Neuroprotective action of diazepam at very low and moderate doses in Alzheimer's disease model rats

Piļipenko, Vladimirs; Narbute, Karīna; Pupure, Jolanta; Rumaks, Juris; Jansone, Baiba; Kluša, Vija

doi:10.1016/j.neuropharm.2018.11.003

Cited by 24 publications

(15 citation statements)

References 34 publications

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“…Interestingly, the enhancement of memory and normalization of GAD67 in this study were similar to that observed in our previous investigations of GABA receptor agonists (Pilipenko et al, ). Thus, muscimol (GABA‐A GABA site), baclofen (GABA‐B), and diazepam (GABA‐A benzodiazepine site) were used at very low (subsedative) doses (ranging from 0.01 to 0.05 mg/kg) that were approximately 100 times lower than those inducing memory impairments.…”

Section: Discussionsupporting

confidence: 92%

GABA‐containing compound gammapyrone protects against brain impairments in Alzheimer’s disease model male rats and prevents mitochondrial dysfunction in cell culture

Piļipenko

Narbute

Amara

et al. 2019

J of Neuroscience Research

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Neuroinflammation, oxidative stress, decreased glucose/energy metabolism, and disrupted neurotransmission are changes that occur early in sporadic Alzheimer’s disease (AD), manifesting as mild cognitive impairment. Recently, the imbalanced function of the gamma‐aminobutyric acid (GABA) system was identified as a critical factor in AD progression. Thus, maintaining balance among neurotransmitter systems, particularly the GABA system, can be considered a beneficial strategy to slow AD progression. The present study investigated the effects of the compound gammapyrone, a molecule containing three GABA moieties: “free” moiety attached to the position 4 of the 1,4‐dihydropyridine (DHP) ring, and two “crypto” moieties as part of the DHP scaffold. The “free” and “crypto” GABA moieties are linked by a peptide bond (–CONH–), resulting in a peptide‐mimicking structure. In a nontransgenic male rat AD model generated by intracerebroventricular (icv) streptozocin (STZ) administration, gammapyrone (0.1 and 0.5 mg/kg ip) mitigated the impairment of spatial learning and memory, prevented astroglial and microglial neuroinflammation, and normalized acetylcholine breakdown and GABA biosynthesis. In PC12 cells, gammapyrone protected against oxidative stress, mitochondrial dysfunction and apoptosis caused by the mitochondrial toxin di‐2‐ethylhexyl phthalate (DEHP). Gammapyrone did not bind to GABA‐A and GABA‐B receptors in vitro; therefore, we cannot attribute its neuroprotective action to a specific interaction with GABA receptors. Nevertheless, we suggest that the peptide‐like regulatory mechanisms of gammapyrone or its allosteric modulatory properties are essential for the observed effects. Since, the icv STZ model resembles the early stages of AD, gammapyrone, and/or its congeners could be useful in the design of anti‐dementia drugs.

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Section: Discussionsupporting

confidence: 92%

GABA‐containing compound gammapyrone protects against brain impairments in Alzheimer’s disease model male rats and prevents mitochondrial dysfunction in cell culture

Piļipenko

Narbute

Amara

et al. 2019

J of Neuroscience Research

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“…In amnestic mild cognitive impairment (aMCI) patients, reducing hippocampal hyperactivity with a low dose of leviracetam -a GABAA receptor agonist -has already proven its effectiveness in improving cognition and reducing progression to the dementia-phase in human Alzheimer's disease 57 . In rodents, a low dose of diazepam also showed beneficial effects in the early pre-dementia stages of Alzheimer's disease 58 . Based on the involvement of P2YR, astrocytes were also identified as a target of interest to normalize network dysfunction in an Alzheimer's disease mouse model 11,43 .…”

Section: Discussionmentioning

confidence: 98%

Astrocyte-neuron interplay is critical for Alzheimer’s disease pathogenesis and is rescued by TRPA1 channel blockade

Paumier

Boisseau

Pernet‐Gallay

et al. 2021

Preprint

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Background: The sequence of cellular dysfunctions in preclinical Alzheimer's disease must be understood if we are to plot new therapeutic routes. Hippocampal neuronal hyperactivity is one of the earliest events occurring during the preclinical stages of Alzheimer's disease in both humans and mouse models. The most common hypothesis describes amyloid β accumulation as the triggering factor of the disease but the effects of such accumulation and the cascade of events leading to cognitive decline remain unclear. In mice, we previously showed that amyloid β-dependent TRPA1 channel activation triggers hippocampal astrocyte hyperactivity, subsequently inducing hyperactivity in nearby neurons. In this work, we investigated the potential protection brought by an early chronic pharmacological inhibition of TRPA1 channel on Alzheimer's disease progression. Methods: We administered a specific inhibitor of TRPA1 channel (HC030031) intraperitoneally from the onset of amyloid β overproduction in the APP/PS1-21 mouse model of Alzheimer's disease. We characterized short-, medium-, and long-term effects of this chronic pharmacological TRPA1 blockade on Alzheimer's disease progression at functional (astrocytic and neuronal activity), structural, biochemical, and behavioural levels. Results: Our results revealed that the first observable disruptions in the Alzheimer's disease transgenic mouse model used correspond to aberrant hippocampal astrocyte and neuron hyperactivity. We showed that chronic TRPA1 blockade normalizes astrocytic activity, avoids perisynaptic astrocytic process withdrawal, prevents neuronal dysfunction, preserves structural synaptic integrity and strengthens the glial plaque barrier. These protective effects preserved spatial working-memory in this Alzheimer's disease mouse model. Conclusion: The toxic effect of amyloid β on astrocytes triggered by TRPA1 channel activation is pivotal to Alzheimer's disease progression. TRPA1 blockade prevent irreversible neuronal dysfunction, making this channel a potential therapeutic target to promote neuroprotection.

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“…Besides impaired neural homeostatic processes, intense firing has been considered another cause of β -amyloid plaque deposition [ 94 , 95 ]. Thus, the preemptive usage of low doses of antiepileptic drugs like diazepam [ 96 ] and levetiracetam [ 97 ] has been shown to have a neuroprotective effect in AD.…”

Section: Discussionmentioning

confidence: 99%

Alzheimer’s Disease as a Result of Stimulus Reduction in a GABA-A-Deficient Brain: A Neurocomputational Model

Aguiar-Furucho

Peláez

2020

Neural Plasticity

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Several research studies point to the fact that sensory and cognitive reductions like cataracts, deafness, macular degeneration, or even lack of activity after job retirement, precede the onset of Alzheimer’s disease. To simulate Alzheimer’s disease earlier stages, which manifest in sensory cortices, we used a computational model of the koniocortex that is the first cortical stage processing sensory information. The architecture and physiology of the modeled koniocortex resemble those of its cerebral counterpart being capable of continuous learning. This model allows one to analyze the initial phases of Alzheimer’s disease by “aging” the artificial koniocortex through synaptic pruning, by the modification of acetylcholine and GABA-A signaling, and by reducing sensory stimuli, among other processes. The computational model shows that during aging, a GABA-A deficit followed by a reduction in sensory stimuli leads to a dysregulation of neural excitability, which in the biological brain is associated with hypermetabolism, one of the earliest symptoms of Alzheimer’s disease.

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Neuroprotective action of diazepam at very low and moderate doses in Alzheimer's disease model rats

Cited by 24 publications

References 34 publications

GABA‐containing compound gammapyrone protects against brain impairments in Alzheimer’s disease model male rats and prevents mitochondrial dysfunction in cell culture

GABA‐containing compound gammapyrone protects against brain impairments in Alzheimer’s disease model male rats and prevents mitochondrial dysfunction in cell culture

Astrocyte-neuron interplay is critical for Alzheimer’s disease pathogenesis and is rescued by TRPA1 channel blockade

Alzheimer’s Disease as a Result of Stimulus Reduction in a GABA-A-Deficient Brain: A Neurocomputational Model

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