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Published on: January 30, 2014
Inhibition of microglial and astrocytic inflammatory responses by the immunosuppressant mycophenolate mofetil
F Dehghani1, M Sayan, A Conrad
1Dr. Senckenbergische Anatomie, Institute of Anatomy 2, Goethe-University, Frankfurt am Main, Germany. faramarz.dehghani@medizin.uni-leipzig.de
Aims:
Nucleotide depletion induced by the immunosuppressant mycophenolate mofetil (MMF) has been shown to exert neuroprotective effects. It remains unclear whether nucleotide depletion directly counteracts neuronal demise or whether it inhibits microglial or astrocytic activation, thereby resulting in indirect neuroprotection.
Methods:
Effects of MMF on isolated microglial cells, astrocyte/microglial cell co-cultures and isolated hippocampal neurones were analysed by immunocytochemistry, quantitative morphometry, and elisa.
Results:
We found that: (i) MMF suppressed lipopolysaccharide-induced microglial secretion of interleukin-1β, tumour necrosis factor-α and nitric oxide; (ii) MMF suppressed lipopolysaccharide-induced astrocytic production of tumour necrosis factor-α but not of nitric oxide; (iii) MMF strongly inhibited proliferation of both microglial cells and astrocytes; (iv) MMF did not protect isolated hippocampal neurones from excitotoxic injury; and (v) effects of MMF on glial cells were reversed after treatment with guanosine.
Conclusions:
Nucleotide depletion induced by MMF inhibits microglial and astrocytic activation. Microglial and astrocytic proliferation is suppressed by MMF-induced inhibition of the salvage pathway enzyme inosine monophosphate dehydrogenase. The previously observed neuroprotection after MMF treatment seems to be indirectly mediated, making this compound an interesting immunosuppressant in the treatment of acute central nervous system lesions.
Insights
Mycophenolate mofetil (MMF) suppresses microglial and astrocytic activation, indicating indirect neuroprotection. This immunosuppressant
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Mycophenolate mofetil (MMF) is an immunosuppressant known to induce nucleotide depletion.
- Previous studies suggest MMF exerts neuroprotective effects, but the mechanism remains unclear.
- It is uncertain whether MMF's neuroprotection is direct or indirect via glial cell modulation.
Purpose of the Study:
- To investigate the direct effects of MMF on neuronal survival.
- To determine if MMF modulates microglial and astrocytic activation.
- To elucidate the indirect mechanisms underlying MMF's neuroprotective potential.
Main Methods:
- Analysis of MMF effects on isolated microglial cells, astrocyte/microglial co-cultures, and hippocampal neurons.
- Utilized immunocytochemistry, quantitative morphometry, and ELISA for analysis.
- Assessed MMF's impact on lipopolysaccharide-induced inflammatory responses.
Main Results:
- MMF inhibited lipopolysaccharide-induced secretion of inflammatory mediators (IL-1β, TNF-α, NO) by microglia.
- MMF suppressed astrocytic TNF-α production but not nitric oxide.
- MMF significantly inhibited both microglial and astrocyte proliferation.
- MMF did not protect isolated neurons from excitotoxic injury.
- Guano sine treatment reversed MMF's effects on glial cells.
Conclusions:
- Nucleotide depletion by MMF inhibits microglial and astrocytic activation and proliferation.
- MMF's immunosuppressive action is mediated by inhibiting inosine monophosphate dehydrogenase.
- Observed neuroprotection is likely indirect, stemming from glial cell modulation.
- MMF is a potential immunosuppressant for treating acute CNS lesions.
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