European Journal of Medicinal Chemistry 174 (2019) 87e115 Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech Review article Comprehensive review on the interaction between natural compounds and brain receptors: Benefits and toxicity * Ana R. Silva a, Clara Grosso b, , Cristina Delerue-Matos b,Joao~ M. Rocha a, c a Centre of Molecular and Environmental Biology (CBMA), Department of Biology (DB), University of Minho (UM), Campus Gualtar, P-4710-057, Braga, Portugal b REQUIMTE/LAQV, Instituto Superior de Engenharia do Instituto Politecnico do Porto, Rua Dr. Antonio Bernardino de Almeida, 431, P-4249-015, Porto, Portugal c REQUIMTE/LAQV, Grupo de investigaçao~ de Química Organica^ Aplicada (QUINOA), Laboratorio de polifenois alimentares, Departamento de Química e Bioquímica (DQB), Faculdade de Ci^encias da Universidade do Porto (FCUP), Rua do Campo Alegre, s/n, P-4169-007, Porto, Portugal article info abstract Article history: Given their therapeutic activity, natural products have been used in traditional medicines throughout the Received 6 December 2018 centuries. The growing interest of the scientific community in phytopharmaceuticals, and more recently Received in revised form in marine products, has resulted in a significant number of research efforts towards understanding their 10 April 2019 effect in the treatment of neurodegenerative diseases, such as Alzheimer's (AD), Parkinson (PD) and Accepted 11 April 2019 Huntington (HD). Several studies have shown that many of the primary and secondary metabolites of Available online 17 April 2019 plants, marine organisms and others, have high affinities for various brain receptors and may play a crucial role in the treatment of diseases affecting the central nervous system (CNS) in mammalians. Keywords: Brain receptors Actually, such compounds may act on the brain receptors either by agonism, antagonism, allosteric Natural products modulation or other type of activity aimed at enhancing a certain effect. The current manuscript Neuroplasticity comprehensively reviews the state of the art on the interactions between natural compounds and brain Neuroinflammation receptors. This information is of foremost importance when it is intended to investigate and develop Oxidative stress cutting-edge drugs, more effective and with alternative mechanisms of action to the conventional drugs Blood-brain barrier presently used for the treatment of neurodegenerative diseases. Thus, we reviewed the effect of 173 natural products on neurotransmitter receptors, diabetes related receptors, neurotrophic factor related receptors, immune system related receptors, oxidative stress related receptors, transcription factors regulating gene expression related receptors and blood-brain barrier receptors. © 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC- ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents 1. Introduction . ................................................. 88 2. Neurotransmitter receptors . ................................................. 89 2.1. Acetylcholine receptors . ........................89 2.1.1. Nicotinic acetylcholine receptors (nAChRs) . ........................89 2.1.2. Muscarinic acetylcholine receptors (mAChRs) .............................................................................91 2.2. Glutamate receptors . ........................93 2.2.1. Ionotropic receptors . ........................93 2.2.2. Metabotropic glutamate receptors (mGluRs) ..............................................................................96 2.3. g-Aminobutyric acid receptors (GABARs) . ........................96 2.4. Cannabinoid receptors (CBRs) . .. ........................97 2.5. Dopamine receptors (DARs) . ........................98 3. Diabetes related receptors . ................................................ 100 3.1. Insulin and insulin-like growth factor (IGF) receptors (IR and IGFR) . .......................100 * Corresponding author. E-mail address: [email protected] (C. Grosso). https://doi.org/10.1016/j.ejmech.2019.04.028 0223-5234/© 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc- nd/4.0/). 88 A.R. Silva et al. / European Journal of Medicinal Chemistry 174 (2019) 87e115 3.2. Receptors for advanced glycation end-product (RAGE) . ...........................101 4. Neurotrophic factor (NTF) related receptors (NTFRs) . .................... 102 5. Immune system related receptors . .................... 103 6. Oxidative stress related receptors . .................... 104 7. Transcription factors regulating gene expression related receptors . .................... 106 8. Blood-brain barrier receptors . .................... 108 8.1. Apolipoprotein E (ApoE) or low-density lipoproteins (LDL) . ...........................108 9. Toxicity of natural compounds . .................... 108 10. Conclusions ............................................................... .................................. .................... 109 Conflicts of interest . .................... 109 Acknowledgements . ..................................................109 Supplementary data . .....................110 References . ..................................................110 1. Introduction concomitant deleterious effects on brain processes, such as learning þ and memory [15]. Excessive release of calcium ions (Ca2 ) e for Over the years, neurodegenerative diseases e such as Alz- instance, through glutamate receptors e contributes to mitochon- heimer's (AD), Parkinson's (PD) and Huntington's (HD) diseases e drial dysfunction, activation of proteases and mechanisms of have been the main focus of the research in neuroscience, so as to apoptosis, as well as to the accumulation of reactive oxygen species recognize the cellular changes and pathophysiological mechanisms (ROS) and to the release of nitric oxide ( NO) [16]. In turn, g-ami- involved [1]. This group of diseases is characterized by a gradual nobutyric (GABA) inhibition, mediated by the type A receptor motor and sensorial loss, as well as deficits of perceptual functions, (GABAAR), is a key element that provides the basis for synchronized knowledge and behaviour associated with neuronal death [2]. This neuronal activity [17]. In addition, the loss of dopaminergic neurons progressive loss of neurons is associated with deposition of pro- is a key mechanism for the neurodegeneration since they are teins in brain leading to changes in its physicochemical properties involved in functions such as voluntary movement, attention, [3]. memory and learning [18]. Furthermore, cannabinoid receptors are AD is related to amyloid-b (or Ab peptides), which is formed and also involved in the process, either by a decrease in the expression deposited in the brain due to the disturbance in the metabolism of of cannabinoid type 1 receptors (CB1Rs) e which is associated with the amyloid precursor protein (APP) e a glycoprotein that un- an increased release of glutamate, thus contributing to excitotox- dergoes proteolytic cleavage, through the a-orb-secretases, within icity mechanisms [19] e or by overexpression of cannabinoid type 2 the Ab domain. Firstly, Ab monomers aggregate into soluble olig- receptors (CB2Rs) e which are involved in processes of neuro- omers that then form insoluble oligomers, generating protofibrils inflammation [20,21]. In addition, the activation of receptors of and fibrils. Soluble Ab1-42 oligomers constitute the more toxic form advanced glycation end-products (RAGE) in neuronal cells pro- of the peptide [4]. Moreover, there are aggregates of hyper- motes synaptic dysfunction and, in microglia cells, induces phosphorylated tau-proteins (or t-proteins) that mediate neuro- inflammation [6,15]. At the genetic level, peroxisome proliferator- pathological processes associated with dementia [5,6] and there is activated receptors (PPARs) play a crucial role in downregulation also a decrease in the acetylcholine (ACh) levels [7]. In the case of of mitochondrial dysfunction, oxidative stress and neuro- PD, intraneuronal inclusions called Lewy bodies are present in the inflammation [22]. Such mechanisms of neuroinflammation substantia nigra. Lewy bodies are composed of abnormal a-synu- involve cells from the immune system (for example, microglia) clein which is nitrated, phosphorylated, abnormally conformed and which, in response to a persistent stimulus (for example, by protein aggregated, and presents altered solubility. Besides Lewy bodies, aggregates), activate the production of neurotoxic factors that abnormal neurites containing granular material and a-synuclein amplify the inflammatory states. At the same time, the scavenger filaments (Lewy neurites) are also found in the substantia nigra of receptors (SCARs) e highly expressed in astrocytes and microglia e PD patients [8]. PD is also characterized by the loss of dopaminergic are involved in the capture of several substrates, such as oxidized neurons [9]. Finally, in HD, the mutant Huntingtin protein alters proteins, lipids and apoptotic cells [23]. Receptors related to neu- neuronal function e being the striatum neurons more susceptible rotrophic factors (NTF) regulate the growth, differentiation and to its toxic effects, which explains the motor symptoms of this survival of the neurons from the central and peripheral nervous pathology [10].