Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: Role of tumor necrosis factor-α

Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA.
Journal of Neurochemistry (Impact Factor: 4.24). 03/2006; 96(3):706-18. DOI: 10.1111/j.1471-4159.2005.03566.x
Source: PubMed

ABSTRACT Activated microglia are implicated in the pathogenesis of disease-, trauma- and toxicant-induced damage to the CNS, and strategies to modulate microglial activation are gaining impetus. A novel action of the tetracycline derivative minocycline is the ability to inhibit inflammation and free radical formation, factors that influence microglial activation. Minocycline is therefore being tested as a neuroprotective agent to alleviate CNS damage, although findings so far have yielded mixed results. Here, we showed that administration of a single low dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine (METH), a paradigm that causes selective degeneration of striatal dopaminergic nerve terminals without affecting the cell body in substantia nigra, increased the expression of mRNAs encoding microglia-associated factors F4/80, interleukin (IL)-1alpha, IL-6, monocyte chemoattractant protein-1 (MCP-1, CCL2) and tumor necrosis factor (TNF)-alpha. Minocycline treatment attenuated MPTP- or METH-mediated microglial activation, but failed to afford neuroprotection. Lack of neuroprotection was shown to be due to the inability of minocycline to abolish the induction of TNF-alpha and its receptors, thereby failing to modulate TNF signaling. Thus, TNF-alpha appeared to be an obligatory component of dopaminergic neurotoxicity. To address this possibility, we examined the effects of MPTP or METH in mice lacking genes encoding IL-6, CCL2 or TNF receptor (TNFR)1/2. Deficiency of either IL-6 or CCL2 did not alter MPTP neurotoxicity. However, deficiency of both TNFRs protected against the dopaminergic neurotoxicity of MPTP. Taken together, our findings suggest that attenuation of microglial activation is insufficient to modulate neurotoxicity as transient activation of microglia may suffice to initiate neurodegeneration. These findings support the hypothesis that TNF-alpha may play a role in the selective vulnerability of the nigrostriatal pathway associated with dopaminergic neurotoxicity and perhaps Parkinson's disease.

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Available from: Diane Miller, Oct 08, 2014
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    • "The legend for the different cell types and phenotypes is provided at the bottom. provided contrasting, model-dependent results, about the contribution of innate inflammation to the acute neurodegeneration of dopaminergic neurons in the SN (Sriram and others 2006; Wu and others 2002). Systemic inflammation , induced by administering IL-1β, was shown to impact the survival of dopaminergic neurons in the 6OHDA model, providing clear evidence of the influence of immune-to-brain communication on the progression of PD (Pott Godoy and others 2008). "
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    • "[34] "
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