scholarly journals The functions of repressor element 1-silencing transcription factor in models of epileptogenesis and post-ischemia

2021 ◽  
Author(s):  
Ruth Butler-Ryan ◽  
Ian C. Wood
Keyword(s):  
Transcription Factor ◽  
Therapeutic Potential ◽  
Receptor Subunit ◽  
Receptor Kinase ◽  
Ampa Glutamate Receptors ◽  
Glutamate Receptor Subunit ◽  
Epilepsy Models ◽  
Animal Models Of Epilepsy ◽  
Repressor Element ◽  
Models Of Epilepsy

AbstractEpilepsy is a debilitating neurological disorder characterised by recurrent seizures for which 30% of patients are refractory to current treatments. The genetic and molecular aetiologies behind epilepsy are under investigation with the goal of developing new epilepsy medications. The transcriptional repressor REST (Repressor Element 1-Silencing Transcription factor) is a focus of interest as it is consistently upregulated in epilepsy patients and following brain insult in animal models of epilepsy and ischemia. This review analyses data from different epilepsy models and discusses the contribution of REST to epileptogenesis. We propose that in healthy brains REST acts in a protective manner to homeostatically downregulate increases in excitability, to protect against seizure through downregulation of BDNF (Brain-Derived Neurotrophic Factor) and its receptor, TrkB (Tropomyosin receptor kinase B). However, in epilepsy patients and post-seizure, REST may increase to a larger degree, which allows downregulation of the glutamate receptor subunit GluR2. This leads to AMPA glutamate receptors lacking GluR2 subunits, which have increased permeability to Ca2+, causing excitotoxicity, cell death and seizure. This concept highlights therapeutic potential of REST modulation through gene therapy in epilepsy patients.

Molecular and electrophysiological characterizations of fGluR3α, an ionotropic glutamate receptor subunit of a teleost fish

1998 ◽  
Vol 57 (2) ◽  
pp. 211-220 ◽  
Author(s):  
Hsiu-Ming Chang ◽  
Yi-Mi Wu ◽  
Yen-Chung Chang ◽  
Yu-Chung Hsu ◽  
Hsiu-Ya Hsu ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Teleost Fish ◽  
Ionotropic Glutamate Receptor ◽  
Receptor Subunit ◽  
Glutamate Receptor Subunit

GDNF Therapy: Can We Make It Work?

2021 ◽  
pp. 1-4
Author(s):  
Anders Björklund
Keyword(s):  
Gene Therapy ◽  
Transcription Factor ◽  
Signaling Pathway ◽  
Therapeutic Potential ◽  
Threshold Level ◽  
New Findings ◽  
The Status ◽  
Interesting Discussion ◽  
Postmortem Studies ◽  
Made In

In two recent postmortem studies, Jeffrey Kordower and colleagues report new findings that open up for an interesting discussion on the status of GDNF/NRTN signaling in patients with Parkinson’s disease (PD), adding an interesting perspective on the, admittedly very limited, signs of restorative effects previously seen in GDNF/NRTN-treated patients. Their new findings show that the level of the GDNF signaling receptor Ret is overall reduced by about 65% relative to non-PD controls, and most severely, up to 80%, in nigral neurons containing α-synuclein inclusions, accompanied by impaired signaling downstream of the Ret receptor. Notably, however, the vast majority of the remaining nigral neurons retained a low level of Ret expression, and hence a threshold level of signaling. Further observations made in two patients who had received AAV-NRTN gene therapy 8–10 years earlier suggest the intriguing possibility that NRTN is able to restore Ret expression and upregulate its own signaling pathway. This “wind-up” mechanism, which is likely to depend on an interaction with dopaminergic transcription factor Nurr1, has therapeutic potential and should encourage renewed efforts to turn GDNF/NRTN therapy into success, once the recurring problem of under-dosing is resolved.

scholarly journals Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes

2004 ◽  
Vol 101 (28) ◽  
pp. 10458-10463 ◽  
Author(s):  
A. W. Bruce ◽  
I. J. Donaldson ◽  
I. C. Wood ◽  
S. A. Yerbury ◽  
M. I. Sadowski ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Repressor Element

scholarly journals Transmembrane topology of the glutamate receptor subunit GluR6.

1994 ◽  
Vol 269 (16) ◽  
pp. 11679-11682
Author(s):  
K.W. Roche ◽  
L.A. Raymond ◽  
C. Blackstone ◽  
R.L. Huganir
Keyword(s):  
Glutamate Receptor ◽  
Receptor Subunit ◽  
Transmembrane Topology ◽  
Glutamate Receptor Subunit

Localization of the glutamate receptor subunit GluR1 on the surface of living and within cultured hippocampal neurons

Neuroscience ◽  
1996 ◽  
Vol 75 (1) ◽  
pp. 69-82 ◽  
Author(s):  
S.A Richmond ◽  
A.J Irving ◽  
E Molnár ◽  
R.A.J McIlhinney ◽  
F Michelangeli ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Hippocampal Neurons ◽  
Receptor Subunit ◽  
Glutamate Receptor Subunit ◽  
Cultured Hippocampal Neurons

Brain angiotensin system: a new promise in the management of epilepsy?

2021 ◽  
Vol 135 (6) ◽  
pp. 725-730
Author(s):  
Alberto Javier Ramos
Keyword(s):  
Therapeutic Potential ◽  
Renin Angiotensin System ◽  
B Cell Lymphoma ◽  
Ang Ii ◽  
Angiotensin System ◽  
Beneficial Effects ◽  
System A ◽  
Pilocarpine Model ◽  
Animal Models Of Epilepsy ◽  
Future Work

Abstract Epilepsy is a highly prevalent neurological disease and anti-epileptic drugs (AED) are almost the unique clinical treatment option. A disbalanced brain renin–angiotensin system (RAS) has been proposed in epilepsy and several reports have shown that angiotensin II (Ang II) receptor-1 (ATR1) activation is pro-inflammatory and pro-epileptogenic. In agreement, ATR1 blockage with the repurposed drug losartan has shown benefits in animal models of epilepsy. Processing of Ang II by ACE2 enzyme renders Ang-(1-7), a metabolite that activates the mitochondrial assembly (Mas) receptor (MasR) pathway. MasR activation presents beneficial effects, facilitating vasodilatation, increasing anti-inflammatory and antioxidative responses. In a recent paper published in Clinical Science, Gomes and colleagues (Clin. Sci. (Lond.) (2020) 134, 2263–2277) performed intracerebroventricular (icv) infusion of Ang-(1-7) in animals subjected to the pilocarpine model of epilepsy, starting after the first spontaneous motor seizure (SMS). They showed that this approach reduced the frequency of SMS, restored animal anxiety, increased exploration, and augmented the hippocampal expression of protective catalase enzyme and antiapoptotic protein B-cell lymphoma 2 (Bcl-2). Interestingly, but surprisingly, Gomes and colleagues showed that MasR expression and mTor activity were reduced in the hippocampus of the epileptic Ang-(1-7) treated animals. These results show that Ang-(1-7) administration could represent a new avenue for developing strategies for the management of epilepsy in clinical settings. However, future work is necessary to evaluate the levels of RAS metabolites and the activity of key enzymes in these experimental interventions to completely understand the therapeutic potential of the brain RAS manipulation in epilepsy.

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