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• W2515698086 abstract "Over the past two decades, only a handful of CNS drugs with new drug targets have received FDA approval. The majority of new CNS drugs seem to target the same targets, some of which have been around for several decades. The selective serotonin reuptake inhibitors (SSRIs) remain the first-line treatment for major depression disorder (MDD) over 30 years after the prototype drug, fluoxetine was approved by the FDA, even though switching to other anti-depressant drug class is warranted for some MDD patients [Bradley and Lenox-Smith, 2013; Tallon et al., 2016]. Likewise, lithium continues to be the first-line treatment for bipolar disorder (BPD) over half a century after being introduced to routine psychiatric use and in spite of its associated adverse events risk [Castro et al., 2016]. Newer atypical antipsychotics mostly target the same dopaminergic and serotonergic receptor subtypes as the older atypical antipsychotics, in spite of the associated metabolic syndrome risk that has not been solved [Van Schependom et al., 2015; Varghese et al., 2016]. It appears that few, if any, new psychiatric drugs with novel targets or substantially improved safety profiles have been approved by the FDA in recent years for treating the most common psychiatric disorders, including MDD, BPD, and schizophrenia. This issue of Drug Development Research contains several review articles discussing new psychotropic drug targets. These include ketamine, an old anesthetic drug recently emerging as tentative treatment for rapid, albeit temporary, relief from treatment-resistant depression [Feifel, 2016; Pešić et al., 2016]. Other reviews discuss the antidepressant potential of S-adenosyl methionine [Karas, 2016], the anticonvulsant activities of new hydrazide/hydrazone derivatives [Angelova et al., 2016], and the promise and pitfalls of multifunctional molecules in psychotropic disorders [Milelli et al., 2016]. In this editorial, I briefly discuss the potential of microRNAs (miRNAs) as novel psychotropic drug targets; this topic is discussed in more depth by Milanesi et al. [2016] in the current issue of Drug Development Research. MiRNAs are key transcriptional regulators of around half of human genes [Mor and Shomron, 2013; Milanesi et al., 2016]. While the role of intracellularly produced miRNAs for modulation of mRNA stability and thereby of transcription has been recognized since over two decades, recent evidence suggests expands their scope as cellular regulators to include intercellular communication. We now know that exosomal-packaged miRNAs take part in hormone-like tissue crosstalk, where miRNA produced inside cells following transcription from DNA, packaged and released inside secreted exosomes, may affect transcription, and thereby cellular phenotypes, in another tissue [Gurwitz, 2015; Ohno and Kuroda, 2016]. This hormone-like action suggests miRNAs as novel drug targets in oncology [Milane et al., 2015; Lugini et al., 2016]. In addition to cancer treatment, miRNAs are emerging as potential drug targets in psychiatric disorders [Forero et al., 2010] in particular as regulators of neuronal plasticity and neuronal stem-cell migration [Bredy et al., 2011]. Alongside, the role of brain-derived exosomes and their miRNA cargo in psychiatric disorders is also gaining awareness as key player in the crosstalk between the brain and the immune system [Théry et al., 2009; Cossetti et al., 2012; Hwang, 2013; Ander et al., 2015; Schafferer et al., 2016]. This brain/immune crosstalk is bidirectional: immune cell exosomes may affect brain physiology [Paschon et al., 2016; Pusic et al., 2016] and vice versa. The secretion of brain or immune cell exosomes is, in part, regulated by neurotransmitters including adrenaline [Padro et al., 2013], glutamate [Chivet et al., 2014], ATP [Pupovac et al., 2015], and serotonin [Glebov et al., 2015]. Thus, it is conceivable that some of the effects of current CNS drugs, including neurotransmitter agonists and antagonists as well as the SSRI antidepressants [Oved et al., 2013] take place (at least partially) via their effects on exosome secretion by brain neurons or glia that in turn carry their miRNA cargo to other brain regions or other brain cells such as microglia, and also to peripheral immune cells. The role of exosomal-mediated brain/immune crosstalk in the mode of action of current CNS drugs is only now beginning to emerge. However, such CNS drug-mediated pathways could underlie some of their therapeutic effects, and hence point the way for developing miRNA-based therapeutics, in particular when the implicated miRNAs are mediators of brain neuroplasticity, augmentation of neuronal stem cell migration and differentiation, or synaptogenesis. Exogenously prepared exosomes with a carefully chosen miRNA cargo, or containing synthetic siRNAs for silencing specific miRNAs, have the potential to be developed as CNS therapeutics. Exosomes or liposomes represent ideal carriers for nucleic acid drugs [Ohno and Kuroda, 2016] and may readily pass the blood-brain barrier [Wood et al., 2011; El Andaloussi et al., 2013]. For example, intranasally administered catalase-loaded exosomes could be detected in mouse brain [Haney et al., 2015]. When prepared in vitro under controlled conditions, exosomes may contain well-defined miRNA composition that may affect target cells. For example, osteoclast-derived miR-214 containing exosomes specifically recognized cultured osteoblasts and affected their activity [Sun et al., 2016]; while miR-21 containing cardiac progenitor cell-derived exosomes prevented apoptosis of cultured cardiomyocytes [Xiao et al., 2016b], and amniotic fluid stem-cell derived exosomes contain miR-146a and miR-10a that allowed preservation of viable ovarian follicles following chemotherapy [Xiao et al., 2016a]. In vivo studies on targeting diseased brain tissue with selected exosomes are at presently limited. Meanwhile, several promising animal model studies have described the use of exogenous exosomes for the delivery of desired miRNAs or siRNAs as cancer therapeutics. This research direction follows on findings that cancer-derived exosomes may promote metastasis [Peinado et al., 2012; Lowry et al., 2015; O'Driscoll, 2015]. In particular, higher levels of the closely related miRNAs miR-221 and miR-222 were strongly implicated in cancer aggressiveness [Li et al., 2016; Pan et al., 2016] and their exosomal-mediated transfer dramatically increased melanoma malignancy [Felicetti et al., 2016]. While treatment of mice bearing human melphalan-refractory multiple myeloma xenografts with systemic locked nucleic acid (LNA) inhibitors of miR-221 improved their melphalan sensitivity [Di Martino et al., 2014; Gullà et al., 2016]. Hopefully, similar approaches with anti-miRs will be assessed in animal models of CNS disorders. For example, miR-186 [Kim et al., 2016] and miR-16 [Zhang et al., 2015] have been implicated in neurodegeneration in Alzheimer's disease (AD), while miR-34 [Kabaria et al., 2015] and miR-133 [Niu et al., 2016] were shown to contribute to Parkinson's disease (PD) pathology. Targeting such miRNAs offers new venues for targeting neurodegenerative disorders. MiRNAs also have novel potential for disease diagnostics. Specific detection of cancer cell-derived exosomes and their miRNAs in the blood shows promise for improved early cancer diagnostics [Melo et al., 2015; Alderton, 2015; Munson and Shukla, 2015]. In particular, exosomal circular RNA in plasma may offer better early cancer diagnosis [Li et al., 2016; Meng et al., 2016]. Brain-derived exosomes and their miRNAs may also aid in improved diagnostics for CNS disorders, however at this time knowledge on this is limited. Insight on CNS disorder-associated blood miRNAs may also guide the development of miRNA-targeted CNS therapeutics. For example, Stuendl et al. [2016] reported that cerebrospinal fluid exosomal α-synuclein species from PD patients with α-synuclein-related neurodegeneration promote disease-associated neurodegeneration; tentatively, targeting the miRNA cargo of such exosomes may lead to novel PD therapeutics. Exosomes may also transmit beneficial effects to the CNS: exosomes isolated from serum of rats exposed to environmental enrichment seem to possess a miRNA cargo that promotes CNS myelination [Pusic et al., 2016]. Several further studies have reported on neuroprotective effects of miRNAs. These include miR-210 [Jiang et al., 2015]; miR-29c [Yang et al., 2015]; rno-miR-676-1 [Pang et al., 2015]; miR-124 [Wang et al., 2016]; miR-132 [Keasey et al., 2016] and several others. Conversely, some miRNAs have been reported to have adverse effects on neurodegeneration, such as, exacerbating the outcome of ischemic stroke, and may represent targets for silencing by siRNAs in neurodegenerative disorders. These include miR-155 [Caballero-Garrido et al., 2015]; miR-146a [Zhou et al., 2016]; miR-497 [Sinoy et al., 2016]; miR-181a [Ren et al., 2016]; and others. Of note, for the majority of these studies a demonstration for the presence of these miRNAs as cargo of CSF or blood exosomes is still lacking. Clarifying this issue remains a crucial aspect for considering miRNA-targeted CNS therapeutics. Compounds are being developed for inhibiting exosome secretion by cancer cells, a process that may promote cancer progression. For example, Wei et al. [2016] reported that shikonin, a naphthoquinone isolated from the traditional Chinese medicine Lithospermum, inhibited proliferation of MCF-7 human breast cancer cells by reducing tumor-derived exosomal miR-128. Similar approaches should be explored for CNS disorders where CSF or plasma exosomes appear to be disease promoters, such as those promoting neurodegeneration. However, it seems that the main obstacles for developing miRNA-targeted therapeutics remain their bioavailability aspects. Little information is presently available on the fate of in vivo injected miRNAs, anti-miRNAs, and related miRNA-sponges [Militello et al., 2016]. The bioavailability and pharmacokinetics of such compounds will definitely be critical to their clinical feasibility as therapeutics for CNS as well as for other disorders. The author is supported by Israel Cancer Research Fund (ICRF) grant 14-56-AG and by the Yoran Institute for Human Genome Research at Tel-Aviv University. David Gurwitz Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel Aviv University, Tel-Aviv, Israel" @default.
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• W2515698086 date "2016-08-29" @default.
• W2515698086 modified "2023-09-26" @default.
• W2515698086 title "MicroRNAs as CNS Drug Targets" @default.
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