Neurochemical Research (2019) 44:735–750 https://doi.org/10.1007/s11064-018-02712-1 REVIEW PAPER Therapeutic Effect of Agmatine on Neurological Disease: Focus on Ion Channels and Receptors Sumit Barua1 · Jong Youl Kim1 · Jae Young Kim1 · Jae Hwan Kim4 · Jong Eun Lee1,2,3 Received: 15 October 2018 / Revised: 19 December 2018 / Accepted: 24 December 2018 / Published online: 4 January 2019 © Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract The central nervous system (CNS) is the most injury-prone part of the mammalian body. Any acute or chronic, central or peripheral neurological disorder is related to abnormal biochemical and electrical signals in the brain cells. As a result, ion channels and receptors that are abundant in the nervous system and control the electrical and biochemical environment of the CNS play a vital role in neurological disease. The N-methyl-D-aspartate receptor, 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid receptor, kainate receptor, acetylcholine receptor, serotonin receptor, α2-adrenoreceptor, and acid-sensing ion channels are among the major channels and receptors known to be key components of pathophysiological events in the CNS. The primary amine agmatine, a neuromodulator synthesized in the brain by decarboxylation of L-arginine, can regu- late ion channel cascades and receptors that are related to the major CNS disorders. In our previous studies, we established that agmatine was related to the regulation of cell differentiation, nitric oxide synthesis, and murine brain endothelial cell migration, relief of chronic pain, cerebral edema, and apoptotic cell death in experimental CNS disorders. In this review, we will focus on the pathophysiological aspects of the neurological disorders regulated by these ion channels and receptors, and their interaction with agmatine in CNS injury. Keywords Agmatine · Ion channels · Receptors · Neurodegenerative disease · Receptor blockade Abbreviations Sumit Barua and Jong Youl Kim have contributed equally to this work. CNS Central nervous system PNS Peripheral nervous system * Jong Eun Lee AD Alzheimer’s disease [email protected] PD Parkinson’s disease Sumit Barua HD Huntington’s disease [email protected] ADC Arginine decarboxylase Jong Youl Kim ROS Reactive oxygen species [email protected] NF-κB Nuclear factor kappa B Jae Young Kim TBI Traumatic brain injury [email protected] NO Nitric oxide Jae Hwan Kim SCI Spinal cord injury [email protected] BMP Bone morphogenetic protein 1 Department of Anatomy, Yonsei University College Aβ Amyloid-beta of Medicine, 50-1 Yonsei-Ro, Seodaemun-gu, Seoul 03722, Nrf2 Nuclear factor (erythroid derived 2)-like 2 Republic of Korea MPTP 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyri- 2 Brain Korea 21 PLUS Project for Medical Science, Yonsei dine University College of Medicine, 50 Yonsei-Ro, Seoul 03722, MES Maximal electroshock seizures Republic of Korea PTZ Pentylenetetrazole 3 Brain Research Institute, Yonsei University College NMDAR N-Methyl-D-aspartate receptor of Medicine, 50 Yonsei-Ro, Seoul 03722, Republic of Korea AMPAR α-Amino-3-hydroxy-5-methylisoxazole-4- 4 Center for Neuroscience Imaging Research (CNIR), Insititute propionic acid receptor for Basic Science, Sungkyunkwan University, Seoul, NOS Nitric oxide synthase Republic of Korea Vol.:(0123456789)1 3 736 Neurochemical Research (2019) 44:735–750 KAR Kainite receptor channel-related diseases termed channelopathies, which GPCR G protein-coupled receptor overlap with acute and chronic neurodegenerative disorders CDS Clonidine displacing substance such as ischemic stroke, traumatic injury, epilepsy, Alzhei- AChR Acetylcholine mer’s disease (AD), schizophrenia, and Huntington’s disease mAChR Muscarinic acetylcholine receptor (HD) [1]. The majority of neurodegenerative diseases are nAChR Nicotinic acetylcholine receptor related to cell death caused by disrupted ion channels and 5-HT 5-Hydroxytryptamine receptors or metabolic functions of neuronal cells [2–5]. In VDCC Voltage-dependent calcium channel the healthy brain, ionic homeostasis is a major component LVA Low-voltage activated of neuronal information transmission via action potentials, HVA High-voltage activated which are also related to synaptic transmission between pre- ENaC/DEG Epithelial Na+ channel/degenerin synaptic and postsynaptic neurons. Loss of synaptic function ASIC Acid-sensing ion channel due to low energy supply in neurodegenerative disorders EL/IL Extracellular/intracellular loops leads to attenuation of ion homeostasis [6, 7]. In the diseased brain, ion homeostasis is maintained by a series of ion chan- nels in brain cells, predominantly in neuron, astrocyte and Introduction microglia, and a myriad of ions that are transported across the cell membrane via those channels (Table 1). Among the Ion channels and receptors are the macromolecular mem- range of associated ions, potassium, sodium, chloride, and brane pores that traffic a series of ions(Na +, K+, Ca2+, Cl−) calcium collectively play a pivotal role in cellular damage and chemicals (neurotransmitters, hormones etc.) in or out [1, 8]. Following central nervous system (CNS) injury, the of the cells and propagate the biochemical and electrical well-orchestrated ion exchange across the membrane via ion signals. Functional initiation of ion channels requires stimuli channels or receptors is disrupted and brain cells lose their such as ligand binding, chemical/mechanical changes, and normal function, leading to death. altered membrane potentials. Therefore, any iatrogenic, Agmatine, an arginine-derived primary amino acid autoimmune, toxic, or genetic dysfunction can cause ion found in the nerve cell body and synaptic terminals, acts as Table 1 Major ion channels and receptors to which agmatine act as a ligand and modulates their functions Ion channel/receptor Ligand Conducting ions Related neurological disorders References + 2+ + NMDA L-Glutamate, NMDA, glycine Na , Ca , K Stoke and traumatic injury, [38, 131, 133, 134] AD, HD, pain, schizophrenia, depression + + 2+ AMPA and kinate L-Glutamate, AMPA Na , K , less Ca Stoke and traumatic injury, [98] AD, epilepsy schizophrenia, depression, amyotrophic lateral sclerosis, autism α2-Adenoceptor: α2-Adenoceptor: epinephrine α2-Adenoceptor : K+, Na+ and Pain, panic disorder, addiction, [164–172] imidazoline recep- norepinephrine, α-methyl H+ depression, anxiety, hyperten- tors DOPA and others Imidazoline receptor: Ca+ sion Imidazoline receptors: imidazo- line compounds AChR Acetylcholine nicotine Na+, Ca2+, K+ Myasthenia gravis, epilepsy, [57, 60, 62–64] AD, PD, schizophrenia, Tou- rette’s syndrome, idiopathic inflammatory bowel disease, addiction, anxiety, depression VDCC Membrane potential Ca2+ Epilepsy, seizures, AD, pain, [77, 78, 80] autism spectrum disorder, migraine, anxiety, depression ASICs Extracellular protons Na+, less Ca2+ Ischemic stroke, traumatic [88, 92, 99, 120] injury, pain, HD, PD, multiple sclerosis, glioblastoma, epilepsy Serotonin (5-HT) Different serotonergic com- Na+, Ca2+, K+ by 5-HT3 AD, anxiety, depression, [107, 108, 130, 169] pounds seizure locomotor activity, aggression 1 3 Neurochemical Research (2019) 44:735–750 737 a neuromodulator that mimics the functional properties of cation [30]. Agmatine is also suggested to behave as mono- other neurotransmitters [9, 10]. The enzyme arginine decar- valent when it interacts with the microscopic channels and boxylase (ADC) synthesizes agmatine by decarboxylation of divalent as a macroscopic charge transfer [30]. L-arginine [11]. On the other hand, studies suggested that in Agmatine can be metabolized into putres- the mammal lacking ADC, decarboxylation of L-arginine is cine by the enzyme agmatinase or oxidized into catalyzed by the ornithine decarboxylase enzyme. Agmatine- γ-guanidinobutyraldehyde by diamine oxidase (Fig. 1). expressing cells have been found in all regions of the brain Agmatinase belongs to the family of hydrolases, those acting such as the hypothalamus, frontal cortex, striatum, medulla, on carbon–nitrogen bonds other than peptide bonds, specifi- hippocampus, and locus coeruleus along with measurable cally in linear amidines, then synthesizes putrescine, one of ADC activity [9, 10, 12–16]. However, the highest number polyamines. Putrescine is metabolized further into the poly- of these cells was observed in the paraventricular (PVN) and amines, spermidine and spermine [31]. On the other hand, supraoptic (SON) nuclei of the hypothalamus, which also diamine oxidase deaminates oxidatively diamines to produce exhibited the highest ADC activity. Diverse mechanisms of aldehydes, ammonia and hydrogen peroxide. Therefore, the neuroprotection by agmatine in response to neurodegenera- amino group of agmatine is metabolized by the action of tive diseases have been reported by many research groups, diamine oxidase to become γ-guanidinobutylbutylic acid- such as blocking of harmful ion channels, suppressing harm- aldehyde, and is further metabolized to γ-guanidinobutyric ful reactive oxygen species (ROS), promoting neurogenesis, acid by aldehyde dehydrogenase (Fig. 1). Agmatine has two angiogenesis, reducing glial scars etc [17–20]. In a recent reactive groups, which increased its possibility of various review, Laube and Bernstein preciously reviewed the recent chemical reactions in vivo. With this potentiality for bio- studies about the agmatine metabolism and clinical applica- chemical reactions, agmatine has been used as an experi- tion including nervous system [21]. In acute brain diseases, mental