The failure to translate successful preclinical studies to clinical trials and new therapies is a really an enormous problem for both scientific community and patients with Parkinson’s disease. The question is why clinical studies designed to test new drugs that halt or slow down the progress of Parkinson’s disease have failed. These clinical studies have been based on successful preclinical studies that have used exogenous neurotoxins. Since the introduction of L-dopa in the palliative treatment of Parkinson’s disease, 54 years have passed, and this continues to be the star drug in the treatment of Parkinson’s disease even though after 4-6 years of chronic treatment side effects appear severe such as dyskinesias.

During the last decades, the investigation of the mechanisms involved in Parkinson’s disease and the proof of concept of possible drugs that can generate new treatments of the disease, have been done with preclinical models based on exogenous neurotoxins such as 6-hydroxydopamine and/or MPTP. Although these neurotoxins induce degeneration of neuromelanin-containing dopaminergic neurons in the nigrostriatal system, the major problem is that they do not exist in humans and the rate of degeneration is extremely rapid. Accidentally drug addicts using synthetic drugs contaminated with MPTP developed a severe Parkinsonism in just 3 days, contrasting to what happens in idiopathic Parkinson’s disease, where the degenerative process takes years. This suggests that exogenous neurotoxins are not suitable to test new drugs for idiopathic Parkinson’s disease.

The extreme slowness of the degenerative process of neuromelanin-containing dopaminergic neurons of the nigrostriatal system suggests that (i) the degenerative process of these neurons is a focused process on a single neuron, explaining that takes years to accumulate the loss of 60-70% of these neurons to develop motor symptoms; and (ii) this neurodegenerative event must be triggered by an endogenous neurotoxin that is formed within neuromelanin-containing dopaminergic neurons.

The use of a preclinic model in which the neurotoxic exogenous agent is not present in Parkinson´s disease patient makes it impossible to determine whether a new drug inhibit the chain of events that ultimately end in the loss of neuromelanin-containing dopaminergic neurons. Therefore, we need to use a preclinical model based on endogenous neurotoxins. It is generally accepted in the scientific community that mitochondrial dysfunction, the formation of neurotoxic oligomers of alpha-synuclein, dysfunction of both lysosomal and proteasomal protein degradation systems, endoplasmic reticulum stress, neuroinflammation and oxidative stress are involved in the loss of neuromelanin-containing dopaminergic neurons.

The discovery of genes associated with a familial Parkinson’s induced by a mutation in genes such as alpha-synuclein has provided valuable information about proteins related to the degenerative process. However, preclinical models based on mutations related to familial Parkinson’s are not useful for testing new drugs for idiopathic Parkinson’s, because the mutations that induce a familial Parkinson’s are not present in idiopathic Parkinson’s disease.

Possible candidates for preclinical models based on endogenous neurotoxins includes DOPAL, alpha-synuclein oligomers, and aminochrome. DOPAL is formed when cytosolic dopamine is degraded by the action of monoamine oxidase that catalyzes the oxidative deamination of dopamine. Subsequently, DOPAL is converted to DOPAC in a reaction catalyzed by aldehyde dehydrogenase 1, which has been observed to have low levels in postmortem tissue of Parkinson’s disease patients. Low levels of aldehyde dehydrogenase-1 in Parkinson’s patients suggest that DOPAL accumulates and can be oxidized to an ortho-quinone that can be neurotoxic. The low levels of expression of aldehyde dehydrogenase-1 in postmortem tissue that survived degenerative events during the disease question the possible neurotoxic role of DOPAL in the loss of neuromelanin-containing dopaminergic neuros in Parkinson’s disease. A mutation induces alpha-synuclein aggregation to neurotoxic oligomers in the familial form of the disease but in the idiopathic form of the disease must be an endogenous neurotoxin that triggers its aggregation. Aminochrome is formed within neuromelanin-containing dopaminergic neurons during neuromelanin synthesis, which requires the formation of 3 ortho-quinones (Dopamine -> dopamine ortho-quinone, aminochrome and 5,6-indolequinone). Aminochrome is the most stable and most studied ortho-quinone. Aminochrome is neurotoxic through inducing neurotoxic mechanisms involved in the degenerative process in idiopathic Parkinson’s disease, such as the aggregation of alpha-synuclein to neurotoxic oligomers, mitochondrial dysfunction, protein degradation dysfunction of both the lysosomal and proteasomal systems, endoplasmic reticulum stress, neuroinflammation, and oxidative stress.

Neuromelanin synthesis and its accumulation with age is a normal and harmless process since dopaminergic neurons containing neuromelanin are intact in postmortem substantia nigra tissues of healthy elderly people. However, neuromelanin synthesis generates the neurotoxin aminochrome suggesting a paradox. This apparent paradox can be explained by the existence of two neuroprotective enzymes that prevent the neurotoxic effects of aminochrome, allowing neuromelanin-containing dopaminergic neurons to remain intact in healthy elderly people. DT-diaphorase reduces aminochrome with two-electrons to leukoaminochrome, preventing the formation of leukoaminochrome ortho-semiquinone radical that is very reactive with oxygen and induces oxidative stress or form adducts with proteins. Glutathione transferase M2-2 conjugates aminochrome to 4-S-glutathionyl-5,6-dihydroxyindoline that is resistant to biological oxidants with oxygen, superoxide and hydrogen peroxide, preventing aminochrome neurotoxicity. Glutathione transferase M2-2 also conjugates the aminochrome precursor, dopamine ortho-quinone to 5-glutathionyl-dopamine.  Normally, to 5-glutathionyl-dopamine degrades to 5-cysteinyl-dopamine that has been found in cerebrospinal fluid and human neuromelanin. 5-Cysteinyl-dopamine is a final product that has been detected in urine. Astrocytes can take up dopamine, which can be oxidized into aminochrome, but glutathione transferase M2-2 prevents the toxic effects of aminochrome in these cells. While glutathione transferase M2-2 protects astrocytes from the neurotoxic effects of aminochrome, this enzyme also protects dopaminergic neurons. Astrocytes secrete exosomes loaded with glutathione transferase M2-2 into the intercellular space that subsequently penetrate dopaminergic neurons, releasing this enzyme in the cytosol of these neurons to protect them from the neurotoxic effects of aminochrome.

Clinical Studies and Therapies in Parkinson’s Disease: Translations from Preclinical Models analyzes preclinical models based on exogenous neurotoxins and why they have failed. Neuroscientists, neurologists, and neuropharmacologists will benefit greatly from the book’s discussion of these newer models, their benefits, and the need for their implementation. This book also provides the basic concepts of dopamine metabolism for students taking courses in neurochemistry, neuroscience, neuropharmacology, biochemistry, and medicine.

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