Glutamate and Neurodegenerative Disease

Schaeffer, Eric; Duplantier, Allen J.

doi:10.1007/7355_2010_11

Cited by 4 publications

(4 citation statements)

References 358 publications

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“…Unlike traditional approaches that target the receptor, targeting the neurotransmitter directly and interfering with its ability to interact with the receptor may prove to be a novel strategy for altering neurotransmitter function. Other neurotransmitters such as glutamate, serotonin, and GABA could be interesting aptamer targets for the study and potential treatment of neurodegenerative diseases, neuropsychiatric diseases, and anxiety and affective disorders [163][164][165].…”

Section: Perspectives and Outlookmentioning

confidence: 99%

Aptamers as Promising Molecular Recognition Elements for Diagnostics and Therapeutics in the Central Nervous System

McConnell

Holahan

DeRosa

2014

Nucleic Acid Therapeutics

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Oligonucleotide aptamers are short, synthetic, single-stranded DNA or RNA able to recognize and bind to a multitude of targets ranging from small molecules to cells. Aptamers have emerged as valuable tools for fundamental research, clinical diagnosis, and therapy. Due to their small size, strong target affinity, lack of immunogenicity, and ease of chemical modification, aptamers are an attractive alternative to other molecular recognition elements, such as antibodies. Although it is a challenging environment, the central nervous system and related molecular targets present an exciting potential area for aptamer research. Aptamers hold promise for targeted drug delivery, diagnostics, and therapeutics. Here we review recent advances in aptamer research for neurotransmitter and neurotoxin targets, demyelinating disease and spinal cord injury, cerebrovascular disorders, pathologies related to protein aggregation (Alzheimer's, Parkinson's, and prions), brain cancer (glioblastomas and gliomas), and regulation of receptor function. Challenges and limitations posed by the blood brain barrier are described. Future perspectives for the application of aptamers to the central nervous system are also discussed.

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Section: Perspectives and Outlookmentioning

confidence: 99%

Aptamers as Promising Molecular Recognition Elements for Diagnostics and Therapeutics in the Central Nervous System

McConnell

Holahan

DeRosa

2014

Nucleic Acid Therapeutics

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“…The ionotropic receptors produce fast-acting excitatory effects, while mGluRs (G proteincoupled receptors) have a crucial role in the modulation of glutamatergic neurotransmission. 1 Since glutamate is not degraded in the extracellular compartment, two major astrocytic transporters, GLT-1 (EAAT2) and GLAST (EAAT1), remove glutamate from the synapses and provide the regulation necessary to orchestrate receptor excitability. 2 The disruption of this finetuning mechanism causes hyperactivation of glutamatergic receptors, a well-established detrimental scenario termed excitotoxicity, which is described as a fundamental player in the pathophysiology of several neurologic and psychiatric disorders.…”

Section: Introductionmentioning

confidence: 99%

Imaging in Vivo Glutamate Fluctuations with [¹¹C]ABP688: A GLT-1 Challenge with Ceftriaxone

Zimmer

Parent

Leuzy

et al. 2015

J Cereb Blood Flow Metab

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Molecular imaging offers unprecedented opportunities for investigating dynamic changes underlying neuropsychiatric conditions. Here, we evaluated whether [11C]ABP688, a positron emission tomography (PET) ligand that binds to the allosteric site of the metabotropic glutamate receptor type 5 (mGluR5), is sensitive to glutamate fluctuations after a pharmacological challenge. For this, we used ceftriaxone (CEF) administration in rats, an activator of the GLT-1 transporter (EAAT2), which is known to decrease extracellular levels of glutamate. MicroPET [11C]ABP688 dynamic acquisitions were conducted in rats after a venous injection of either saline (baseline) or CEF 200 mg/kg (challenge). Binding potentials (BPND) were obtained using the simplified reference tissue method. Between-condition statistical parametric maps indicating brain regions showing the highest CEF effects guided placement of microdialysis probes for subsequent assessment of extracellular levels of glutamate. The CEF administration increased [11C]ABP688 BPND in the thalamic ventral anterior (VA) nucleus bilaterally. Subsequent microdialysis assessment revealed declines in extracellular glutamate concentrations in the VA. The present results support the concept that availability of mGluR5 allosteric binding sites is sensitive to extracellular concentrations of glutamate. This interesting property of mGluR5 allosteric binding sites has potential applications for assessing the role of glutamate in the pathogenesis of neuropsychiatric conditions.

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“…Although the pathogenic mechanisms underlying bvFTD have yet to be fully elucidated, aberrant glutamatergic neurotransmission has been hypothesized to play a role. The primary excitatory neurotransmitter in the mammalian brain, glutamate acts via ionotropic and metabotropic receptors (Schaeffer and Duplantier 2010). Whereas ionotropic receptors mediate fast excitatory neurotransmission, metabotropic glutamate receptors (mGluRs) play an important role in synaptic modulation via regulation of neuronal excitability, transmitter release, synaptic plasticity and glial function.…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, activation of mGluR5 was shown to regulate glutamatergic neurotransmission via modulation of NMDA receptor functionality (Llansola and Felipo 2010;Niswender and Conn 2010;Perroy et al 2008). Moreover, mGluR5 signaling has been shown to be critically involved in the normal cognitive functioning of various neuronal populations (Schaeffer and Duplantier 2010), including those within FTLD predilection sites (Ferraguti and Shigemoto 2006).…”

Section: Introductionmentioning

confidence: 99%

In vivo characterization of metabotropic glutamate receptor type 5 abnormalities in behavioral variant FTD

et al. 2015

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Although the pathogenesis underlying behavioral variant frontotemporal dementia (bvFTD) has yet to be fully understood, glutamatergic abnormalities have been hypothesized to play an important role. The aim of the present study was to determine the availability of the metabotropic glutamate receptor type 5 (mGluR5) using a novel positron emission tomography (PET) radiopharmaceutical with high selectivity for mGluR5 ([(11)C]ABP688) in a sample of bvFTD patients. In addition, we sought to determine the overlap between availability of mGluR5 and neurodegeneration, as measured using [(18)F]FDG-PET and voxel-based morphometry (VBM). Availability of mGluR5 and glucose metabolism ([(18)F]FDG) were measured in bvFTD (n = 5) and cognitively normal (CN) subjects (n = 10). [(11)C]ABP688 binding potential maps (BPND) were calculated using the cerebellum as a reference region, with [(18)F]FDG standardized uptake ratio maps (SUVR) normalized to the pons. Grey matter (GM) concentrations were determined using VBM. Voxel-based group differences were obtained using RMINC. BvFTD patients showed widespread decrements in [(11)C]ABP688 BPND throughout frontal, temporal and subcortical areas. These areas were likewise characterized by significant hypometabolism and GM loss, with overlap between reduced [(11)C]ABP688 BPND and hypometabolism superior to that for GM atrophy. Several regions were characterized only by decreased binding of [(11)C]ABP688. The present findings represent the first in vivo report of decreased availability of mGluR5 in bvFTD. This study suggests that glutamate excitotoxicity may play a role in the pathogenesis of bvFTD and that [(11)C]ABP688 may prove a suitable marker of glutamatergic neurotransmission in vivo.

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Glutamate and Neurodegenerative Disease

Cited by 4 publications

References 358 publications

Aptamers as Promising Molecular Recognition Elements for Diagnostics and Therapeutics in the Central Nervous System

Aptamers as Promising Molecular Recognition Elements for Diagnostics and Therapeutics in the Central Nervous System

Imaging in Vivo Glutamate Fluctuations with [¹¹C]ABP688: A GLT-1 Challenge with Ceftriaxone

In vivo characterization of metabotropic glutamate receptor type 5 abnormalities in behavioral variant FTD

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Glutamate and Neurodegenerative Disease

Cited by 4 publications

References 358 publications

Aptamers as Promising Molecular Recognition Elements for Diagnostics and Therapeutics in the Central Nervous System

Aptamers as Promising Molecular Recognition Elements for Diagnostics and Therapeutics in the Central Nervous System

Imaging in Vivo Glutamate Fluctuations with [11C]ABP688: A GLT-1 Challenge with Ceftriaxone

In vivo characterization of metabotropic glutamate receptor type 5 abnormalities in behavioral variant FTD

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Imaging in Vivo Glutamate Fluctuations with [¹¹C]ABP688: A GLT-1 Challenge with Ceftriaxone