JPP 2009, 61: 1563–1569 ß 2009 The Authors Received July 8, 2009 Accepted August 18, 2009 DOI 10.1211/jpp/61.11.0017 ISSN 0022-3573 Correspondence: Han-Jung Chae, Department of Pharmacology, Medical School, Chonbuk University and Research Center for Pulmonary Disorders, Chonbuk Hospital, Jeonju, Chonbuk, Republic of Korea. E-mail: hjchae@chonbuk.ac.kr Han-Jung Chae and Hyung-Ryong Kim contributed equally to this work. Short Communication Protective effects of sodium para-amino salicylate on manganese-induced neuronal death: the involvement of reactive oxygen species Hyonok Yoon a , Do-Sung Kim a , Geum-Hwa Lee a , Ji Ye Kim b , Diana H. Kim f , Kee-Won Kim a , Soo-Wan Chae a , Wan-Hee You c,d , Yong Chul Lee c,d , Seoung Ju Park c,d , Hyung-Ryong Kim e and Han-Jung Chae a,d a Department of Pharmacology, School of Medicine, Chonbuk National University, Jeonju, Chonbuk, b School of Medicine, Yonsei University, Seoul, c Department of Internal Medicine, Medical School, Chonbuk University, Jeonju, d Research Center for Pulmonary Disorders, Chonbuk Hospital, Jeonju, e Department of Dental Pharmacology, School of Dentistry, Wonkwang University, Iksan, Chonbuk, Republic of Korea and f College of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA Abstract Objectives This study tested whether sodium para-amino salicylic dihydrate, an antibacterial drug for tuberculosis, could block manganese-induced apoptosis in SK-N-MC neurons. Methods Cell viability, Hoechst staining, dichlorofluorescin diacetate analysis for reactive oxygen species measurement, and immunoblotting were performed. Key findings In vitro, manganese chloride significantly decreased the viability of SK- N-MC cells, accompanied by apoptotic features such as changes in nuclear morphology. Sodium para-amino salicylic dihydrate inhibited these apoptotic characteristics through reducing intracellular reactive oxygen species generation, protecting mitochondrial membrane potential and caspase-3 activation. Conclusions Sodium para-amino salicylic dihydrate inhibits manganese-induced apop- tosis in neurons and may reduce manganese-mediated neurodegeneration. Keywords apoptosis; manganese; manganism; PAS-Na; ROS Introduction The neurometabolism of heavy metals has received very little attention from neuroscientists until the last decade, but there is a direct relationship between heavy metal neurometabolism and neurodegenerative diseases. Environmental heavy metals, including manganese (Mn), may cause neuronal degeneration. [1–3] Mn is an abundant, naturally occurring element in the Earth’s crust, most frequently found in the form of oxides, carbonates and silicates. [4] Mn exposure represents a significant public health concern because of its use as a catalyst in countless industrial processes and its presence in gasoline additives and in fungicides. [5,6] Excessive exposure to Mn is an important occupational hazard, and inhalation of particulate Mn compounds is associated with the deposition of Mn within the striatum and cerebellum. [7] Occupational exposure to Mn for periods from 6 months to 2 years can cause an extrapyramidal syndrome, referred to as manganism, closely resembling Parkinson’s disease (PD) at both the molecular and clinical levels. [8–9] PD risk is also increased with exposure to industrial emissions of Mn and Mn-containing compounds such as fuel additives. [10] Therefore, exposure to ambient Mn may accelerate the incidence of PD. [10] Mn in the brain is normally deposited in degenerative lesions of the globus pallidus, subthalamic nucleus, caudate nucleus and putamen, [11] but is sometimes deposited in lesions of the substantia nigra, the primary degenerative structure in PD. [12] Non-steroidal anti-inflammatory drugs, including analogues of salicylates, may have neuroprotective benefits, because inflammatory processes play a role in the pathogenesis of neurodegenerative diseases. [13,14] Interestingly, sodium para-amino salicylic dihydrate (PAS-Na) improved Mn-induced PD in several cases. [15,16] However, the mechanism 1563