Progressive Dopamine Neuron Loss in Parkinson's Disease: The Multiple Hit Hypothesis

Abstract

Animal models have been an essential tool for researchers and clinicians in their efforts to study and treat Parkinson's disease (PD). Thus, the various ways 6-hydroxydopamine is employed, the use of MPTP in rodents and nonhuman primates, the prenatal exposure to bacterial endotoxin, the postnatal exposure to environmental toxins such as paraquat and rotenone, the assessment of dopamine (DA) neurons in genetic knockout mouse, and even the behavioral analysis of fruit flies and worms have added significantly to our knowledge base of PD-or have they? Are these animal models manifesting a true model of PD? Have the 7786 published studies (to date) on PD with animal models led to a clearer understanding of its etiology, treatment, or progression? In this review we critically assess this question. We begin with a succinct history of the major contributions, which have led to the current animal models of PD. We then evaluate the primary issue of the progressive loss of DA neurons, which, except for a few studies, has not been addressed in animal models of PD, even though this is the major pathological characteristic of the disease. Lastly, we discuss the possibility that more than one risk factor for PD may be necessary to develop an animal model that shows synergy-the progressive loss of DA neurons. Thus, the multiple hit hypothesis of PD-that is, the effect of more then one risk factor-may be the start of new era in animal models of PD that is one step closer to mimicking the pathology of PD in humans. Key words: Parkinson's disease Dopamine neurons Progression Multiple hit hypothesis PARKINSON'S DISEASEwith an estimated 50-60% loss of DA neurons in the substantia nigra pars compacta (SNpc) (2,26,81). Idiopathic PD generally develops after the age of 60. HowJames Parkinson first systematically described the symptoms of Parkinson's disease (PD) in the early ever, patients younger than 40 years of age have been identified, and many have been shown to have one of 1800s, which he labeled the "shaking palsy." The cardinal features of PD are tremor, rigidity, brady-/akinesis, several genetic mutations, suggesting that early onset PD may be familial (18,41,69,88). PD is a progressive and postural instability. Approximately 40,000 people in the US are diagnosed with PD every day, and over 1 neurodegenerative disease. When first diagnosed, most patients exhibit mild unilateral symptoms that inexoramillion Americans have this disease. The daily cost is estimated at $66 million, including direct and indirect bly progress to bilateral debilitating signs and symptoms that require full-time nursing care in late-stage disease. costs such as the inability to work and medical/longterm care (75). PD is the second most prevalent neuroTo date there is no proven strategy to stop or slow the progression of PD. However, significant advancements degenerative disease next to Alzheimer's disease. No cure currently exists.in alleviating the symptoms of PD using drug therapy and surgical procedures have evolved. The most widely The symptoms of...

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