Inhibition of microglial and astrocytic inflammatory responses by the immunosuppressant mycophenolate mofetil
2010 (English)In: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 36, no 7, 598-611 p.Article in journal (Refereed) Published
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-1 beta, tumour necrosis factor-alpha and nitric oxide; (ii) MMF suppressed lipopolysaccharide-induced astrocytic production of tumour necrosis factor-alpha 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.
Place, publisher, year, edition, pages
2010. Vol. 36, no 7, 598-611 p.
astrocytes, inflammation, microglia, mycophenolate mofetil, nitric oxide, proinflammatory cytokines
Medical and Health Sciences Surgery
Research subject Orthopaedics
IdentifiersURN: urn:nbn:se:uu:diva-139258DOI: 10.1111/j.1365-2990.2010.01104.xISI: 000284073000002OAI: oai:DiVA.org:uu-139258DiVA: diva2:380941