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03

Csa-like compounds

We evaluated 876 FDA-approved compounds in zebrafish larvae. Read more at our preprint:

Adrenergic Receptors

Other

Dopamine Receptors

Serotonin Receptors

Calcium Channels

Steroid Hormones

Preprint

Dopamine Receptors

Dopaminergic system dysfunction has been associated with Alzheimer's disease (AD) through multiple post-mortem and in vivo studies measuring dopamine levels, cortical plasticity, and dopaminergic neuron degeneration (D’Amelio et al., 2018; Kemppainen et al., 2003; Nobili et al., 2017; Storga et al., 1996). We found a total of 9 dopamine receptor antagonists and 2 dopamine receptor agonists of interest during our screening. The majority of the dopamine receptor antagonists in our list have not been studied in the context of AD; however, some dopamine receptor antagonists - including Haloperidol - have been chosen for clinical trials (D’Amelio et al., 2018). Furthermore, the 4 remaining dopamine-associated compounds found in our CsA-like cluster have all been linked to AD pathology, mostly through the inhibition of Aβ aggregation and improvement of cognitive function.

Adrenergic Receptors

β-adrenergic receptors (βARs) are G protein-coupled receptors (GPCRs) responsible for regulating synaptic plasticity and memory formation(Kemp & Manahan-Vaughan, 2008). Specifically, β2-adrenergic receptor (β2AR) agonists are emerging therapeutic targets for neurological diseases (Li, 2023). During our screening, we found 5 β2AR agonists of interest with varying levels of supporting literature in the context of AD. Interestingly, there has been evidence of a reduction in AD prevalence in patients prescribed with β-blockers to treat hypertension (Khachaturian et al., 2006; Rosenberg et al., 2008). This protective trend also applies to other antihypertensive drugs (Ding et al., 2020; Wei et al., 2015), which include α1-adrenergic receptor antagonists such as Doxazosin. α-adrenergic receptors (αARs) have been extensively linked to cognition as well as glucose metabolism - both part of AD symptomatology (Gannon et al., 2015). αAR antagonists, in particular, have been investigated both in vitro and in vivo as promising therapeutic targets of AD(Karczewski et al., 2018; Katsouri et al., 2013; Yu et al., 2022).

Calcium Channels and Related Pathways

The potential role of calcium homeostasis dysregulation in AD has been broadly explored through the impairment of mitochondrial function in the presence of excessive calcium levels (Calvo-Rodriguez & Bacskai, 2021), the induction of mitochondrial calcium overload by Aβ oligomers (Calvo-Rodríguez et al., 2016; Sanz-Blasco et al., 2008), and the direct effect of insoluble tau on calcium dyshomeostasis (Esteras et al., 2021; Mahoney et al., 2020). L-type calcium channels are substantially expressed on neurons (Zamponi, 2016), thus making L-type calcium channel blockers such as nimodipine, amiodarone, nicardipine, and dronedarone attractive targets for calcium regulation in the context of AD. Given our initial interest in calcineurin inhibitor CsA, we also emphasize both Pimecrolimus and Tacrolimus as compounds of interest due to both their shared mechanism of action and comprehensive supporting research on the subject of neurodegenerative diseases.

Steroid Hormones

The primary steroid hormones estrogen, progesterone, and testosterone can be found in various regions of the central nervous system (Garcia-Ovejero et al., 2005). Steroidogenesis has been proven to be a natural mechanism to combat neurodegenerative conditions, and in vivo studies have shown an increase in AD-like neuropathology following gonadectomy (Carroll & Rosario, 2012). While hormone therapy seems promising as a preventive therapy in neurodegeneration, epidemiological studies and clinical trials reveal controversial results (Henderson, 2014). Treatment timing and dosage are important factors to consider in future research involving these agents.

Serotonin Receptors

The serotonergic system has been associated with cognitive function and performance in neurological diseases including schizophrenia, epilepsy, and AD (Švob Štrac et al., 2016). Neurotransmitter serotonin (5-HT) is involved in the regulation of various physiological processes including cognition and emotional behavior (Ciranna, 2006). Cerebrospinal fluid 5-HT levels in AD patients were significantly decreased compared to healthy controls (Tohgi et al., 1992), and post mortem studies show a decrease in brain 5-HT levels (Palmer et al., 1987). Given the overwhelming evidence of serotonergic influence in cognitive function, there has been interest in various 5-HT receptor (5-HTR) agonists and antagonists for the treatment of AD, including 5-HT2A (Garcia-Romeu et al., 2022; Lu et al., 2021) and 5-HT6 (Geldenhuys & Van der Schyf, 2009; Kucwaj-Brysz et al., 2021). We have identified 6 5-HTR antagonists with various 5-HT receptor targets: dihydroergotamine, clozapine, amoxapine, nefazodone, flibanserin, and brexpiprazole.