期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 803, 期 -, 页码 148-158出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2017.03.023
关键词
3-Nitropropianic acid; Huntington's disease; Excitotoxicity; NMDA receptors; Bioenergetics; BDNF
资金
- Drugs and Pharmaceutical Research Programme (DPRP), Department of Science & Technology, Govt. of India
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 NAV(+;) and increases TNF alpha, 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-alpha 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.
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