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: Wei Zheng, Yue-Ming Jiang, Yanshu Zhang, Wendy Jiang, Xueqian Wang, Dallas M Cowan
• Journal: Neurotoxicology (Neurotoxicology) Vol. 30 Issue 2 Pg. 240-8 (Mar 2009) ISSN: 1872-9711 [Electronic] Netherlands
• PMID: 19150464 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Manganese
• Aminosalicylic Acid

Topics

• Aminosalicylic Acid (pharmacology, therapeutic use)
• Animals
• Chelation Therapy (methods)
• Male
• Manganese (metabolism, toxicity)
• Manganese Poisoning (drug therapy, metabolism)
• Rats
• Rats, Sprague-Dawley
• Tissue Distribution (drug effects, physiology)