Effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on methylmercury-induced locomotor deficits and cerebellar toxicity in mice.
Chelating therapy has been reported as a useful approach for counteracting mercurial toxicity. Moreover, 2,3-dimercapto-1-propanesulfonic acid (DMPS), a tissue-permeable metal chelator, was found to increase urinary mercury excretion and decrease mercury content in rat brain after methylmercury (MeHg) exposure. We evaluated the capability of DMPS to reduce MeHg-induced motor impairment and cerebellar toxicity in adult mice. Animals were exposed to MeHg (40 mg/L in drinking water, ad libitum) during 17 days. In the last 3 days of exposure (days 15-17), animals received DMPS injections (150 mg/kg, i.p.; once a day) in order to reverse MeHg-induced neurotoxicity. Twenty-four hours after the last injection (day 18), behavioral tests related to the motor function (open field and rotarod tasks) and biochemical analyses on oxidative stress-related parameters (cerebellar glutathione, protein thiol and malondyaldehyde levels, glutathione peroxidase and glutathione reductase activities) were carried out. Histological analyses for quantifying cellular damage and mercury deposition in the cerebellum were also performed. MeHg exposure induced a significant motor deficit, observed as decreased locomotor activity in the open field and decreased falling latency in the rotarod apparatus. DMPS treatment displayed an ameliorative effect toward such behavioral parameters. Cerebellar glutathione and protein thiol levels were not changed by MeHg or DMPS treatment. Conversely, the levels of cerebellar thiobarbituric acid reactive substances (TBARS), a marker for lipid peroxidation, were increased in MeHg-exposed mice and DMPS administration minimized such phenomenon. Cerebellar glutathione peroxidase activity was decreased in the MeHg-exposed animals, but DMPS treatment did not prevent such event. Histological analyses showed a reduced number of cerebellar Purkinje cells in MeHg-treated mice and this phenomenon was completely reversed by DMPS treatment. A marked mercury deposition in the cerebellar cortex was observed in MeHg-exposed animals (granular layer>Purkinje cells>molecular layer) and DMPS treatment displayed a significant ameliorative effect toward these phenomena. These findings indicate that DMPS displays beneficial effects on reversing MeHg-induced motor deficits and cerebellar damage in mice. Histological analyses indicate that these phenomena are related to its capability of removing mercury from cerebellar cortex.
Carvalho
Márcia C
MC
Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
Franco
Jeferson L
JL
Ghizoni
Heloisa
H
Kobus
Karoline
K
Nazari
Evelise M
EM
Rocha
João B T
JB
Nogueira
Cristina W
CW
Dafre
Alcir L
AL
Müller
Yara M R
YM
Farina
Marcelo
M
D000704:Analysis of Variance; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D002526:Cerebellar Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D008767:Methylmercury Compounds / Q000633:toxicity*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D019957:Motor Skills Disorders / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013438:Sulfhydryl Compounds / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors; D014494:Unithiol / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D000931:Antidotes; D008767:Methylmercury Compounds; D013438:Sulfhydryl Compounds; D017392:Thiobarbituric Acid Reactive Substances; D014494:Unithiol; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005978:Glutathione; C004925:methylmercuric chloride