Abstract
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-α 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.
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a protoxicant that, after crossing the Blood Brain Barrier, is metabolized by astrocytic MAO-B to MPDP+, a pyridinium intermediate, which undergoes further two-electron oxidation to yield the toxic metabolite MPP+ (methyl-phenyltetrahydropyridinium) that is then selectively transported into nigral neurons via the mesencephalic dopamine transporter. In this study, we demonstrated that MPTP induced death of dopaminergic neurons, microgliosis, increase of gliapses, motor impairment and neuroinflammation in mice, which were inhibited by combined 1-deoxynojirimycin and ibuprofen treatment.
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Abbreviations
- PD:
-
Parkinson’Disease
- 1-DNJ:
-
1-deoxynojirimycin
- Actb:
-
Actin beta
- ANOVA:
-
One-or Two-way analysis of variance
- ARG:
-
Arginase
- B-B:
-
Contact between a microglial cell body and a dopaminergic neuron cell body
- B-Pr:
-
Contact between a microglial cell body and a dopaminergic process
- CD68+ :
-
Cluster of Differentiation 68
- CNS:
-
Central nervous system
- DAPI:
-
4′,6 diamino-2-phenylindole
- DNA:
-
Deoxyribonucleic acid
- EGF:
-
Growth factor
- Fc:
-
Fragment crystallizable
- H2O2 :
-
Hydrogen peroxide
- HPRT1:
-
Hypoxanthine Phosphoribosyl Transferase 2
- Iba-1:
-
Ionized calcium binding adaptor molecule 1
- IBU:
-
Ibuprofen
- IL10:
-
Interleukin 10
- IL-1β:
-
Interleukin-1-beta
- IL6:
-
Interleukin 6
- MMP:
-
Matrix metalloproteinases
- MMPs:
-
Matrix Metalloproteinases
- MPTP:
-
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- mRNA:
-
Messenger ribonucleic acid
- NSAIDs:
-
Nonsteriodal anti-inflammatory drugs
- PBS:
-
Phosphate buffered saline
- PFA:
-
Paraformaldehyd
- Pr-B:
-
Contact between a microglial process and a dopaminergic neuron cell body
- Pr-Pr:
-
Contact between a microglial process and a dopaminergic process
- qPCR:
-
Polymerase chain reaction quantitative real time
- RNA:
-
Ribonucleic acid
- SNpc:
-
Substantia nigra pars compacta
- SNpc:
-
Substantia nigra pars compacta
- TH:
-
Tyrosine Hydroxylase
- TNF-α:
-
Tumor necrosis factor alpha
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Acknowledgements and Funding
This research was supported by a grant from the Federación Española de Parkinson, the Spanish Ministry of Science and Innovation (FIS PI13 01293), the Fundación Séneca (19540/PI/14) to MTH; Bahia State Research Foundation (FAPESB, Call 011/2013 - Support for Network Research Projects, Project RED0016/2013), and the National Council for Scientific and Technological Development (CNPq, Call MCTI//Universal 14/2014, Process 443723/2014-1, and SLC Reseach Fellowship by Research Productivity) to SLC. We also Thanks to Coordination for the Improvement of Higher Education Personnel for PhD fellowships to TCC (CAPES, Process DSE BEX 8332/13-4 and process 0001).
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Costa, T., Fernandez-Villalba, E., Izura, V. et al. Combined 1-Deoxynojirimycin and Ibuprofen Treatment Decreases Microglial Activation, Phagocytosis and Dopaminergic Degeneration in MPTP-Treated Mice. J Neuroimmune Pharmacol 16, 390–402 (2021). https://doi.org/10.1007/s11481-020-09925-8
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DOI: https://doi.org/10.1007/s11481-020-09925-8