Small Molecules: Therapeutic Application in Neuropsychiatric and Neurodegenerative Disorders

Stefania Schiavone, Luigia Trabace
2018 Molecules  
In recent years, an increasing number of studies have been published, focusing on the potential therapeutic use of small catalytic agents with strong biological properties. So far, most of these works have only regarded specific clinical fields, such as oncology, infectivology and general pathology, in particular with respect to the treatment of significant inflammatory processes. However, interesting data on possible therapeutic applications of small molecules for the treatment of
more » ... ent of neuropsychiatric and neurodegenerative illnesses are emerging, especially with respect to the possibility to modulate the cellular redox state. Indeed, a crucial role of redox dysregulation in the pathogenesis of these disorders has been widely demonstrated by both pre-clinical and clinical studies, being the reduction of the total amount of free radicals a promising novel therapeutic approach for these diseases. In this review, we focused our interest on studies published during the last ten years reporting therapeutic potential of small molecules for the treatment of neuropsychiatric and neurodegenerative disorders, also based on the biological efficiency of these compounds in detecting intracellular disturbances induced by increased production of reactive oxygen species. Molecules 2018, 23, 411 2 of 23 removed for further screening. We then excluded 42 papers which were not written in English or were other than original research papers or reviews. A second round of exclusion concerned papers (29) which did not provide a detailed description of the chemical characteristics of the considered small molecules. Finally, 73 papers were included in the analysis. The total number of references of this paper also included the ones used for the introducing statements of the different sections of the manuscript. The Use of Small Molecules in Neuropsychiatric Disorders The main findings related to the possible therapeutic potential of small molecules in the treatment of schizophrenia, mood disorders, anxiety and autism are reported in Table 1 . The chemical structures (https://pubchem.ncbi.nlm.nih.gov/) [17] of specific small molecules with therapeutic potential in neuropsychiatric disorders are shown in Figure 1 . Molecules 2018, 23, x 2 of 23 [22,26] Autism Cdc2-like kinase 2 (CLK2) inhibitors Inhibition of CLK2 -Decrease of synaptic deficits in neurons derived from patients with symptoms of autism spectrum disorder -Restore of normal sociability in an animal model of autism [27] Molecules 2018, 23, 411 4 of 23 The Use of Small Molecules in Neurodegenerative Disorders Therapeutic Potential for Alzheimer's Disease A crucial event in the pathogenesis of Alzheimer's disease (AD) is represented by the amyloid-β peptide (Aβ) aggregation which initiates a cascade of molecular pathways, finally resulting in neuronal death and degeneration [28] . Importantly, abnormal Aβ metabolism can be detected several years before AD onset [29] and this aspect represents an important pharmacological target for early therapeutic interventions. However, so far, no compound specifically targeting the process of Aβ accumulation, and mainly developed by using animal models of the disease, has been translated into clinical practice [30] . Therefore, the identification of small molecules, acting on Aβ accumulation and aggregation, has represented the focus of an increasing number of studies in this field, in the perspective of opening a novel and promising "chapter" in the history of compounds to be used in AD. One of the most complete and straightforward works in this sense is represented by a very recent paper by Habchi and co-workers, in which the authors reported the systematic development of some small molecules, classified as "set A" (seven molecules showing a similar or greater effect than the bexarotene) and "set B" (five molecules able to totally inhibit Aβ42 aggregation for a period of at least 10 h), that inhibit specific steps of Aβ42 aggregation [31] . However, for the sake of clarity, it should be specified that some of the small molecules identified in this work, such as MM11253 and adapalene, were previously described by other authors to significantly impact not only the onset of the aggregation but also Aβ42 oligomer proliferation [32, 33] . The other records found with our research strategy, highlight, rather, the development of small molecules targeting another crucial pathogenetic process in AD progression, i.e., the loss of metal ion homeostasis and their impaired compartmentalization [34, 35] , especially concerning the redox active Fe(II/III) and Cu(I/II), that have been found as highly concentrated in senile plaques [36, 37] , in the cortex and hippocampus [38, 39] . Hence, these reactive metals can bind to Aβ species, then undergoing Fenton reaction, resulting in the production of specific reactive oxygen species (ROS), such as hydrogen peroxide and hydroxyl radical, which may facilitate Aβ aggregation and trigger neurodegeneration [35] . Therefore, a valuable therapeutic strategy to reduce neurotoxicity, induced by the interaction between metals and Aβ species, and to re-establish metal ion homeostasis in the brain, might be represented by the metal-Aβ association outbreak via metal chelation. So far, the most used chelators in AD therapy included ethylenediaminetetraacetic acid (EDTA), clioquinol and PBT2, an 8-hydroxyquinoline derivative. In the attempt to translate preclinical findings to possible clinical application, the last two compounds were also tested in phase II clinical trials and they have been reported to significantly improve cognitive functions [40, 41] , despite their serious side effects, such as the subacute myelo-optic neuropathy induced by clioquinol. Consistent efforts have been also addressed to the development of small molecules, such ascyclen, KLVFF peptide, curcumin, IMPY, and p-I-stilbene that were able to synergistically link both metal ions and Aβ [42] [43] [44] , in order to overcome the limit of the previously developed metal chelating compounds, especially related to blood-brain barrier permeability. Therapeutic Potential for Parkinson's Disease Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of the dopaminergic neurons in the substantia nigra. Several pathogenetic mechanisms have been proposed for this Central nervous system (CNS) disorder. One of the most investigated is related to mitochondrial and redox dysfunctions [45, 46] , including mutations in the mitochondria-specific kinase PTEN-induced kinase 1 (PINK1), as well as in the E3 ubiquitin ligase Parkin, a mitochondria-associated protein [47] . In line with this concept, several papers reported the therapeutic potential of PINK1/Parkin pathway activation in PD [48, 49] . However, despite the widely known mechanism of small molecule-mediated activation of kinases, typically accomplished by binding their allosteric regulatory sites, PINK1 has been shown to not contain small molecule-binding sites, being, therefore, its pharmacological activation Molecules 2018, 23, 411 5 of 23 mediated by other mechanisms [49]. On the other hand, mildronate [3-(2,2,2-trimethylhydrazinium) propionate dihydrate], a small molecule with charged nitrogen and oxygen atoms that protect mitochondria, has been described to act as neuroprotective compound in a mouse model of neurotoxicity induced by azidothymidine, via suppression of brain inflammation and apoptosis, as well as decrease of cytochrome oxidase c, caspase-3, inducible Nitric Oxide Synthase (iNOS) and cellular apoptosis susceptibility-protein [50] . The mildronate-related neuroprotection was further confirmed in a study performed by using a rat model of PD that was obtained by unilateral intra-striatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA). Indeed, mildronate administration to 6-OHDA-injected animals prevented the loss of specific biomarkers, such as tyrosine hydroxylase, ubiquitin and Notch-3, which are known to assure neural and glial integrity, simultaneously decreasing the expression of specific markers of inflammation, such as iNOS [51] . In line with mitochondria dysfunctions, another crucial pathogenetic mechanism associated to the development of PD is related, at molecular levels, to dysfunctions of GTPases, especially the ones regulating the dynamic processes of mitochondria fission and fusion, the organelle transport along axons, the axon maintenance, as well as the neuronal survival, and to neuroinflammation and oxidative stress enhancement [52] . With respect to redox imbalance, the small GTPase Rac1, which crucially regulates the functioning of the free radical producer NOX1, has been reported to accumulate in dopaminergic neurons of patients affected by PD [53] . Interestingly, a library containing 5 million small molecules has been probed as modulator for different GTPases, such as Rab5, Rab7, Cdc42, wild type Ras and mutant Ras, Rho, and Rac that selectively activate GTPase subfamilies [52] . Another significant acquired knowledge in the field of molecular mechanisms leading to PD, deals with the role of specific proteins, including α-synuclein. Indeed, in a very interesting paper of Misook and co-workers, authors attempted to synthesize a library of small molecules, in order to rapidly and efficiently identify potential pharmacological "chaperones", i.e., small molecules that bind proteins and stabilize them against degradation, as well as novel chaperone inhibitors against α-synuclein [54]. The chemical structures (https://pubchem.ncbi.nlm.nih.gov/) [17] of small molecules with therapeutic potential in AD and PD are shown in Figure 2 . Molecules 2018, 23, x 5 of 23
doi:10.3390/molecules23020411 pmid:29438357 fatcat:4hqxi6mzszbxhjciegw3fe3qwa