Simultaneous blockade of NMDA receptors and PARP-1 activity synergistically alleviate immunoexcitotoxicity and bioenergetics in 3-nitropropionic acid intoxicated mice: Evidences from memantine and 3-aminobenzamide interventions.
Interlink between excitotoxicity and cellular bioenergetics depletion is implicated as one of the central deteriorative pathways in many neurodegenerative diseases including Huntington's disease (HD). Chronic administration of 3-nitropropionic acid (3-NP) depletes ATP and NAD+;and increases TNFα, IL-6 and glutamate content resulting in "immunoexcitotoxicity". Present study was designed to determine whether the combination of memantine (MN) and 3-aminobenzamide (3-AB), PARP inhibitor, can ameliorate immunoexcitotoxicity and improve bioenergetics in a better manner than individual administration against 3-NP intoxication in mice. Animals were divided into eight groups (n =20/group) and allocated to different treatment protocols. 3-NP (10mg/kg, i.p.) was administered once in 4 days interval for a period of 28 days (total dose: 70mg/kg; in seven divided doses). Striatal succinate dehydrogenase (SDH), ATP and NAD levels (as bioenergetic markers); glutamate, microglial marker (IBA-1), astroglial marker (GFAP), cytokines (TNF-α and IL-6), and neurotrophin (BDNF) as immunoexcitotoxicity components were measured. Combination treatment (MN +3-AB) decreased brain glutamate, down-regulated IBA-1, up-regulated GFAP and BDNF expressions in 3-NP intoxicated mice. Further, combination (COM) treatment restored ATP/NAD and SDH activity, and also improved motor performance; and thus conferred a synergetic neuroprotection than individual treatments. To conclude, simultaneous blockade of NMDAr and suppression of PARP activity is necessary to ameliorate immunoexcitotoxicity and improve bioenergetics in 3-NP induced neurodegeneration. Treatment with MN+3-AB can be an efficient regimen in the symptomatic management of HD, at least partly.
Department of Pharmacology, J.S.S College of Pharmacy, Jagadguru Sri Shivarathreeswara University, S.S Nagar, Mysuru, 570015 KA, India. Electronic address: csaravanababu@gmail.com.
Saravana Babu
SB
Chidambaram
Department of Biotechnology, Dr. M.G.R. Educational and Research Institute University, Chennai 600095, TN, India.
Ranju
R
Vijayan
Department of Biotechnology, Dr. M.G.R. Educational and Research Institute University, Chennai 600095, TN, India.
Sathiya
S
Sekar
Research and Development Centre, Bharathiar University, Coimbatore 641046, India.
Sugumar
S
Mani
Central Inter - Disciplinary Research Facility, Sri Balaji Vidyapeeth University, Puducherry 605014, India.
Barathidsan
B
Rajamani
CEFT, Sri Ramachandra University, Chennai 116, TN, India.
Ramakrishnan
R
Ganapathy
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009569:Nitric Oxide / Q000378:metabolism; D009574:Nitro Compounds / Q000633:toxicity*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors*; D011422:Propionates / Q000633:toxicity*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
C491049:Aif1 protein, mouse; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D016194:Receptors, N-Methyl-D-Aspartate; C528900:glial fibrillary astrocytic protein, mouse; D009569:Nitric Oxide; C025160:3-aminobenzamide; D000071137:Poly (ADP-Ribose) Polymerase-1; C015392:3-nitropropionic acid; D008559:Memantine
3-Nitropropianic acid; BDNF; Bioenergetics; Excitotoxicity; Huntington's disease; NMDA receptors