title: Neuroprotective properties of mildronate, a small molecule, in a rat model of Parkinson's disease.
abstract: Previously, we have found that mildronate [3-(2,2,2-trimethylhydrazinium) propionate dihydrate], a small molecule with charged nitrogen and oxygen atoms, protects mitochondrial metabolism that is altered by inhibitors of complex I and has neuroprotective effects in an azidothymidine-neurotoxicity mouse model. In the present study, we investigated the effects of mildronate in a rat model of Parkinson's disease (PD) that was generated via a unilateral intrastriatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA). We assessed the expression of cell biomarkers that are involved in signaling cascades and provide neural and glial integration: the neuronal marker TH (tyrosine hydroxylase); ubiquitin (a regulatory peptide involved in the ubiquitin-proteasome degradation system); Notch-3 (a marker of progenitor cells); IBA-1 (a marker of microglial cells); glial fibrillary acidic protein, GFAP (a marker of astrocytes); and inducible nitric oxide synthase, iNOS (a marker of inflammation). The data show that in the 6-OHDA-lesioned striatum, mildronate completely prevented the loss of TH, stimulated Notch-3 expression and decreased the expression of ubiquitin, GFAP and iNOS. These results provide evidence for the ability of mildronate to control the expression of an array of cellular proteins and, thus, impart multi-faceted homeostatic mechanisms in neurons and glial cells in a rat model of PD. We suggest that the use of mildronate provides a protective effect during the early stages of PD that can delay or halt the progression of this neurodegenerative disease.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Latvia, Riga, Latvia.
authors.forename: Vija Z
authors.initials: VZ
authors.lastname: Klusa
authors.forename: Sergejs
authors.initials: S
authors.lastname: Isajevs
authors.forename: Darja
authors.initials: D
authors.lastname: Svirina
authors.forename: Jolanta
authors.initials: J
authors.lastname: Pupure
authors.forename: Ulrika
authors.initials: U
authors.lastname: Beitnere
authors.forename: Juris
authors.initials: J
authors.lastname: Rumaks
authors.forename: Simons
authors.initials: S
authors.lastname: Svirskis
authors.forename: Baiba
authors.initials: B
authors.lastname: Jansone
authors.forename: Zane
authors.initials: Z
authors.lastname: Dzirkale
authors.forename: Ruta
authors.initials: R
authors.lastname: Muceniece
authors.forename: Ivars
authors.initials: I
authors.lastname: Kalvinsh
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D008297:Male; D008763:Methylhydrazines / Q000494:pharmacology* / Q000627:therapeutic use; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: C100745:Aif1 protein, rat; D015415:Biomarkers; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008763:Methylhydrazines; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; C498556:Notch3 protein, rat; D000071656:Receptor, Notch3; D051880:Receptors, Notch; C050147:3-(2,2,2-trimethylhydrazine)propionate; D016627:Oxidopamine; D052247:Nitric Oxide Synthase Type II; D014446:Tyrosine 3-Monooxygenase