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

    loading  Checking for direct PDF access through Ovid


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 (10 mg/kg, i.p.) was administered once in 4 days interval for a period of 28 days (total dose: 70 mg/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.

Related Topics

    loading  Loading Related Articles