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New Paradigms in Neuroscience and Related Targets for Drug Discovery

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Neuropsychiatric disorders are highly prevalent and devastating diseases, but they are yet poorly treated; in fact, most of the available drug-treatments can be considered as symptomatic, while very few are able to impact on the progression and/or the long term outcomes. Furthermore, despite the great effort ...

Neuropsychiatric disorders are highly prevalent and devastating diseases, but they are yet poorly treated; in fact, most of the available drug-treatments can be considered as symptomatic, while very few are able to impact on the progression and/or the long term outcomes. Furthermore, despite the great effort of the scientific community and the financial support of public funding for neuroscience-related research, the approval of innovative drugs acting on central nervous system (CNS) has been rare in recent years. Many CNS conditions share similar molecular and cellular mechanisms, finally leading to neurodegeneration. Neuroprotection, i.e. a treatment aimed at sparing/slowing neuron loss is therefore a primary goal, but still remains an open challenge. Indeed, while a plethora of substances have been shown to exert neuroprotective effects in animal models of ischemia, traumatic injury, neurodegenerative diseases, no specific treatment has so far reached approval (though several compounds, including prescription drugs, over-the-counter, nutraceuticals, vitamins are claimed to exert neuroprotective effects, mainly because of their putative antioxidant activity). The announcement by Pfizer Inc. that they will pull out of research programs for neurodegenerative diseases, including Parkinsons and Alzheimers, has caused a stir and suggests that drug discovery for neuropsychiatric disorders might not improve in the coming years.

Focusing on drugs that target the pathophysiology underlying the disease, which increases the likelihood of identifying efficacious agents rather than symptomatic treatments, is essential to enhance drug discovery. However, mechanisms behind CNS disorders are still poorly understood, while reliable biomarkers to identify which patient will benefit from a given treatment, when to treat, and what clinical outcome can be expected, need to be set and validated in extensive clinical trials. Alzheimer’s disease represents an example where an intense research effort has been produced to understand the cellular and molecular mechanisms while a considerable number of biomarkers have been studied, but paradoxically, not a single new drug has reached approval. The pathology-to-drug discovery takes the understanding of the pathophysiology as the initial step in identifying pharmacological targets. The reverse approach, (the so-called reverse translation approach), which aims at gathering new data from clinical trials to formulate hypotheses experimentally testable in basic science might provide specific drug targets for treating human diseases, and deserves further attention. Decline in cognition is a major, long term problem in psychotic disorders and its effective treatment still represent an unmet need. To improve the impact of drug treatments on cognition and memory, we need not only a better understand of cellular and molecular neuroscience, but also reliable animal paradigms for drug testing, i.e. experimental models which provide functional (behavioral) data predictive of human outcomes.

This Research Topic hosts studies on novel experimental paradigms in neuroscience that aim at providing druggable targets and/or on relevant insights from clinical settings that deserve to be further investigated in preclinical settings (in silico, in vitro, in vivo) - those that are likely to unravel so far unperceived druggable mechanisms and/or lead to drug repositioning, i.e. use of available approved drugs for novel indications.


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