title: Doxycycline restrains glia and confers neuroprotection in a 6-OHDA Parkinson model.
abstract: 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.
authors.affiliation: Department of Morphology, Physiology and Pathology, School of Odontology of Ribeirão Preto (FORP), University of São Paulo (USP), Ribeirão Preto, SP, Brazil.
authors.forename: Marcio
authors.initials: M
authors.lastname: Lazzarini
authors.forename: Sabine
authors.initials: S
authors.lastname: Martin
authors.forename: Mišo
authors.initials: M
authors.lastname: Mitkovski
authors.forename: Rita Raisman
authors.initials: RR
authors.lastname: Vozari
authors.forename: Walter
authors.initials: W
authors.lastname: Stühmer
authors.forename: Elaine Del
authors.initials: ED
authors.lastname: Bel
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004318:Doxycycline / Q000627:therapeutic use*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D005904:Glial Fibrillary Acidic Protein; D016177:Macrophage-1 Antigen; D018696:Neuroprotective Agents; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019278:Matrix Metalloproteinase 3; D004318:Doxycycline