Commentary: A Humanized Clinically Calibrated Quantitative Systems Pharmacology Model for Hypokinetic Motor Symptoms in Parkinson's Disease
نویسندگان
چکیده
This publication proposes a computer-based platform to explore novel targets for symptomatic treatment, based on the known neuroanatomy and neurophysiology of the basal ganglia (Roberts et al., 2016). However, this theoretical proposal should also take into consideration other aspects, such as the possible molecule(s) involved in the loss of dopaminergic neurons containing neuromelanin, because there is a long list of molecules that failed to translate successful preclinical to clinical studies and new therapies. The discovery that PD motor symptoms were linked to the loss of dopaminergic neurons containing neuromelanin was a very important input in the search for new pharmacological treatments and understanding the mechanism underlying the degeneration of the nigrostriatal system (Fahn, 2015). This discovery also had a great influence on preclinical models that were developed by using exogenous neurotoxins that induce the degeneration of nigrostriatal neurons. The first exogenous neurotoxins used as a preclinical model of PD were 6-hydroxydopamine and later1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone. For decades, these preclinical models have been used both to study the molecular mechanisms of the disease and to test new possible drugs or treatments. A long list of drugs and even gene therapy has been tested with these preclinical models, showing successful results, but these failed in clinical studies In our opinion, the failure to translate the successful results obtained in preclinical studies to clinical studies is not a problem of incorrect targets but depends on (i) the identity of the neurotoxin causing the loss of dopaminergic neurons, containing neuromelanin in the substantia nigra, which remains unknown. The discovery of genes associated with a familial form of PD provided an enormous input to the basic research into understanding the mechanism involved in the degeneration of the nigrostriatal system. However, it is unclear what induces the dysfunction of these genes in the sporadic form of disease. There is a general agreement in the scientific community that the degeneration of the nigrostriatal neurons in PD involves mitochondrial dysfunction,
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A Humanized Clinically Calibrated Quantitative Systems Pharmacology Model for Hypokinetic Motor Symptoms in Parkinson’s Disease
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عنوان ژورنال:
دوره 7 شماره
صفحات -
تاریخ انتشار 2016