The α5-Containing GABAA Receptors—a Brief Summary

Mohamad, Fatin H; Has, Ahmad Tarmizi Che

doi:10.1007/s12031-018-1246-4

Cited by 28 publications

(19 citation statements)

References 117 publications

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“…The composition of GABA A receptors could also be involved in cognitive alterations related to hypnotic drugs. It has been reported that the binding of BZDs to the α5GABA A subunit, which is almost exclusively found in the hippocampus and deep layers of the cortex, impairs memory for contextual information in monkeys (Wan et al, 2004;Mohamad et al, 2019). Of note, Zolpidem did not impair the performance of a task based on visual cues which could be explained by its affinity for the α1GABA A , instead of α5GABA A (Mohamad et al, 2019).…”

Section: The Potential Molecular Mechanisms Involved In Benzodiazepinmentioning

confidence: 85%

“…In addition, the loss of social networks in aging people could act as an additional factor that may also affect cognitive function. Likewise, BZD treatment for sleep disturbances in aging could limit the capacity to create social communication networks and precipitate the development of dementia (Wan et al, 2004;Pariente et al, 2016;Mohamad et al, 2019).…”

Section: The Potential Molecular Mechanisms Involved In Benzodiazepinmentioning

confidence: 99%

“…It has been reported that the binding of BZDs to the α5GABA A subunit, which is almost exclusively found in the hippocampus and deep layers of the cortex, impairs memory for contextual information in monkeys (Wan et al, 2004;Mohamad et al, 2019). Of note, Zolpidem did not impair the performance of a task based on visual cues which could be explained by its affinity for the α1GABA A , instead of α5GABA A (Mohamad et al, 2019). Moreover, it has been reported that the memory-impairing effects of BZDs are not blocked by the α1GABAA-selective BZD antagonist β-carboline-3-carboxylate-3-butyl-ester, whereas the α5GABA A antagonist XLi-093 blocked the effects of triazolam but not zolpidem (Caraiscos et al, 2004;Mohamad et al, 2019).…”

Section: The Potential Molecular Mechanisms Involved In Benzodiazepinmentioning

confidence: 99%

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Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer's Disease Dementia

Ettcheto

Olloquequi

Busquets

et al. 2020

Front. Aging Neurosci.

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Benzodiazepines (BZDs) and Z-drugs are compounds widely prescribed in medical practice due to their anxiolytic, hypnotic, and muscle relaxant properties. Yet, their chronic use is associated with cases of abuse, dependence, and relapse in many patients. Furthermore, elderly people are susceptible to alterations in pharmacodynamics, pharmacokinetics as well as to drug interaction due to polypharmacy. These situations increase the risk for the appearance of cognitive affectations and the development of pathologies like Alzheimer's disease (AD). In the present work, there is a summary of some clinical studies that have evaluated the effect of BZDs and Z-drugs in the adult population with and without AD, focusing on the relationship between their use and the loss of cognitive function. Additionally, there is an assessment of preclinical studies focused on finding molecular proof on the pathways by which these drugs could be involved in AD pathogenesis. Moreover, available data (1990-2019) on BZD and Z-drug use among elderly patients, with and without AD, was compiled in this work. Finally, the relationship between the use of BZD and Z-drugs for the treatment of insomnia and the appearance of AD biomarkers was analyzed. Results pointed to a vicious circle that would worsen the condition of patients over time. Likewise, it put into relevance the need for close monitoring of those patients using BZDs that also suffer from AD. Consequently, future studies should focus on optimizing strategies for insomnia treatment in the elderly by using other substances like melatonin agonists, which is described to have a much more significant safety profile.

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Section: The Potential Molecular Mechanisms Involved In Benzodiazepinmentioning

confidence: 85%

Section: The Potential Molecular Mechanisms Involved In Benzodiazepinmentioning

confidence: 99%

Section: The Potential Molecular Mechanisms Involved In Benzodiazepinmentioning

confidence: 99%

See 1 more Smart Citation

Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer's Disease Dementia

Ettcheto

Olloquequi

Busquets

et al. 2020

Front. Aging Neurosci.

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show abstract

“…Second, it has been reported that the binding of BZDs and α5GABA A subunit, which is mainly expressed in the hippocampus, impairs monkeys' memory of context information. However, Zolpidem does not impair the performance of visual cue based tasks due to the a nity for α1GABA A rather than α5GABA A [21]. Those results suggest that α5GABA A receptor plays a special role in BZDs related cognitive impairment.…”

Section: Discussionmentioning

confidence: 70%

Association Between Z Drugs Use and Risk of Cognitive Impairment in Older Patients With Chronic Insomnia

Guo

Zhang

et al. 2020

Preprint

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Background Benzodiazepines (BZDs) and Z drugs are widely used for patients with chronic insomnia. The long term use of BZDs in older patients can cause cognitive impairment and potentially increase the risk of dementia. However, evidence for an association with Z drugs is limited. This study aimed to investigate the association between the risk of cognitive impairment and exposure to Z drugs in older patients with chronic insomnia.Methods We recorded older patients with chronic insomnia who visited the outpatient department of neurology, Beijing Friendship Hospital, and assessed the global cognitive function (MoCA) and five cognitive domains (CVLT, TMT-B, BNT-30, CDT and DST). Multiple regression analysis was conducted to determine the independent factors of cognition, and evaluate the effect of Z drugs use (zolpidem and zopiclone) on cognition.Results A total of 88 subjects were identified. BZDs use (P=0.03, B=2.67, 95% CI 0.36-4.97) and BZDs exposure density (P=0.01, B=1.22, 95% CI 0.33-2.11) were independent risk factors of cognitive impairment in older patients with chronic insomnia. Neither Z drugs use (P=0.11) nor Z drugs exposure density (P=0.92) correlated with global cognitive function. Moreover, compared with BZDs users, there were positive associations between Z drugs use and memory (P=0.00), attention (P=0.00) and verbal function (P=0.04). Additionlly, education level (P=0.02, OR=0.74, 95% CI 0.57-0.95), duration of insomnia (P=0.04, OR=1.05, 95% CI 1.00-1.11) and severity of insomnia (P=0.03, OR=1.27, 95% CI 1.02-1.57) were also independent factors of global cognitive function.Conclusion We found no evidence that Z drugs use and Z drugs exposure density were associated with cognitive impairment in older patients with chronic insomnia. However, the use of BZDs and BZDs exposure density were associated with an increased risk of cognitive impairment. Thus, BZDs use should be avoided，and Z drugs should be prescribed with extreme caution in the elderly.

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“…A study done by (Atack 2010), upheld the findings by showing, triazolophthalazine, a negative modulator that decreases GABA responses particularly at α5 GABAARs, enhanced intellectual performance without causing anxiety or convulsions in rodents. Cognitive performance was impaired by the use of α5 GABAARs positive-allosteric modulators indicating the involvement of this subunit in learning and memory and cognitive tasks (Xu et al 2018;Mohamad and Has 2019). Thus, compounds created to be specific for α5 GABAARs can possibly be utilized as memory enhancing medications without symptoms such as, sedation, which is caused by α1-containing GABAARs.…”

Section: Cognitive Impairmentmentioning

confidence: 99%

Glutamate-gated chloride channel receptors and mechanisms of drug resistance in pathogenic species

Atif¹

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A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2019 Queensland Brain Institute ii Dedicated to my beloved parents & my demised brother who I miss everyday iii Thesis AbstractPentameric ligand-gated ion channels (pLGICs) are important therapeutic targets for a wide range of neurological disorders that include cognitive impairment, stroke, psychiatric conditions and peripheral pain. They are also targets for treating parasite infections and controlling pest species in agriculture, veterinary practice and human health. Here we focus on one family of the pLGICs i.e., the glutamate-gated chloride channel receptors (GluClRs) which are expressed at inhibitory synapses of invertebrates. Ivermectin (IVM) is one of the main drugs used to control pest species and parasites, and it works by activating GluClRs in nematode and arthropod muscle and nerves. IVM resistance is becoming a major problem in many invertebrate pathogens, necessitating the development of novel anti-parasitic drugs.This project started with the simple aim of determining the sensitivity to glutamate and IVM of GluClRs from two different pest species: the parasitic nematode Haemonchus contortus (HcoGluClRs) and the mosquito malaria vector Anopheles gambiae (AgGluClRs).In chapter 3, we found that the β homomeric GluClRs of H.contortus were insensitive to IVM (EC50> 10 µM), whereas α homomeric HcoGluClRs were highly sensitive (EC50 = 20 nM).Heteromeric αβ HcoGluClRs exhibited an intermediate sensitivity to IVM (EC50 = 135 nM). By contrast, the EC50 values for glutamate at α homomeric and αβ heteromeric receptors were not distinguishable; falling between 20-30 µM. GluClR-mediated IPSCs were significantly different for α relative to αβ receptors, with αβ GluClRs exhibiting a faster decay rate of 17 ms in contrast to α GluClRs which had a decay rate of 40ms. 5 nM IVM slowed the decay rates of IPSCs mediated by both isoforms with α GluClRs reaching a mean decay rate of 100 ms and αβ GluClRs decaying at a mean rate of 72ms. Evaluating the biophysical properties of single heteromeric αβ and homomeric β GluClRs revealed that different stoichiometric GluClR isoforms exhibited different open state amplitudes. The α GluClR had the biggest current (1.8 pA) followed by the αβ (1:1) GluClR (two different amplitudes -1.2 pA, 90% and 0.7 pA, 10%) and the smallest being β homomer (0.4 pA). The β and αβ GluClRs had mean active durations of 5.5 ms and 43 ms, respectively, in response to 2 µM glutamate. This duration increased to 126 ms and 876 ms, respectively, when 2 µM glutamate was co-applied with 5 nM IVM.Collectively, the data from both the IPSCs and the single channel measurements show a correlation between shorter active periods; faster IPSC decay rates and decreased IVM sensitivity.xiii Financial supportThis research was supported by The University of Queensland International scholarship and University of Queensland living allowance scholarship. Travel support to conferences was provided by Queensland Brain Institute tr...

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The α5-Containing GABAA Receptors—a Brief Summary

Cited by 28 publications

References 117 publications

Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer's Disease Dementia

Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer's Disease Dementia

Association Between Z Drugs Use and Risk of Cognitive Impairment in Older Patients With Chronic Insomnia

Glutamate-gated chloride channel receptors and mechanisms of drug resistance in pathogenic species

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