Neuroprotective properties of mildronate, a mitochondria-targeted small molecule.
Mildronate, a representative of the aza-butyrobetaine class of drugs with proven cardioprotective efficacy, was recently found to prevent dysfunction of complex I in rat liver mitochondria. The present study demonstrates that mildronate also acts as a neuroprotective agent. In a mouse model of azidothymidine (anti-HIV drug) neurotoxicity, mildronate reduced the azidothymidine-induced alterations in mouse brain tissue: it normalized the increase in caspase-3, cellular apoptosis susceptibility protein (CAS) and iNOS expression assessed by quantitative and semi-quantitative analysis. Mildronate also normalized the changes in cytochrome c oxidase (COX) expression, reduced the expression of glial fibrillary acidic protein (GFAP) and cellular infiltration. The present results show that the neuroprotective action of mildronate results at least partially from anti-neurodegenerative (anti-apoptotic) and anti-inflammatory mechanisms. It might be suggested that the molecular conformation of mildronate can facilitate its easy binding to mitochondria, and regulate the expression of different signal molecules, hence maintaining cellular signaling and survival.
Pupure
Jolanta
J
Department of Pharmacology, Faculty of Medicine, University of Latvia, 1A Sarlotes, LV-1001, Riga, Latvia. pupure@e-apollo.lv
Isajevs
Sergejs
S
Skapare
Elina
E
Rumaks
Juris
J
Svirskis
Simons
S
Svirina
Darja
D
Kalvinsh
Ivars
I
Klusa
Vija
V
D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology*; D053148:Caspase 3 / Q000378:metabolism; D029563:Cellular Apoptosis Susceptibility Protein / Q000378:metabolism; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D008763:Methylhydrazines / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000503:physiopathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D015215:Zidovudine / Q000633:toxicity
D019380:Anti-HIV Agents; D029563:Cellular Apoptosis Susceptibility Protein; D005904:Glial Fibrillary Acidic Protein; D008763:Methylhydrazines; D018696:Neuroprotective Agents; D015215:Zidovudine; C050147:3-(2,2,2-trimethylhydrazine)propionate; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D003576:Electron Transport Complex IV; C505409:Casp3 protein, mouse; D053148:Caspase 3