title: Protective effect of magnesium acetyltaurate against NMDA-induced retinal damage involves restoration of minerals and trace elements homeostasis.
abstract: Glutamate-mediated excitotoxicity involving N-methyl-d-aspartate (NMDA) receptors has been recognized as a final common outcome in pathological conditions involving death of retinal ganglion cells (RGCs). Overstimulation of NMDA receptors results in influx of calcium (Ca) and sodium (Na) ions and efflux of potassium (K). NMDA receptors are blocked by magnesium (Mg). Such changes due to NMDA overstimulation are also associated with not only the altered levels of minerals but also that of trace elements and redox status. Both the decreased and elevated levels of trace elements such as iron (Fe), zinc (Zn), copper (Cu) affect NMDA receptor excitability and redox status. Manganese (Mn), and selenium (Se) are also part of antioxidant defense mechanisms in retina. Additionally endogenous substances such as taurine also affect NMDA receptor activity and retinal redox status. Therefore, the aim of this study was to evaluate the effect of Mg acetyltaurate (MgAT) on the retinal mineral and trace element concentration, oxidative stress, retinal morphology and retinal cell apoptosis in rats after-NMDA exposure. One group of Sprague Dawley rats received intravitreal injection of vehicle while 4 other groups similarly received NMDA (160nmolL-1). Among the NMDA injected groups, 3 groups also received MgAT (320nmolL-1) as pre-treatment, co-treatment or post-treatment. Seven days after intravitreal injection, rats were sacrificed, eyes were enucleated and retinae were isolated for estimation of mineral (Ca, Na, K, Mg) and trace element (Mn, Cu, Fe, Se, Zn) concentration using Inductively Coupled Plasma (DRC ICP-MS) techniques (NexION 300D), retinal oxidative stress using Elisa, retinal morphology using H&E staining and retinal cell apoptosis using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Intravitreal NMDA injection resulted in increased concentration of Ca (4.6 times, p<0.0001), Mg (1.5 times, p<0.01), Na (3 times, p<0.0001) and K (2.3 times, p<0.0001) compared to vehicle injected group. This was accompanied with significant increase of Ca/Mg and Na/K ratios, 3 and 1.27 times respectively, compared to control group. The trace elements such as Cu, Fe and Zn also showed a significant increase amounting to 3.3 (p<0.001), 2.3 (p<0.0001) and 3 (p<0.0001) times respectively compared to control group. Se was increased by 60% (p<0.005). Pre-treatment with MgAT abolished effect of NMDA on minerals and trace elements more effectively than co- and post-treatment. Similar observations were made for retinal oxidative stress, retinal morphology and retinal cell apoptosis. In conclusion, current study demonstrated the protective effect of MgAT against NMDA-induced oxidative stress and retinal cell apoptosis. This effect of MgAT was associated with restoration of retinal concentrations of minerals and trace elements. Further studies are warranted to explore the precise molecular targets of MgAT. Nevertheless, MgAT seems a potential candidate in the management of diseases involving NMDA-induced excitotoxicity.
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia.
authors.forename: Azliana Jusnida Ahmad
authors.initials: AJA
authors.lastname: Jafri
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia.
authors.forename: Natasha Najwa Nor
authors.initials: NNN
authors.lastname: Arfuzir
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia.
authors.forename: Lidawani
authors.initials: L
authors.lastname: Lambuk
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia; Volgograd State Medical University, Research Institute of Pharmacology, Volgograd, Russia. Electronic address: iezhitsa@yandex.ru.
authors.forename: Igor
authors.initials: I
authors.lastname: Iezhitsa
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia.
authors.forename: Renu
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: International Medical University, IMU Clinical School, Seremban, Malaysia.
authors.forename: Puneet
authors.initials: P
authors.lastname: Agarwal
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia.
authors.forename: Norhafiza
authors.initials: N
authors.lastname: Razali
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia.
authors.forename: Anna
authors.initials: A
authors.lastname: Krasilnikova
authors.affiliation: Volgograd State Medical University, Research Institute of Pharmacology, Volgograd, Russia; Institute of Pharmacy, Department of Pharmacology and Toxicology, University of Innsbruck, Center for Chemistry and Biomedicine, Innrain 80 - 82/III, A-6020, Innsbruck, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Kharitonova
authors.affiliation: Russian Society of Trace Elements in Medicine, 46 Zemlyanoy Val str., Moscow, 105064, Russia.
authors.forename: Vasily
authors.initials: V
authors.lastname: Demidov
authors.affiliation: Russian Society of Trace Elements in Medicine, 46 Zemlyanoy Val str., Moscow, 105064, Russia.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Serebryansky
authors.affiliation: Russian Society of Trace Elements in Medicine, 46 Zemlyanoy Val str., Moscow, 105064, Russia; Peoples' Friendship University of Russia, Moscow, Russia; All-Russian Research Institute of Medicinal and Aromatic Plants, Moscow, Russia.
authors.forename: Anatoly
authors.initials: A
authors.lastname: Skalny
authors.affiliation: Volgograd State Medical University, Research Institute of Pharmacology, Volgograd, Russia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Spasov
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia.
authors.forename: Ahmad Pauzi Md
authors.initials: APM
authors.lastname: Yusof
authors.affiliation: Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia.
authors.forename: Nafeeza Mohd
authors.initials: NM
authors.lastname: Ismail
mesh_terms: D000818:Animals; D005260:Female; D006706:Homeostasis / Q000187:drug effects*; D008297:Male; D008903:Minerals / Q000378:metabolism*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012164:Retinal Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D013654:Taurine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D014131:Trace Elements / Q000378:metabolism*
chemical_list: D008903:Minerals; D020011:Protective Agents; D014131:Trace Elements; C083076:acetyltaurine; D013654:Taurine; D016202:N-Methylaspartate
keywords: Calcium (Ca); Copper (Cu); Excitotoxicity; Ganglion cell layer (GCL); Inductively coupled plasma-mass spectrometry (ICP-MS); Iron (Fe); Magnesium (Mg); Magnesium acetyltaurate (MgAT); Manganese (Mn); Minerals; N-methyl-d-aspartate (NMDA); Potassium (K); Retina; Selenium (Se); Sodium (Na); Trace elements; Zinc (Zn)