title: Chelation therapy of manganese intoxication with para-aminosalicylic acid (PAS) in Sprague-Dawley rats.
abstract: Para-aminosalicylic acid (PAS), an FDA-approved anti-tuberculosis drug, has been used successfully in the treatment of severe manganese (Mn)-induced Parkinsonism in humans [Jiang Y-M, Mo X-A, Du FQ, Fu X, Zhu X-Y, Gao H-Y, et al. Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study. J Occup Environ Med 2006;48:644-9]. This study was conducted to explore the capability of PAS in reducing Mn concentrations in body fluids and tissues of Mn-exposed animals. Sprague-Dawley rats received daily intraperitoneally (i.p.) injections of 6mg Mn/kg, 5 days/week for 4 weeks, followed by a daily subcutaneously (s.c.) dose of PAS (100 and 200mg/kg as the PAS-L and PAS-H group, respectively) for another 2, 3 or 6 weeks. Mn exposure significantly increased the concentrations of Mn in plasma, red blood cells (RBC), cerebrospinal fluid (CSF), brain and soft tissues. Following PAS-H treatment for 3 weeks, Mn levels in liver, heart, spleen and pancreas were significantly reduced by 25-33%, while 3 weeks of PAS-L treatment did not show any effect. Further therapy with PAS-H for 6 weeks reduced Mn levels in striatum, thalamus, choroid plexus, hippocampus and frontal cortex by 16-29% (p<0.05). Mn exposure greatly increased iron (Fe) and copper (Cu) concentrations in CSF, brain and liver. Treatment with PAS-H restored Fe and Cu levels comparable with control. These data suggest that PAS likely acts as a chelating agent to mobilize and remove tissue Mn. A high-dose and prolonged PAS treatment appears necessary for its therapeutic effectiveness.
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA. wzheng@purdue.edu
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Jiang
authors.forename: Yanshu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wendy
authors.initials: W
authors.lastname: Jiang
authors.forename: Xueqian
authors.initials: X
authors.lastname: Wang
authors.forename: Dallas M
authors.initials: DM
authors.lastname: Cowan
mesh_terms: D010131:Aminosalicylic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D015913:Chelation Therapy / Q000379:methods*; D008297:Male; D008345:Manganese / Q000378:metabolism / Q000633:toxicity*; D020149:Manganese Poisoning / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D008345:Manganese; D010131:Aminosalicylic Acid