Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-alpha.

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