Aminochrome as preclinical model for Parkinson's disease

It is essential the existence of suitable preclinical models to elucidate the molecular mechanism of a disease and to test potential drugs and therapies. One of the major problems to discover new pharmacological therapies in Parkinson’s disease is the lack of suitable preclinical model. This explains why L-dopa is still the most effective drug despite the severe side effects observed after 4-6 years of treatment. There is a long list of clinical studies failed despite being based on robust preclinical results obtained with exogenous neurotoxins as preclinical model. The use of preclinical models based on exogenous neurotoxins (6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone) is an important problem to translate successful results to clinical studies and new therapies in Parkinson’s disease [1]. The discovery that glial cell-derived neurotrophic factor (GDNF) preserved nigrostriatal circuitry and reversed motor disability in animals lesioned with systemic MPTP or unilateral striatal injections of 6-hydroxydopamine opened a huge hope to obtain a new treatment in Parkinson’s disease. It was expected that GDNF halts the progression of the disease and regenerate dopaminergic neurons. However, clinical studies with GDNF revealed no significant difference between control and patients [2]. The question is why we cannot translate successful preclinical studies performed with exogenous neurotoxins to clinical studies. In my opinion, the failure to translate results from preclinical to clinical studies depends on (i) the use of preclinical models based on exogenous neurotoxins that do not replicate what happen in Parkinson’s disease. These preclinical models induce an extremely rapid and massive degeneration of the nigrostriatal dopaminergic neurons. For example MPTP induces a severe Parkinsonism in just 3 days in humans exposed to this neurotoxin while the degenerative process in Parkinson’s disease takes years before the motor symptoms are evident. In addition, the progression of the disease is also extremely slow in comparison to the rapid effects of these exogenous neurotoxins [3]; and (ii) the mechanism that triggers the degeneration of dopaminergic neurons containing neuromelanin in Parkinson’s disease is still unknown. However, there is a general agreement in the scientific community that mitochondrial dysfunction, generation of neurotoxic oligomers of alpha-synuclein, Editorial