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Pharmacological Management of Alzheimer’s Disease
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Rakesh Kumar, Rajan Kumar, Abhinav Anand, Neha Sharma, Navneet Khurana
It is developed as a potential cognition enhancer and 5-HT6 receptor antagonist. Blockade of the 5-HT6 receptor is found to improve the cognitive function. Cognitive dysfunction is recognized as a key symptom of the AD; SB-271046 can be useful as therapeutic potential in the treatment of the AD. In various research articles, it has been found to improve cognitive function. Still, there is a lack of facts availability regarding SB-271046 (Upton et al., 2008).
Advances in the pharmacotherapeutic management of dementia with Lewy bodies
Published in Expert Opinion on Pharmacotherapy, 2018
Giovanni Palermo, Roberto Ceravolo, Ubaldo Bonuccelli
Another 5-HT2A inverse agonist, nelotanserin, is currently being evaluated in a Phase II double-blind placebo controlled trial in patients with LBD experiencing VHs (see clinicaltrials.gov NCT02640729) [70]. More recently, it has been identified the 5-HT6 receptor as one of the member of the serotonin receptor family [71]. 5-HT6 are expressed primarily in brain areas involved in learning and memory processes and their activation suppresses cholinergic neurotransmission, suggesting a potential therapeutic role in cognitive and psychiatric diseases. In this sense, 5-HT6 receptor antagonists may enhance cholinergic neurotransmission, offering further potential to increase treatment options in dementias [72]. One of the selective 5-HT6 receptor antagonist is the interpirdine or RVT-101, currently in Phase II and III trials for DLB (see the HEADWAY-DLB study, clinicaltrials.gov NCT02669433 and its extension NCT02928445). However, the latter was terminated early because intepirdine did not meet its primary efficacy endpoints.
The role of 5 HT6-receptor antagonists in Alzheimer’s disease: an update
Published in Expert Opinion on Investigational Drugs, 2018
Rita Khoury, Noam Grysman, Jake Gold, Kush Patel, George T. Grossberg
There are at least 16 different types of serotonin receptors, divided into seven subcategories: 5-HT1 to 5-HT7, based on their mechanism of action [17]. The 5-HT6 receptor, discovered in 1993, is a metabotropic post-synaptic serotonin receptor that activates adenylate cyclase and cyclic AMP [16]. It has been consistently shown that 5-HT6 receptor effects on memory are mediated, at least partially by increased cholinergic transmission, as the effect of antagonizing these receptors has been shown to be reversed by the administration of the muscarinic antagonist atropine [18]. However, experimental evidence has demonstrated the absence of 5-HT6 receptors on cholinergic neurons [19]. These receptors are mostly expressed on the GABAergic neurons in the striatum, nucleus accumbens and olfactory bulb, followed by the glutamatergic neurons in the hippocampus and throughout the cortex, and a subset of GABAergic interneurons in the superficial layers of the cortex, all of which are distinctive brain regions implicated in memory and learning [20].
Pharmacotherapy for the treatment of depression in patients with alzheimer’s disease: a treatment-resistant depressive disorder
Published in Expert Opinion on Pharmacotherapy, 2018
Madia Lozupone, Maddalena La Montagna, Francesca D’Urso, Carla Piccininni, Rodolfo Sardone, Vittorio Dibello, Gianluigi Giannelli, Vincenzo Solfrizzi, Antonio Greco, Antonio Daniele, Nicola Quaranta, Davide Seripa, Antonello Bellomo, Giancarlo Logroscino, Francesco Panza
Therefore, at present, no clear pharmacological treatment algorithms for depression in AD and dementia exist. Emerging evidence on the neurobiological substrates of depression in AD has led to investigation of repositioned and novel antidepressant drugs in dementia as an alternative to classical antidepressant [81]. Idalopirdine, a serotonin 5-hydroxytryptamine-6 (5-HT6) receptor antagonist, has cholinergic, glutamatergic, dopaminergic and noradrenergic properties and the potential to augment multiple neurotransmitter systems to improve cognition. Although two dosages of idalopirdine failed in a Phase III RCT on cognition of AD patients [82], a growing number of preclinical/clinical studies supported the use of 5-HT6 receptor antagonism to treat not only cognitive dysfunction but also behavioral alterations in AD [19]. 5-HT6 receptor antagonists have shown to induce antidepressant-like activity in rodents [83,84]. Systemic administration of the 5-HT6 receptor antagonist produced a significant reduction in immobility time in the rat forced swimming test, with a similar profile in terms of 5-HT6 receptor occupancy, measured by binding assay. These data suggest that 5-HT6 antagonists, at doses corresponding to those that occupy central 5-HT6 receptors, could have an antidepressant effect in humans. This may differentiate 5-HT6 antagonists from acetylcholinesterase inhibitors (AChEIs) with respect to mood control in the symptomatic treatment of AD [85].