Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

Abstract

Parkinson's disease (PD) is an age‐related neurodegenerative disorder characterized by motor symptoms such as tremor, slowness of movement, rigidity, and postural instability, as well as non‐motor features like sleep disturbances, loss of ability to smell, depression, constipation, and pain. Motor symptoms are caused by depletion of dopamine in the striatum due to the progressive loss of dopamine neurons in the substantia nigra pars compacta. Approximately 10% of PD cases are familial arising from genetic mutations in α‐synuclein, LRRK2, DJ‐1, PINK1, parkin, and several other proteins. The majority of PD cases are, however, idiopathic, i.e., having no clear etiology. PD is characterized by progressive accumulation of insoluble inclusions, known as Lewy bodies, mostly composed of α‐synuclein and membrane components. The cause of PD is currently attributed to cellular proteostasis deregulation and mitochondrial dysfunction, which are likely interdependent. In addition, neuroinflammation is present in brains of PD patients, but whether it is the cause or consequence of neurodegeneration remains to be studied. Rodents do not develop PD or PD‐like motor symptoms spontaneously; however, neurotoxins, genetic mutations, viral vector‐mediated transgene expression and, recently, injections of misfolded α‐synuclein have been successfully utilized to model certain aspects of the disease. Here, we critically review the advantages and drawbacks of rodent PD models and discuss approaches to advance pre‐clinical PD research towards successful disease‐modifying therapy. © 2020 The Authors.

Neuroprotective Effects of Methyl Caffeate against Hydrogen Peroxide-Induced Cell Damage: Involvement of Caspase 3 and Cathepsin D Inhibition

“…An additional new finding from the present study is the observation that MC attenuated, though to a smaller extent and in the RA-SH-SY5Y cells only, the cell damage induced by 6-OHDA, the neurotoxin widely used in animal models of Parkinson’s disease [ 58 ]. This effect was connected with inhibition of apoptotic and necrotic processes induced by 6-OHDA which is in line with our finding from the model of H 2 O 2 -induced cell damage.…”

Application of In Vitro Metabolism Activation in High-Throughput Screening

“…Compounds which have been classified as neurotoxic agents damage the brain or peripheral nervous system. They can induce neurological diseases, including attention-deficit hyperactivity disorder (ADHD), autism, Alzheimer's disease, and Parkinson's disease [98][99][100]. A reliable method to test compounds for neurotoxic characteristics is to perform HCS checking cell morphology, or neurite outgrowth [4,101,102].…”

Molecular Regulatory Mechanism and Toxicology of Neurodegenerative Processes in MPTP/Probenecid-Induced Progressive Parkinson’s Disease Mice Model Revealed by Transcriptome

“…The MPTP/p-induced PD mice showed dopaminergic neurons losing in substantia nigra, lacking typical clinical symptoms consistent with PD patients [ 31 , 32 ], such as stiffness, tremor, and gait. Our results were also consistent with this argument on the whole.…”