Review article Potential neurotoxic ‘‘agents provocateurs’’ in Parkinson’s disease Michael A. Collins * , Edward J. Neafsey Department of Cell Biology, Neurobiology, and Anatomy, Division of Biochemistry, Loyola University School of Medicine, 2160 South First Avenue, Maywood, IL 60153, USA Received 16 January 2002; accepted 24 January 2002 Dedicated to Professor Toshiharu Nagatsu on the occasion of his 70th birthday Abstract Idiopathic Parkinson’s disease (PD), one of the most common neurodegenerative disorders associated with aging, is characterized neurochemically by abnormal and profound loss of nigrostriatal dopamine (DA) neurons. A prominent current view is that the excessive degeneration of the dopaminergic system is the outcome of extended insults by environmental neurotoxins or endogenous neurotoxic factors in genetically vulnerable or susceptible individuals. Recent insights into the identities and mechanisms of potential neurotoxic species, which span pesticides, environmental contaminants including heterocyclic amines with b-carboline (bC) and isoquinoline (IQ) structures, endogenous DA metabolites or intermediates, neuromelanin, metals, and infectious agents, are presented. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Parkinsonism; Pesticides; Dopamine; Carbolines; Isoquinolines 1. Introduction Considerable progress has been made toward identifying neurotoxic agents possibly associated with the etiology and/or progression of idiopathic, aging-related Parkinson’s disease (PD). The research that spurred this progress is both neurobiological and epidemiological. First and foremost, the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri- dine (MPTP) and its monoamine oxidase (MAO)-depend- ent activation to MPP + , a pyridinium cation with a predominantly mitochondrial-based toxic mechanism in the nigrostriatal neurons, greatly helped to focus attention on pesticides and contaminants in the environment that could chronically imitate this process and on underlying mitochondrial deficiencies or predisposition. The key research regarding MPTP is summarized in Speciale’s article (this issue). Second, epidemiological findings in the past decade have supported the view, perhaps to a greater extent than with other neurodegenerative disorders, that environmental fac- tors are at least as important as genetics in the etiology of late onset PD. Notably, an oft-cited large twin study con- cluded that heredity apparently does not have a major role in the etiology of typical disease, leaving nongenetic factors (e.g., pesticide exposure) as the primary antecedents [85]. Most recently, a study of 310 orchardists indicated that parkinsonism may be associated with long-term occu- pational exposure to pesticides [28]. A meta-analysis of peer-reviewed studies on PD in the past decade concluded that rural environments and pesticides constitute significant risk factors [70]. A number of potential agents emerge as candidate neuro- toxins, some with poorly understood preference for the nigrostriatal dopaminergic system (Table 1). Most attention has focused on exogenous (environmental) compounds or metals such as iron or manganese, either naturally present in or introduced into our environments, and these are initially discussed. Second, a substantial part of the repertoire is constituted by endogenous and primarily dopamine (DA)- derived molecules. In some cases, the above exogenous or endogenous factors require important metabolic steps for activation, brain accumulation, and selective uptake, e.g., oxidation (including nitrogen or sulfur), N-methylation (quaternization), and/or conjugation. Last, there is the 0892-0362/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII:S0892-0362(02)00210-6 * Corresponding author. Tel.: +1-708-216-4560; fax: +1-708-216-8523. E-mail address: mcollin@lumc.edu (M.A. Collins). www.elsevier.com/locate/neutera Neurotoxicology and Teratology 24 (2002) 571 – 577