Inhibition of DPP4 enhances inhibitory synaptic transmission through activating the GLP-1/GLP-1R signaling pathway in a rat model of febrile seizures

Liu, Yunli; Xu, Jian; Sun, Qi; Yu, Fangfang; Cheng, Jia; Peng, Biwen; Liu, Wanhong; Xiao, Zheman; Yin, Jun; Han, Song; He, Xiaohua

doi:10.1016/j.bcp.2018.08.004

Cited by 24 publications

(19 citation statements)

References 36 publications

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“…Experimental FS model were generated in rats using hot water bath immersion as previously described [3].The seizures were scored according to the Racine scale [10]. Animals exhibiting stage 3 seizures (forelimb clonus) were regarded as exhibiting seizure behavior.…”

Section: Generation Of Experimental Fs In Vivomentioning

confidence: 99%

“…(Shanghai, China) according to previous report [3]. Neurons were maintained on 10-14 days and transfected with siRNA mediated DPP4 (5'-GCUGAUAGCGCGAGAACUUTT-3'/5'-AAGUUCUCGCGCUAUCAGCTT) following to the manual instructions.…”

Section: Sirna Assaymentioning

confidence: 99%

“…The spontaneous inhibitory postsynaptic currents (sIPSCs) in the cultured hippocampal neurons (10- were diluted immediately prior to use and acutely applied by bath superfusion (PH:7.20, osmolarity: 300-310 mosm/liter). The temperature (39.5°C) was monitored using a small thermistor placed directly in the recording chamber with continuous perfusion of a standard external solution at a rate of 2 ml/min [3]. Sita and CXCL12(10 nM, PeproTech, USA) were added into perfusion bath before recording.…”

Section: Electrophysiological Recordingsmentioning

confidence: 99%

“…Febrile convulsions (FS) are a common type of pathological brain activity in childhood, and longer seizure onsets are accompanied by serious clinical outcomes [1][2][3]. It is an important task to explore and develop new drug targets for the prevention and treatment of febrile convulsions.…”

Section: Introductionmentioning

confidence: 99%

“…Some data indicated that dipeptidyl peptidase-IV (DPP4) involved in the occurrence of febrile seizure, and DPP4 inhibition increased miniature inhibitory post-synaptic currents (mIPSCs), however, its underlying molecular mechanism remains unclear [3]. Previous data indicated that DPP4 inhibition could increase glucagon-like peptide-1(GLP-1) and GLP-1 receptor (GLP-1R) levels to effect FS development in rats [3]. Increasing evidence suggest that immune inflammatory factors play an important role in the pathogenesis of FS.…”

Section: Introductionmentioning

confidence: 99%

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The CXCL12/CXCR4 signaling is required for DPP4 regulation of spontaneous inhibitory postsynaptic currents (sIPSCs)

Chen¹,

Yang²,

Han³

2020

Preprint

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Background: Previous data suggested that dipeptidyl peptidase-IV (DPP4) involved in the occurrence of febrile seizure (FS), but its potential mechanism remains to be determined. Here, we investigated whether DPP4 regulated gamma-aminobutyric acid (GABA) mediated spontaneous inhibitory postsynaptic currents (sIPSCs) via the downstream C-X-C Motif Chemokine Ligand 12 (CXCL12)/ C-X-C chemokine receptor type 4 (CXCR4) signaling in cultured hippocampal neurons submitted to hyperthermia(39.5-40°C). Methods: Whole cell patch- clamp method was used to test sIPSC in vitro after DPP4 inhibition or CXCL12 administration. The level of CXCL12 and CXCR4 was tested using western blot analysis. The effect of CXCR4 antagonist AMD3100 (5 mg/ml, i.c.v) on seizures were tested using electroencephalogram (EEG) in a FS model. Results: We found that pharmacological DPP4 inhibitor sitagliptin (Sita,100μM) treatment or siRNA-mediated DPP4 knockdown enhanced the mean amplitude and frequency of sIPSCs in vitro. DPP4 knockdown with siRNA increased protein level of CXCL12 and CXCR4. Furthermore, CXCL12 (10 nM) treatment enhanced inhibitory transmission by increasing the mean frequency and amplitude of sIPSCs in vitro. AMD3100 administration decreased seizure severity by increasing hippocampal GABA content in vivo. Conclusions: Our data suggest that CXCL12/CXCR4 signaling is required for DPP4 regulation of sIPSCs, supporting that DPP4 played a key role in the pathogenesis of FS.

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Section: Generation Of Experimental Fs In Vivomentioning

confidence: 99%

Section: Sirna Assaymentioning

confidence: 99%

Section: Electrophysiological Recordingsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The CXCL12/CXCR4 signaling is required for DPP4 regulation of spontaneous inhibitory postsynaptic currents (sIPSCs)

Chen¹,

Yang²,

Han³

2020

Preprint

Self Cite

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Nonenzymatic function of DPP4 in diabetes‐associated mitochondrial dysfunction and cognitive impairment

Sun

Xiao

et al. 2021

Alzheimer's & Dementia

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Dipeptidyl peptidase-4 (DPP4) has been proven to exert its functions by both enzymatic and nonenzymatic pathways. The nonenzymatic function of DPP4 in diabetesassociated cognitive impairment remains unexplored. We determined DPP4 protein concentrations or its enzymatic activity in type 2 diabetic patients and db/db mice and tested the impact of the non-enzymatic function of DPP4 on mitochondrial dysfunction and cognitive impairment both in vivo and in vitro. The results show that increased DPP4 activity was an independent risk factor for incident mild cognitive impairment (MCI) in type 2 diabetic patients. In addition, DPP4 was highly expressed in the hippocampus of db/db mice and contributed to mitochondria dysfunction and cognitive impairment. Mechanistically, DPP4 might bind to PAR2 in the hippocampus and trigger GSK-3β activation, which downregulates peroxisome proliferator-activated receptor gamma coactivator 1 alpha expression and leads to mitochondria dysfunction, thereby promoting cognitive impairment in diabetes. Our findings indicate that the nonenzymatic function of DPP4 might promote mitochondrial dysfunction and cognitive impairment in diabetes.

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A novel mouse model of glucagon‐like peptide‐1 receptor expression: A look at the brain

Graham

Durai

Trammell

et al. 2020

J of Comparative Neurology

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Glucagon-like peptide-1 (GLP-1) is an incretin hormone with a number of functions to maintain energy homeostasis and contribute to motivated behavior, both peripherally and within the central nervous system (CNS). These functions, which include insulin secretion, gastric emptying, satiety, and the hedonic aspects of food and drug intake, are primarily mediated through stimulation of the GLP-1 receptor. While this receptor plays an important role in a variety of physiological outcomes, data regarding its CNS expression has been primarily limited to regional receptor binding and single-label transcript expression studies. We thus developed a bacterial artificial chromosome transgenic mouse, in which expression of a red fluorescent protein (mApple) is driven by the GLP-1R promoter. Using this reporter mouse, we characterized the regional and cellular expression patterns of GLP-1R expressing cells in the CNS, using double-label immunohistochemistry and in situ hybridization. GLP-1R-expressing cells were enriched in several key brain regions and circuits, including the lateral septum, hypothalamus, amygdala, bed nucleus of the stria terminalis, hippocampus, ventral midbrain, periaqueductal gray and cerebral cortex. In most regions, GLP-1R primarily colocalized with GABAergic neurons, except within some regions such as the hippocampus, where it was co-expressed in glutamatergic neurons. GLP-1R-mApple cells were highly co-expressed with 5-HT3 receptor-containing neurons within the cortex and striatum, as well as with dopamine receptor-and calbindin-expressing cells within the lateral septum, the brain region in which GLP-1R is most highly expressed. In this manuscript, we provide detailed images of GLP-1R-mApple expression and distribution within the brain and characterization of these neurons.

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Inhibition of DPP4 enhances inhibitory synaptic transmission through activating the GLP-1/GLP-1R signaling pathway in a rat model of febrile seizures

Cited by 24 publications

References 36 publications

The CXCL12/CXCR4 signaling is required for DPP4 regulation of spontaneous inhibitory postsynaptic currents (sIPSCs)

The CXCL12/CXCR4 signaling is required for DPP4 regulation of spontaneous inhibitory postsynaptic currents (sIPSCs)

Nonenzymatic function of DPP4 in diabetes‐associated mitochondrial dysfunction and cognitive impairment

A novel mouse model of glucagon‐like peptide‐1 receptor expression: A look at the brain

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