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

• Published in: European journal of pharmacology Vol. 803; pp. 148 - 158
• Main Authors: Chidambaram, Saravana Babu, Vijayan, Ranju, Sekar, Sathiya, Mani, Sugumar, Rajamani, Barathidsan, Ganapathy, Ramakrishnan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.05.2017
• Subjects: 3-Nitropropianic acid; Animals; BDNF; Behavior, Animal - drug effects; Benzamides - pharmacology; Bioenergetics; Brain-Derived Neurotrophic Factor - metabolism; Calcium-Binding Proteins - metabolism; Drug Synergism; Energy Metabolism - drug effects; Excitotoxicity; Gene Expression Regulation - drug effects; Glial Fibrillary Acidic Protein - metabolism; Huntington's disease; Male; Memantine - pharmacology; Mice; Mice, Inbred C57BL; Microfilament Proteins - metabolism; Neurons - drug effects; Neurons - immunology; Neurons - metabolism; Neurotoxins - antagonists & inhibitors; Neurotoxins - toxicity; Nitric Oxide - metabolism; Nitro Compounds - toxicity; NMDA receptors; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Propionates - toxicity; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; 3-Nitropropianic acid; Bioenergetics; Huntington's disease; NMDA receptors; BDNF; Excitotoxicity
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2017.03.023

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.