Etazolate, an α-secretase activator, reduces neuroinflammation and offers persistent neuroprotection following traumatic brain injury in mice

Siopi, Eleni; Llufriu-Dabén, Gemma; Cho, Angelo H.; Vidal-Lletjós, Sandra; Plotkine, Michel; Marchand-Leroux, Catherine; Jafarian-Tehrani, Mehrnaz

doi:10.1016/j.neuropharm.2012.11.009

Cited by 40 publications

(23 citation statements)

References 84 publications

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“…sAPPα is neurotrophic [74][75][76][77][78][79][80][81][82] . The intraventricular administration of sAPPα enhances memory function of mice 83 , and sAPPα mediates numerous APP-mediated actions on brain development and cognition 68,74,[84][85][86] .…”

Section: Discussionmentioning

confidence: 99%

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

et al. 2020

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Rivastigmine (or Exelon) is a cholinesterase inhibitor, currently used as a symptomatic treatment for mild-to-moderate Alzheimer's disease (AD). Amyloid-β peptide (Aβ) generated from its precursor protein (APP) by β-secretase (or BACE1) and γ-secretase endoproteolysis. Alternative APP cleavage by α-secretase (a family of membrane-bound metalloproteases-Adamalysins) precludes the generation of toxic Aβ and yields a neuroprotective and neurotrophic secreted sAPPα fragment. Several signal transduction pathways, including protein kinase C and MAP kinase, stimulate α-secretase. We present data to suggest that rivastigmine, in addition to anticholinesterase activity, directs APP processing away from BACE1 and towards α-secretases. We treated rat neuronal PC12 cells and primary human brain (PHB) cultures with rivastigmine and the α-secretase inhibitor TAPI and assayed for levels of APP processing products and α-secretases. We subsequently treated 3×Tg (transgenic) mice with rivastigmine and harvested hippocampi to assay for levels of APP processing products. We also assayed postmortem human control, AD, and AD brains from subjects treated with rivastigmine for levels of APP metabolites. Rivastigmine dose-dependently promoted α-secretase activity by upregulating levels of ADAM-9, -10, and -17 α-secretases in PHB cultures. Co-treatment with TAPI eliminated rivastigmine-induced sAPPα elevation. Rivastigmine treatment elevated levels of sAPPα in 3×Tg mice. Consistent with these results, we also found elevated sAPPα in postmortem brain samples from AD patients treated with rivastigmine. Rivastigmine can modify the levels of several shedding proteins and directs APP processing toward the nonamyloidogenic pathway. This novel property of rivastigmine can be therapeutically exploited for disease-modifying intervention that goes beyond symptomatic treatment for AD.

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Section: Discussionmentioning

confidence: 99%

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

et al. 2020

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“…In another study, etazolate was also found to improve cognitive performance in aged rats (Drott et al 2010). More recently, Siopi et al (2013) showed that etazolate treatment was associated with reduced inflammation in mice following brain injury, as well as improved performance in behavioral tasks. Vellas et al were the first to investigate the effect of etazolate in combination with an acetycholinesterase inhibitor in a sample of 159 AD patients (ClinicalTrials.gov Identifier: NCT00880412).…”

Section: Neurosteroidsmentioning

confidence: 94%

“…More recently, Siopi et al . () showed that etazolate treatment was associated with reduced inflammation in mice following brain injury, as well as improved performance in behavioral tasks. Vellas et al .…”

Section: Allosteric Modulators Of Gabaa Receptorsmentioning

confidence: 99%

The GABAergic system as a therapeutic target for Alzheimer's disease

Guzmán

Vinnakota

Govindpani

et al. 2018

Journal of Neurochemistry

126

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Glutamatergic and cholinergic dysfunction are well-attested features of Alzheimer's disease (AD), progressing with other pathological indices of the disorder and exacerbating neuronal and network dysfunction. However, relatively little attention has been paid to the inhibitory component of the excitatory/inhibitory (E/I) network, particularly dysfunction in the gamma-aminobutyric acid (GABA) signaling system. There is growing evidence in support of GABAergic remodeling in the AD brain, potentially beginning in early stages of disease pathogenesis, and this could thus be a valid molecular target for drug development and pharmacological therapies. Several GABAergic drugs have been tested for efficacy in attenuating or reversing various features and symptoms of AD, and this could represent a novel path by which we might address the growing need for more effective and benign therapies.

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“…Drugs targeting extrasynaptic GABA A Rs are currently being explored, with some being tested in pre-clinical and clinical studies for their potential to improve cognition [ 336 , 337 , 338 ]; these might offer a promising route in the symptomatic treatment of the disease. The possibility of targeting other GABA-mediated pathways is also being explored, with the GABA A R-targeting drug etazolate having been tested in Phase II clinical trials for its neuroprotective and anti-amyloidogenic effects in AD patients [ 336 , 339 , 340 , 341 , 342 ]. Attention is also increasingly being paid to the relationship between BZ use and the risk of developing AD [ 343 , 344 ].…”

Section: Disruption Of the Excitatory/inhibitory (E/i) Balance In mentioning

confidence: 99%

Towards a Better Understanding of GABAergic Remodeling in Alzheimer’s Disease

Govindpani

Guzmán

Vinnakota

et al. 2017

IJMS

158

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γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the vertebrate brain. In the past, there has been a major research drive focused on the dysfunction of the glutamatergic and cholinergic neurotransmitter systems in Alzheimer’s disease (AD). However, there is now growing evidence in support of a GABAergic contribution to the pathogenesis of this neurodegenerative disease. Previous studies paint a complex, convoluted and often inconsistent picture of AD-associated GABAergic remodeling. Given the importance of the GABAergic system in neuronal function and homeostasis, in the maintenance of the excitatory/inhibitory balance, and in the processes of learning and memory, such changes in GABAergic function could be an important factor in both early and later stages of AD pathogenesis. Given the limited scope of currently available therapies in modifying the course of the disease, a better understanding of GABAergic remodeling in AD could open up innovative and novel therapeutic opportunities.

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Etazolate, an α-secretase activator, reduces neuroinflammation and offers persistent neuroprotection following traumatic brain injury in mice

Cited by 40 publications

References 84 publications

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

The GABAergic system as a therapeutic target for Alzheimer's disease

Towards a Better Understanding of GABAergic Remodeling in Alzheimer’s Disease

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