Inhibition of microglial and astrocytic inflammatory responses by the immunosuppressant mycophenolate mofetil.
OBJECTIVE
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.
Dehghani
F
F
Dr. Senckenbergische Anatomie, Institute of Anatomy 2, Goethe-University, Frankfurt am Main, Germany. faramarz.dehghani@medizin.uni-leipzig.de
Sayan
M
M
Conrad
A
A
Evers
J
J
Ghadban
C
C
Blaheta
R
R
Korf
H-W
HW
Hailer
N P
NP
D000818:Animals; D000893:Anti-Inflammatory Agents; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D006151:Guanosine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000502:physiology*; D018613:Microscopy, Confocal; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D006151:Guanosine; D009569:Nitric Oxide; D009173:Mycophenolic Acid