Doxycycline restrains glia and confers neuroprotection in a 6‐OHDA Parkinson model

GLIA - Tập 61 Số 7 - Trang 1084-1100 - 2013
Márcio Lazzarini1,2, Sabine Martin3,4, Mišo Mitkovski3,5, Rita Raisman Vozari6, Walter Stühmer3,4, Elaine Aparecida Del Bel1,2
1Department of Morphology, Physiology and Pathology School of Odontology of Ribeirão Preto (FORP) University of São Paulo (USP) Ribeirão Preto SP Brazil
2Department of Neurology, Medical School FMRP University of São Paulo (USP) Ribeirão Preto SP Brazil
3Cluster of Excellence “Center Nanoscale Microscopy and Molecular Physiology of the Brain” (CNMPB) Göttingen Germany
4Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Göttingen, Germany
5Light Microscopy Facility Max Planck Institute of Experimental Medicine Göttingen Germany
6INSERM UMR 975 – CNRS UMR 7225 Université Pierre et Marie Curie CRICM6 ICM Thérapeutique Expérimentale de la Neurodégénérescence Paris France

Tóm tắt

Neuron–glia interactions play a key role in maintaining and regulating the central nervous system. Glial cells are implicated in the function of dopamine neurons and regulate their survival and resistance to injury. Parkinson's disease is characterized by the loss of dopamine neurons in the substantia nigra pars compacta, decreased striatal dopamine levels and consequent onset of extrapyramidal motor dysfunction. Parkinson's disease is a common chronic, neurodegenerative disorder with no effective protective treatment. In the 6‐OHDA mouse model of Parkinson's disease, doxycycline administered at a dose that both induces/represses conditional transgene expression in the tetracycline system, mitigates the loss of dopaminergic neurons in the substantia nigra compacta and nerve terminals in the striatum. This protective effect was associated with: (1) a reduction of microglia in normal mice as a result of doxycycline administration per se; (2) a decrease in the astrocyte and microglia response to the neurotoxin 6‐OHDA in the globus pallidus and substantia nigra compacta, and (3) the astrocyte reaction in the striatum. Our results suggest that doxycycline blocks 6‐OHDA neurotoxicity in vivo by inhibiting microglial and astrocyte expression. This action of doxycycline in nigrostriatal dopaminergic neuron protection is consistent with a role of glial cells in Parkinson's disease neurodegeneration. The neuroprotective effect of doxycycline may be useful in preventing or slowing the progression of Parkinson's disease and other neurodegenerative diseases linked to glia function.

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