Elliot Glotfelty, Ph.D.

@article{pmid37401784,

title = {Microglial Nogo delays recovery following traumatic brain injury in mice},

author = {Elliot J Glotfelty and Shih-Chang Hsueh and Quia Claybourne and Alicia Bedolla and Katherine O Kopp and Tonya Wallace and Binhai Zheng and Yu Luo and Tobias E Karlsson and Ross A McDevitt and Lars Olson and Nigel H Greig},

url = {https://pubmed.ncbi.nlm.nih.gov/37401784/},

doi = {10.1002/glia.24436},

issn = {1098-1136},

year  = {2023},

date = {2023-10-01},

urldate = {2023-10-01},

journal = {Glia},

volume = {71},

number = {10},

pages = {2473--2494},

abstract = {Nogo-A, B, and C are well described members of the reticulon family of proteins, most well known for their negative regulatory effects on central nervous system (CNS) neurite outgrowth and repair following injury. Recent research indicates a relationship between Nogo-proteins and inflammation. Microglia, the brain's immune cells and inflammation-competent compartment, express Nogo protein, although specific roles of the Nogo in these cells is understudied. To examine inflammation-related effects of Nogo, we generated a microglial-specific inducible Nogo KO (MinoKO) mouse and challenged the mouse with a controlled cortical impact (CCI) traumatic brain injury (TBI). Histological analysis shows no difference in brain lesion sizes between MinoKO-CCI and Control-CCI mice, although MinoKO-CCI mice do not exhibit the levels of ipsilateral lateral ventricle enlargement as injury matched controls. Microglial Nogo-KO results in decreased lateral ventricle enlargement, microglial and astrocyte immunoreactivity, and increased microglial morphological complexity compared to injury matched controls, suggesting decreased tissue inflammation. Behaviorally, healthy MinoKO mice do not differ from control mice, but automated tracking of movement around the home cage and stereotypic behavior, such as grooming and eating (termed cage "activation"), following CCI is significantly elevated. Asymmetrical motor function, a deficit typical of unilaterally brain lesioned rodents, was not detected in CCI injured MinoKO mice, while the phenomenon was present in CCI injured controls 1-week post-injury. Overall, our studies show microglial Nogo as a negative regulator of recovery following brain injury. To date, this is the first evaluation of the roles microglial specific Nogo in a rodent injury model.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid37408199,

title = {The RhoA-ROCK1/ROCK2 Pathway Exacerbates Inflammatory Signaling in Immortalized and Primary Microglia},

author = {Elliot J Glotfelty and Luis B Tovar-Y-Romo and Shih-Chang Hsueh and David Tweedie and Yazhou Li and Brandon K Harvey and Barry J Hoffer and Tobias E Karlsson and Lars Olson and Nigel H Greig},

url = {https://pubmed.ncbi.nlm.nih.gov/37408199/},

doi = {10.3390/cells12101367},

issn = {2073-4409},

year  = {2023},

date = {2023-05-01},

urldate = {2023-05-01},

journal = {Cells},

volume = {12},

number = {10},

abstract = {Neuroinflammation is a unifying factor among all acute central nervous system (CNS) injuries and chronic neurodegenerative disorders. Here, we used immortalized microglial (IMG) cells and primary microglia (PMg) to understand the roles of the GTPase Ras homolog gene family member A (RhoA) and its downstream targets Rho-associated coiled-coil-containing protein kinases 1 and 2 (ROCK1 and ROCK2) in neuroinflammation. We used a pan-kinase inhibitor (Y27632) and a ROCK1- and ROCK2-specific inhibitor (RKI1447) to mitigate a lipopolysaccharide (LPS) challenge. In both the IMG cells and PMg, each drug significantly inhibited pro-inflammatory protein production detected in media (TNF-α, IL-6, KC/GRO, and IL-12p70). In the IMG cells, this resulted from the inhibition of NF-κB nuclear translocation and the blocking of neuroinflammatory gene transcription (iNOS, TNF-α, and IL-6). Additionally, we demonstrated the ability of both compounds to block the dephosphorylation and activation of cofilin. In the IMG cells, RhoA activation with Nogo-P4 or narciclasine (Narc) exacerbated the inflammatory response to the LPS challenge. We utilized a siRNA approach to differentiate ROCK1 and ROCK2 activity during the LPS challenges and showed that the blockade of both proteins may mediate the anti-inflammatory effects of Y27632 and RKI1447. Using previously published data, we show that genes in the RhoA/ROCK signaling cascade are highly upregulated in the neurodegenerative microglia (MGnD) from APP/PS-1 transgenic Alzheimer's disease (AD) mice. In addition to illuminating the specific roles of RhoA/ROCK signaling in neuroinflammation, we demonstrate the utility of using IMG cells as a model for primary microglia in cellular studies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35234334,

title = {Role of chronic neuroinflammation in neuroplasticity and cognitive function: A hypothesis},

author = {Daniela Lecca and Yoo Jin Jung and Michael T Scerba and Inho Hwang and Yu Kyung Kim and Sun Kim and Sydney Modrow and David Tweedie and Shih-Chang Hsueh and Dong Liu and Weiming Luo and Elliot Glotfelty and Yazhou Li and Jia-Yi Wang and Yu Luo and Barry J Hoffer and Dong Seok Kim and Ross A McDevitt and Nigel H Greig},

url = {https://pubmed.ncbi.nlm.nih.gov/35234334/},

doi = {10.1002/alz.12610},

issn = {1552-5279},

year  = {2022},

date = {2022-11-01},

urldate = {2022-11-01},

journal = {Alzheimers Dement},

volume = {18},

number = {11},

pages = {2327--2340},

abstract = {OBJECTIVE: Evaluating the efficacy of 3,6'-dithioPomalidomide in 5xFAD Alzheimer's disease (AD) mice to test the hypothesis that neuroinflammation is directly involved in the development of synaptic/neuronal loss and cognitive decline.nnBACKGROUND: Amyloid-β (Aβ) or tau-focused clinical trials have proved unsuccessful in mitigating AD-associated cognitive impairment. Identification of new drug targets is needed. Neuroinflammation is a therapeutic target in neurodegenerative disorders, and TNF-α a pivotal neuroinflammatory driver.nnNEW HYPOTHESIS: AD-associated chronic neuroinflammation directly drives progressive synaptic/neuronal loss and cognitive decline. Pharmacologically mitigating microglial/astrocyte activation without altering Aβ generation will define the role of neuroinflammation in AD progression.nnMAJOR CHALLENGES: Difficulty of TNF-α-lowering compounds reaching brain, and identification of a therapeutic-time window to preserve the beneficial role of neuroinflammatory processes.nnLINKAGE TO OTHER MAJOR THEORIES: Microglia/astroglia are heavily implicated in maintenance of synaptic plasticity/function in healthy brain and are disrupted by Aβ. Mitigation of chronic gliosis can restore synaptic homeostasis/cognitive function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34569615b,

title = {The metabolite GLP-1 (9-36) is neuroprotective and anti-inflammatory in cellular models of neurodegeneration},

author = {Yazhou Li and Elliot J Glotfelty and Tobias Karlsson and Lowella V Fortuno and Brandon K Harvey and Nigel H Greig},

url = {https://pubmed.ncbi.nlm.nih.gov/34569615/},

doi = {10.1111/jnc.15521},

issn = {1471-4159},

year  = {2021},

date = {2021-12-01},

urldate = {2021-12-01},

journal = {J Neurochem},

volume = {159},

number = {5},

pages = {867--886},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33408188,

title = {Neuronal delivery of antibodies has therapeutic effects in animal models of botulism},

author = {Patrick M McNutt and Edwin J Vazquez-Cintron and Luis Tenezaca and Celinia A Ondeck and Kyle E Kelly and Mark Mangkhalakhili and James B Machamer and Christopher A Angeles and Elliot J Glotfelty and Jaclyn Cika and Cesar H Benjumea and Justin T Whitfield and Philip A Band and Charles B Shoemaker and Konstantin Ichtchenko},

url = {https://pubmed.ncbi.nlm.nih.gov/33408188/},

doi = {10.1126/scitranslmed.abd7789},

issn = {1946-6242},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {Sci Transl Med},

volume = {13},

number = {575},

abstract = {Botulism is caused by a potent neurotoxin that blocks neuromuscular transmission, resulting in death by asphyxiation. Currently, the therapeutic options are limited and there is no antidote. Here, we harness the structural and trafficking properties of an atoxic derivative of botulinum neurotoxin (BoNT) to transport a function-blocking single-domain antibody into the neuronal cytosol where it can inhibit BoNT serotype A (BoNT/A1) molecular toxicity. Post-symptomatic treatment relieved toxic signs of botulism and rescued mice, guinea pigs, and nonhuman primates after lethal BoNT/A1 challenge. These data demonstrate that atoxic BoNT derivatives can be harnessed to deliver therapeutic protein moieties to the neuronal cytoplasm where they bind and neutralize intracellular targets in experimental models. The generalizability of this platform might enable delivery of antibodies and other protein-based therapeutics to previously inaccessible intraneuronal targets.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32412796,

title = {Glucagon-like peptide-1 (GLP-1)-based receptor agonists as a treatment for Parkinson's disease},

author = {Elliot J Glotfelty and Lars Olson and Tobias E Karlsson and Yazhou Li and Nigel H Greig},

url = {https://pubmed.ncbi.nlm.nih.gov/32412796/},

doi = {10.1080/13543784.2020.1764534},

issn = {1744-7658},

year  = {2020},

date = {2020-06-01},

urldate = {2020-06-01},

journal = {Expert Opin Investig Drugs},

volume = {29},

number = {6},

pages = {595--602},

abstract = {INTRODUCTION: Accumulating evidence supports the evaluation of glucagon-like peptide-1 (GLP-1) receptor (R) agonists for the treatment of the underlying pathology causing Parkinson's Disease (PD). Not only are these effects evident in models of PD and other neurodegenerative disorders but recently in a randomized, double-blind, placebo-controlled clinical trial, a GLP-1R agonist has provided improved cognition motor functions in humans with moderate PD.nnAREAS COVERED: In this mini-review, we describe the development of GLP-1R agonists and their potential therapeutic value in treating PD. Many GLP-1R agonists are FDA approved for the treatment of metabolic disorders, and hence can be rapidly repositioned for PD. Furthermore, we present preclinical data offering insights into the use of monomeric dual- and tri-agonist incretin-based mimetics for neurodegenerative disorders. These drugs combine active regions of GLP-1 with those of glucose-dependent insulinotropic peptide (GIP) and/or glucagon (Gcg).nnEXPERT OPINION: GLP-1Ragonists offer a complementary and enhanced therapeutic value to other drugs used to treat PD. Moreover, the use of the dual- or tri-agonist GLP-1-based mimetics may provide combinatory effects that are even more powerful than GLP-1R agonism alone. We advocate for further investigations into the repurposing of GLP-1R agonists and the development of classes of multi-agonists for PD treatment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31730763,

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

author = {Yazhou Li and Elliot J Glotfelty and Inbar Namdar and David Tweedie and Lars Olson and Barry J Hoffer and Richard D DiMarchi and Chagi G Pick and Nigel H Greig},

url = {https://pubmed.ncbi.nlm.nih.gov/31730763/},

doi = {10.1016/j.expneurol.2019.113113},

issn = {1090-2430},

year  = {2020},

date = {2020-02-01},

urldate = {2020-02-01},

journal = {Exp Neurol},

volume = {324},

pages = {113113},

abstract = {A synthetic monomeric peptide triple receptor agonist, termed "Triagonist" that incorporates glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (Gcg) actions, was previously developed to improve upon metabolic and glucose regulatory benefits of single and dual receptor agonists in rodent models of diet-induced obesity and type 2 diabetes. In the current study, the neurotrophic and neuroprotective actions of this Triagonist were probed in cellular and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in both the young and elderly. Triagonist dose- and time-dependently elevated cyclic AMP levels in cultured human SH-SY5Y neuronal cells, and induced neurotrophic and neuroprotective actions, mitigating oxidative stress and glutamate excitotoxicity. These actions were inhibited only by the co-administration of antagonists for all three receptor types, indicating the balanced co-involvement of GLP-1, GIP and Gcg receptors. To evaluate physiological relevance, a clinically translatable dose of Triagonist was administered subcutaneously, once daily for 7 days, to mice following a 30 g weight drop close head injury. Triagonist fully mitigated mTBI-induced visual and spatial memory deficits, evaluated at 7 and 30 days post injury. These results establish Triagonist as a novel neurotrophic/protective agent worthy of further evaluation as a TBI treatment strategy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31396586,

title = {Incretin Mimetics as Rational Candidates for the Treatment of Traumatic Brain Injury},

author = {Elliot J Glotfelty and Thomas Delgado and Luis B Tovar-Y-Romo and Yu Luo and Barry Hoffer and Lars Olson and Tobias Karlsson and Mark P Mattson and Brandon Harvey and David Tweedie and Yazhou Li and Nigel H Greig},

url = {https://pubmed.ncbi.nlm.nih.gov/31396586/},

doi = {10.1021/acsptsci.9b00003},

issn = {2575-9108},

year  = {2019},

date = {2019-04-01},

urldate = {2019-04-01},

journal = {ACS Pharmacol Transl Sci},

volume = {2},

number = {2},

pages = {66--91},

abstract = {Traumatic brain injury (TBI) is becoming an increasing public health issue. With an annually estimated 1.7 million TBIs in the United States (U.S) and nearly 70 million worldwide, the injury, isolated or compounded with others, is a major cause of short- and long-term disability and mortality. This, along with no specific treatment, has made exploration of TBI therapies a priority of the health system. Age and sex differences create a spectrum of vulnerability to TBI, with highest prevalence among younger and older populations. Increased public interest in the long-term effects and prevention of TBI have recently reached peaks, with media attention bringing heightened awareness to sport and war related head injuries. Along with short-term issues, TBI can increase the likelihood for development of long-term neurodegenerative disorders. A growing body of literature supports the use of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (Gcg) receptor (R) agonists, along with unimolecular combinations of these therapies, for their potent neurotrophic/neuroprotective activities across a variety of cellular and animal models of chronic neurodegenerative diseases (Alzheimer's and Parkinson's diseases) and acute cerebrovascular disorders (stroke). Mild or moderate TBI shares many of the hallmarks of these conditions; recent work provides evidence that use of these compounds is an effective strategy for its treatment. Safety and efficacy of many incretin-based therapies (GLP-1 and GIP) have been demonstrated in humans for the treatment of type 2 diabetes mellitus (T2DM), making these compounds ideal for rapid evaluation in clinical trials of mild and moderate TBI.},

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pubstate = {published},

tppubtype = {article}

}