropropionic Acid Rat Model

et al. 2020

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Vildagliptin (Vilda), a dipeptidyl peptidase-4 (DPP-4) inhibitor, has been highlighted as a promising therapeutic agent for neurodegenerative diseases as Alzheimer's and Parkinson's diseases. Vilda's effect is mostly linked to PI3K/Akt signaling in CNS. Moreover, PI3K/Akt activation reportedly enhanced survival and dampened progression of Huntington's disease (HD). However, Vilda's role in HD is yet to be elucidated. Thus, the aim of the study is to uncover the potentiality of Vilda in HD and unfold its link with PI3K/Akt pathway in 3-nitropropionic acid (3NP) rat model. Rats were randomly assigned into 4 groups; group 1 received saline, whereas, groups 2, 3 and 4 received 3NP (10 mg/kg/day; i.p.) for 14 days, concomitantly with Vilda (5 mg/kg/day; p.o.) in groups 3 and 4, and wortmannin (WM), a PI3K inhibitor, (15 μg/kg/day; i.v.) in group 4. Vilda improved cognitive and motor perturbations induced by 3NP, as confirmed by striatal histopathological specimens and immunohistochemical examination of GFAP. The molecular signaling of Vilda was estimated by elevation of GLP-1 level and protein expressions of survival proteins; p85/p55 (pY458/199)-PI3K, pS473-Akt. Together, it boosted striatal neurotrophic factors and receptor; pS133-CREB, BDNF, pY515-TrKB, which subsequently maintained mitochondrial integrity, as indicated by enhancing both SDH and COX activities, and the redox modulators; Sirt1, Nrf2. Such neuroprotection restored imbalance of neurotransmitters through increasing GABA and suppressing glutamate as well PDE10A. These effects were reversed by WM pre-administration. In conclusion, Vilda purveyed significant anti-Huntington effect which may be mediated, at least in part, via activation of GLP-1/PI3K/Akt pathway in 3NP rat model.

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Section: Introductionmentioning

confidence: 99%

Vildagliptin Attenuates Huntington's Disease through Activation of GLP-1 Receptor/PI3K/Akt/BDNF Pathway in 3-Nitropropionic Acid Rat Model

et al. 2020

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“…The current research work is a continuation of our repurposing strategy to our earlier research works that involved in targeting DPP-IV inhibitors for Alzheimer's disease [ 14 , 37 , 38 ]. CA stands in place after curcumin in in s ilico analysis for the selected receptor.…”

Section: Discussionmentioning

confidence: 99%

“…This serine protease acts at proline or alanine at the N-terminal penultimate (P) position and promotes either activation or inactivation of the substrates. The non-glycaemic actions of these drugs also proved that repurposing of these molecules can be advantageous for other few complicated disorders like Alzheimer's disease for which our lab is currently working [ [13] , [14] , [15] ]. Hence, in this context we have carried out i n silico studies viz ., Molecular mechanics combined with generalized Born model and solvent accessibility method (MMGB-SA), induced fit docking (IFD) and (simulation) dynamics for 50 nanoseconds (ns) to understand the possible behaviour of the molecule in the active site followed by enzyme inhibition assay to confirm the inhibitory action of the molecule.…”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl peptidase-IV inhibitory action of Calebin A: An in silico and in vitro analysis

Chalichem

Jupudi

Nagarkar

et al. 2021

Journal of Ayurveda and Integrative Medicine

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Background Dipeptidyl peptidase-IV (DPP-IV) inhibitors, the enhancers of incretin are used for the treatment of diabetes. The non-glycaemic actions of these drugs (under developmental stage) also proved that repurposing of these molecules may be advantageous for other few complicated disorders like cardiovascular diseases, Parkinson's disease, Alzheimer's disease, etc. Objective The present study was aimed to investigate the DPP-IV inhibitory potential of Calebin-A, one of the constituents of Curcuma longa . Material and methods The phytoconstituent was subjected for various in silico studies (using Schrödinger Suite) like, Docking analysis, molecular mechanics combined with generalized Born model and solvent accessibility method (MMGBSA) and Induced fit docking (IFD) after validating the protein using Ramachandran plot. Further, the protein-ligand complex was subjected to molecular dynamic simulation studies for 50 nanoseconds. And finally, the results were confirmed through enzyme inhibition study. Results In silico results revealed possible inhibitory binding interactions in the catalytic pocket (importantly Glu205, Glu206 and Tyr 662 etc.) and binding affinity in terms of glide g-score and MMGBSA dG bind values were found to be −6.2 kcal/mol and −98.721 kcal/mol. Further, the inhibitory action towards the enzyme was confirmed by an enzyme inhibition assay, in which it showed dose-dependent inhibition, with maximum % inhibition of 55.9 at 26.3 μM. From molecular dynamic studies (50 nanoseconds), it was understood that Calebin A was found to be stable for about 30 nanoseconds in maintaining inhibitory interactions. Conclusion From the in silico and in vitro analysis, the current research emphasizes the consideration of Calebin A to be as a promising or lead compound for the treatment of several ailments where DPP-IV action is culprit.

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“…Inhibition of DPP4 by Diprotin A or Val‐Pyr maintains the CXCL12 concentration at the site of ischemic injury, promoting stem cell migration, and engraftment potential of ischemic tissue 72 . Maintaining concentration gradients of CXCL12 by DPP4 inhibition has the potential to enhance stem cell repopulation in an array of stem cell therapies, recent work looks at its ability to promote hippocampal neurogenesis in Alzheimer's disease 73 …”

Section: Cxcr4 Ligandsmentioning

confidence: 99%

Polyfunctionality of the CXCR4/CXCL12 axis in health and disease: Implications for therapeutic interventions in cancer and immune‐mediated diseases

Britton¹,

Poznansky²,

Reeves³

2021

The FASEB Journal

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Historically the chemokine receptor CXCR4 and its canonical ligand CXCL12 are associated with the bone marrow niche and hematopoiesis. However, CXCL12 exhibits broad tissue expression including brain, thymus, heart, lung, liver, kidney, spleen, and bone marrow. CXCR4 can be considered as a node which is integrating and transducing inputs from a range of ligand-receptor interactions into a responsive and divergent network of intracellular signaling pathways that impact multiple cellular processes such as proliferation, migration, and stress resistance. Dysregulation of the CXCR4/CXCL12 axis and consequent fundamental cellular processes, are associated with a panoply of disease. This review frames the polyfunctionality of the receptor at a molecular, physiological, and pathophysiological levels. Transitioning our perspective of this axis from a single gene/protein:single function model to a polyfunctional signaling cascade highlights the potential for finer therapeutic intervention and cautions against a reductionist approach.

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Possible role of DPP4 inhibitors to promote hippocampal neurogenesis in Alzheimer’s disease

Cited by 14 publications

References 72 publications

Vildagliptin Attenuates Huntington's Disease through Activation of GLP-1 Receptor/PI3K/Akt/BDNF Pathway in 3-Nitropropionic Acid Rat Model

Vildagliptin Attenuates Huntington's Disease through Activation of GLP-1 Receptor/PI3K/Akt/BDNF Pathway in 3-Nitropropionic Acid Rat Model

Dipeptidyl peptidase-IV inhibitory action of Calebin A: An in silico and in vitro analysis

Polyfunctionality of the CXCR4/CXCL12 axis in health and disease: Implications for therapeutic interventions in cancer and immune‐mediated diseases

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