Experimental Disease Models 608331 Neurotoxin models

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Several neurotoxins have been used to produce selective dopaminergic neuron loss to model sporadic disease, and, in some species, e.g., the nonhuman primate, parkinsonism-like symptoms are evident following exposures.67 The three major toxins used to lesion the brain are 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP: 52), 6-hydroxydop-amine (6-OHDA: 53), and rotenone 54. Unilateral lesion of the substantia nigra, medial forebrain bundle, or striatum with 6-OHDA produces dopaminergic neuron loss, albeit at different rates, leading to a 'hemiparkinson' model where the injected side of the brain exhibits degeneration. Administration of DA agonists like apomorphine or the stimulant amphetamine elicits rotation or circling toward the contralateral side in animals, unmasking the DA loss. Although 6-OHDA causes dopaminergic neuron loss, other neurons affected in PD (e.g., lower brainstem nuclei and locus coeruleus) are unaffected and Lewy bodies do not occur.

The MPTP model of PD is based on the idiopathic parkinsonism seen in individuals abusing synthetic heroin contaminated with MPTP. MPTP is converted by glial cells to a toxic metabolite methylpyridium (MPP + ), a complex I inhibitor, which selectively affects DA neurons as it is a ligand for DAT. MPTP neurotoxicity varies across species (the rat is not susceptible), with mouse, particularly the C57Bl6 strain, and nonhuman primates being the most extensively studied. Both acute and chronic administration of MPTP is used to model PD and to evaluate NCEs. In acute models, a high dose of MPTP causes a rapid degenerative response while in chronic models multiple applications of low doses of MPTP cause a more protracted degenerative response, more closely resembling human PD progression. Shortcomings of the MPTP model include the lack of Lewy body formation (although cytoplasmic inclusions occur) and the lack of degeneration in other monoaminergic structures (e.g., the locus coeruleus) that are also affected in PD.

Based on epidemiological studies, rotenone, a naturally occurring complex ketone and high-affinity inhibitor of complex I used as a herbicide, has been used to develop a model of PD. Systemic administration of rotenone to rats results in a selective loss of dopaminergic neurons, despite widespread depression of complex I activity throughout the brain, suggesting that dopaminergic neurons are uniquely susceptible to this toxin. Like other PD toxin models, the rotenone model displays PD-like behavioral disturbances, including postural instability, gait unsteadiness, and paw tremor. However, unlike other models, the neuropathology of PD is closely mimicked, e.g., a-synuclein and ubiquitin-containing inclusions develop with ultrastructural similarities in fibril formation to those of Lewy bodies. Microglial activation also occurs prior to overt dopaminergic neurodegeneration. The enhanced toxicity of rotenone may be associated with an inflammatory response and to NADPH oxidase-derived O2 release from microglial cells.

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