Journal
JOURNAL OF NEUROIMMUNE PHARMACOLOGY
Volume 16, Issue 2, Pages 390-402Publisher
SPRINGER
DOI: 10.1007/s11481-020-09925-8
Keywords
Neuroinflammation; Microgliosis; Phagocytosis; Parkinson's disease; Neurodegeneration
Categories
Funding
- Federacion Espanola de Parkinson
- Spanish Ministry of Science and Innovation [FIS PI13 01293]
- Fundacion Seneca [19540/PI/14]
- Bahia State Research Foundation (FAPESB) [RED0016/2013]
- National Council for Scientific and Technological Development (CNPq) [443723/2014-1]
- Coordination for the Improvement of Higher Education Personnel (CAPES) [DSE BEX 8332/13-4, 0001]
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Inflammation is a key factor in neurodegenerative diseases like Parkinson's disease, and sustained neuroinflammation can exacerbate nigrostriatal degeneration. The study showed that a combination treatment of MMPs inhibitor (1-DNJ) and anti-inflammatory drug (ibuprofen) prevented neuronal loss, reduced microglial activation, and improved behavioral changes in MPTP-treated mice compared to single treatments with 1-DNJ or ibuprofen.
Inflammation is a predominant aspect of neurodegenerative diseases and experimental studies performed in animal models of Parkinson's disease (PD) suggesting that a sustained neuroinflammation exacerbates the nigrostriatal degeneration pathway. The central role of microglia in neuroinflammation has been studied as a target for potential neuroprotective drugs for PD, for example nonsteroidal anti-inflammatory drugs (NSAIDs) and matrix metalloproteinases (MMP) inhibitors that regulates microglial activation and migration. The aim of this study was to investigate the neuroprotective response of the iminosugar 1-deoxynojirimycin (1-DNJ) and compare its effect with a combined treatment with ibuprofen. MPTP-treated mice were orally dosed with ibuprofen and/or 1-DNJ 1. Open-field test was used to evaluate behavioral changes. Immunohistochemistry for dopaminergic neurons marker (TH+) and microglia markers (Iba-1(+); CD68(+)) were used to investigate neuronal integrity and microglial activation in the substantia nigra pars compacta (SNpc). The pro-inflammatory cytokines TNF-alpha and IL-6 were analysed by qPCR. Treatments with either 1-DNJ or Ibuprofen alone did not reduce the damage induced by MPTP intoxication. However, combined treatment with 1-DNJ and ibuprofen prevents loss of mesencephalic dopaminergic neurons, decreases the number of CD68(+)/ Iba-1(+)cells, the microglia/neurons interactions, and the pro-inflammatory cytokines, and improves behavioral changes when compared with MPTP-treated animals. In conclusion, these data demonstrate that the combined treatment with a MMPs inhibitor (1-DNJ) plus an anti-inflammatory drug (ibuprofen) has neuroprotective effects open for future therapeutic interventions.
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