Neurotrophic and neuroprotective effects of a monomeric GLP-1/GIP/Gcg receptor triagonist in cellular and rodent models of mild traumatic brain injury

Li, Yazhou; Glotfelty, Elliot J.; Namdar, I.; Tweedie, David; Olson, Lar̀s; Hoffer, Barry J.; DiMarchi, Richard D.; Pick, Chagi G.; Greig, Nigel H.

doi:10.1016/j.expneurol.2019.113113

Cited by 21 publications

(7 citation statements)

References 75 publications

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“…We previously demonstrated that GLP‐1 receptor agonists (including dual and triagonist mimetics) are neurotrophic and neuroprotective across numerous physiological and pathological insults (Bader et al, 2018, 2020; Chen et al, 2018; Li et al, 2017, 2020, 2009). To characterize the neurotrophic and neuroprotective effects of GLP‐1 (9‐36), we first treated SH‐SY5Y cells in a concentration‐dependent (1, 10, 100, 1000 nM) manner for 24 h and assessed cell survival by MTS assay.…”

Section: Resultsmentioning

confidence: 99%

“…A value of p < 0.05 or less is considered statistically significant. The sample size was selected based on our prior studies (Li et al, 2017(Li et al, , 2020(Li et al, , 2009) and a power analysis (Charan & Kantharia, 2013). Blinding was performed in relation to α-syn and Aβ challenge studies, where a different experimenter analyzed results.…”

Section: Statisticsmentioning

confidence: 99%

“…We previously demonstrated that GLP-1 receptor agonists (including dual and triagonist mimetics) are neurotrophic and neuroprotective across numerous physiological and pathological insults (Bader et al, 2018(Bader et al, , 2020Chen et al, 2018;Li et al, 2017Li et al, , 2020Li et al, , 2009. To characterize the neurotrophic and neuroprotective…”

Section: Neurotrophic and Neuroprotective Actions Of Glp-1 (9-36)mentioning

confidence: 99%

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The metabolite GLP‐1 (9‐36) is neuroprotective and anti‐inflammatory in cellular models of neurodegeneration

Glotfelty

Karlsson

et al. 2021

Journal of Neurochemistry

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Glucagon‐like peptide‐1 (GLP‐1) is best known for its insulinotropic action following food intake. Its metabolite, GLP‐1 (9‐36), was assumed biologically inactive because of low GLP‐1 receptor (GLP‐1R) affinity and non‐insulinotropic properties; however, recent studies contradict this assumption. Increased use of FDA approved GLP‐1 analogues for treating metabolic disorders and neurodegenerative diseases raises interest in GLP‐1 (9‐36)’s biological role. We use human SH‐SY5Y neuroblastoma cells and a GLP‐1R over‐expressing variety (#9), in both undifferentiated and differentiated states, to evaluate the neurotrophic/neuroprotective effects of GLP‐1 (9‐36) against toxic glutamate exposure and other oxidative stress models (via the MTS, LDH or ROS assays). In addition, we examine GLP‐1 (9‐36)’s signaling pathways, including cyclic‐adenosine monophosphate (cAMP), protein kinase‐A (PKA), and 5’ adenosine monophosphate‐activated protein kinase (AMPK) via the use of ELISA, pharmacological inhibitors, or GLP‐1R antagonist. Human HMC3 and mouse IMG microglial cell lines were used to study the anti‐inflammatory effects of GLP‐1 (9‐36) against lipopolysaccharide (LPS) (via ELISA). Finally, we applied GLP‐1 (9‐36) to primary dissociation cultures challenged with α‐synuclein or amyloid‐β and assessed survival and morphology via immunochemistry. We demonstrate evidence of GLP‐1R, cAMP, PKA, and AMPK‐mediated neurotrophic and neuroprotective effects of GLP‐1 (9‐36). The metabolite significantly reduced IL‐6 and TNF‐α levels in HMC3 and IMG microglial cells, respectively. Lastly, we show mild but significant effects of GLP‐1 (9‐36) in primary neuron cultures challenged with α‐synuclein or amyloid‐β. These studies enhance understanding of GLP‐1 (9‐36)’s effects on the nervous system and its potential as a primary or complementary treatment in pathological contexts.

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Section: Resultsmentioning

confidence: 99%

Section: Statisticsmentioning

confidence: 99%

Section: Neurotrophic and Neuroprotective Actions Of Glp-1 (9-36)mentioning

confidence: 99%

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The metabolite GLP‐1 (9‐36) is neuroprotective and anti‐inflammatory in cellular models of neurodegeneration

Glotfelty

Karlsson

et al. 2021

Journal of Neurochemistry

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“…Both triple and dual receptor agonists show similar enhancement of cAMP production in comparison to single GLP-1 receptor agonists [ 75 ]. However, recently, a superior effect of triple agonists has been indicated, with triple agonists providing a greater neuroprotective benefit against glutamate excitotoxicity compared with dual receptor agonists [ 126 ]. As a result, further research is required into whether triple agonists are beneficial in neurodegenerative populations.…”

Section: Glp-1mentioning

confidence: 99%

Incretin and insulin signaling as novel therapeutic targets for Alzheimer’s and Parkinson’s disease

2022

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Despite an ever-growing prevalence and increasing economic burden of Alzheimer’s disease (AD) and Parkinson’s disease (PD), recent advances in drug development have only resulted in minimally effective treatment. In AD, along with amyloid and tau phosphorylation, there is an associated increase in inflammation/glial activation, a decrease in synaptic function, an increase in astrocyte activation, and a state of insulin resistance. In PD, along with α-synuclein accumulation, there is associated inflammation, synaptic dysfunction, dopaminergic neuronal loss, and some data to suggest insulin resistance. Therapeutic strategies for neurodegenerative disorders have commonly targeted individual pathological processes. An effective treatment might require either utilization of multiple drugs which target the individual pathological processes which underlie the neurodegenerative disease or the use of a single agent which could influence multiple pathological processes. Insulin and incretins are compounds with multiple effects on neurodegenerative processes. Preclinical studies have demonstrated that GLP-1 receptor agonists reduce neuroinflammation, reduce tau phosphorylation, reduce amyloid deposition, increase synaptic function, and improve memory formation. Incretin mimetics may act through the restoration of insulin signaling pathways, inducing further neuroprotective effects. Currently, phase 2 and phase 3 trials are underway in AD and PD populations. Here, we provide a comprehensive review of the therapeutic potential of incretin mimetics and insulin in AD and PD.

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“…Regarding the nervous systems, it has been reported that in post-traumatic brain injury, glucagon produced a significant neuroprotective effect [10]. Recently, Li et al reported that a triagonist of glucagon-like peptide-1(GLP-1)/gastric inhibitory polypeptide/glucagon receptors produced neurotrophic and neuroprotective action by reduc-ing cell cytotoxicity and glutamate excitotoxicity by elevating cyclic adenosine monophosphate (cAMP) levels in human neuroblastoma cell-line SH-SY5Y [11]. However, no previous study has reported the neuroprotective effect of glucagon in the peripheral nervous system.…”

Section: Introductionmentioning

confidence: 99%

Glucagon Prevents Cytotoxicity Induced by Methylglyoxal in a Rat Neuronal Cell Line Model

et al. 2021

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Although diabetic polyneuropathy (DPN) is a frequent diabetic complication, no effective therapeutic approach has been established. Glucagon is a crucial hormone for glucose homeostasis but has pleiotropic effects, including neuroprotective effects in the central nervous system. However, the importance of glucagon in the peripheral nervous system (PNS) has not been clarified. Here, we hypothesized that glucagon might have a neuroprotective function in the PNS. The immortalized rat dorsal root ganglion (DRG) neuronal cell line 50B11 was treated with methylglyoxal (MG) to mimic an in vitro DPN model. The cells were cultured with or without glucagon or MG. Neurotoxicity, survival, apoptosis, neurite projection, cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA) were examined. Glucagon had no cytotoxicity and rescued the cells from neurotoxicity. Cell survival was increased by glucagon. The ratio of apoptotic cells, which was increased by MG, was reduced by glucagon. Neurite outgrowth was accelerated in glucagon-treated cells. Cyclic AMP and PKA accumulated in the cells after glucagon stimulation. In conclusion, glucagon protected the DRG neuronal cells from MG-induced cellular stress. The cAMP/PKA pathway may have significant roles in those protective effects of glucagon. Glucagon may be a potential target for the treatment of DPN.

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Neurotrophic and neuroprotective effects of a monomeric GLP-1/GIP/Gcg receptor triagonist in cellular and rodent models of mild traumatic brain injury

Cited by 21 publications

References 75 publications

The metabolite GLP‐1 (9‐36) is neuroprotective and anti‐inflammatory in cellular models of neurodegeneration

The metabolite GLP‐1 (9‐36) is neuroprotective and anti‐inflammatory in cellular models of neurodegeneration

Incretin and insulin signaling as novel therapeutic targets for Alzheimer’s and Parkinson’s disease

Glucagon Prevents Cytotoxicity Induced by Methylglyoxal in a Rat Neuronal Cell Line Model

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