Neuron Glia Biology

Minocycline attenuates nitric oxide-mediated neuronal and axonal destruction in vitro

a1 Centre for Brain Repair and Dept of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 2PY, UK
a2 Dept of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive West, Madison, WI 53706, USA

Article author query
wilkins a   [PubMed][Google Scholar] 
nikodemova m   [PubMed][Google Scholar] 
compston a   [PubMed][Google Scholar] 
duncan i   [PubMed][Google Scholar] 


Minocycline, a tetracycline derivative with pleiotropic biological effects, exhibits anti-inflammatory properties in several models of CNS disease. In addition to reducing production of inflammatory mediators, it has been postulated that minocycline might also be directly neuroprotective under these circumstances. Therefore, we investigated the effect of minocycline on primary cortical neuronal cultures exposed to a nitric oxide (NO)-donor. Cultures were assessed for neuronal survival, axon survival and markers of intracellular signaling pathways. The NO donor significantly increased neuronal death and minocycline was protective under these conditions. Furthermore NO-induced reductions in axonal length were significantly attenuated by minocycline. Improvements in axonal length were dependent on mitogen-activated protein kinase (MAP kinase)/extracellular signal-related kinase (Erk) signaling, whereas phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signaling was important in neuronal survival. Further investigation into MAP kinase signaling pathways revealed inhibition of p38 MAP kinase and c-jun N-terminal kinase (JNK) signaling by minocycline. JNK pathways were activated by trophic factor-withdrawal and minocycline attenuated neuronal death induced by trophic withdrawal. These results indicate that, in addition to anti-inflammatory properties, minocycline has direct protective effects on neurons and provides further evidence for its use in disorders of the CNS.

Key Words: neuroprotection; axon; MAP kinase; nitric oxide.

c1 Alastair Wilkins, Dept of Clinical Neurosciences and Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 2PY, UK. phone: +44 1223 331186; fax: +44 1223 331174. email: