title: Degeneration of dopaminergic neurons induced by thrombin injection in the substantia nigra of the rat is enhanced by dexamethasone: role of monoamine oxidase enzyme.
abstract: Anti-inflammatory strategies receive growing attention for their potential to prevent pathological deterioration in disorders such as Parkinson's disease, which is accompanied by inflammatory reactions that might play a critical role in the degeneration of nigral dopaminergic neurons. We investigated the influence of dexamethasone - a potent synthetic member of the glucocorticoids class of steroid hormones that acts as an anti-inflammatory - on the degeneration of the dopaminergic neurons of rats observed after intranigral injection of thrombin, a serine protease that induces inflammation through microglia proliferation and activation. We evaluated tyrosine hydroxylase (TH)-positive neurons as well as astroglial and microglial populations; dexamethasone prevented the loss of astrocytes but was unable to stop microglial proliferation induced by thrombin. Moreover, dexamethasone produced alterations in the levels of nexin and the thrombin receptor PAR-1, and facilitated accumulation of alpha-synuclein induced by thrombin in dopaminergic neurons. Dexamethasone increased oxidative stress and expression of monoamine oxidase A and B, along with changes on different MAP kinases related to degenerative processes, resulting in a bigger loss of dopaminergic neurons after intranigral injection of thrombin in dexamethasone-treated animals. It is interesting to ascertain that inhibition of monoamine oxidase by tranylcypromine prevented neurodegeneration of dopaminergic neurons, thus suggesting that the deleterious effects of dexamethasone might be mediated by monoamine oxidase.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Sandro
authors.initials: S
authors.lastname: Argüelles
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Herrera
authors.forename: Eloisa
authors.initials: E
authors.lastname: Carreño-Müller
authors.forename: Rocío M
authors.initials: RM
authors.lastname: de Pablos
authors.forename: Ruth F
authors.initials: RF
authors.lastname: Villarán
authors.forename: Ana M
authors.initials: AM
authors.lastname: Espinosa-Oliva
authors.forename: Alberto
authors.initials: A
authors.lastname: Machado
authors.forename: Josefina
authors.initials: J
authors.lastname: Cano
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D005904:Glial Fibrillary Acidic Protein; D005938:Glucocorticoids / Q000494:pharmacology*; D006649:Histocompatibility Antigens / Q000378:metabolism; D006834:Hydrazines / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced*; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018179:Receptors, Thrombin / Q000378:metabolism; D013053:Spectrophotometry / Q000379:methods; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects*; D013449:Sulfonamides / Q000378:metabolism; D013917:Thrombin; D013997:Time Factors; D014191:Tranylcypromine / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D005938:Glucocorticoids; D006649:Histocompatibility Antigens; D006834:Hydrazines; D008996:Monoamine Oxidase Inhibitors; D018179:Receptors, Thrombin; D013449:Sulfonamides; D051844:alpha-Synuclein; C446799:dinitrophenylhydrazine; D014191:Tranylcypromine; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; D051058:Oncogene Protein v-akt; D013917:Thrombin; C012655:nimesulide