Drug Repurposing in Neurodegenerative and Neuropsychiatric Disorders

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Background

The development of new drugs for the treatment of disorders affecting the central nervous system (CNS) has one of the highest rates of attrition in drug development, therefore making this process a slow and highly expensive one. As a response to this, drug repurposing is gaining increasing attention and has become a compelling option for academic and industry researchers in the pursuit of new treatments.

Drug repurposing, or repositioning, is a strategy aimed at identifying new uses for already approved or investigational drugs, which fall outside their original medical indication. This strategy has led not only to the successful preclinical and clinical testing in multiple neurological disorders, of compounds currently prescribed for other pathologies but also to the reevaluation of disused drugs, epitomized by the remarkable case of thalidomide.

In recent years drug repurposing has covered a wide range of neurological disorders, from neurodegenerative and neuropsychiatric to drug abuse-related disorders.

Alzheimer’s disease and Parkinson's disease, for example, are the two most common neurodegenerative diseases, for which only symptomatic therapies are available, while neuroprotective drugs are still an urgent unmet need. They are therefore in the top list of neurological disorders for the investigation of repurposed drugs, targeting both the disease neuropathology and symptoms.

In the context of Alzheimer’s disease, drugs investigated for repositioning include but are not limited to cardiovascular agents such as insulin, cilostazol, probucol, telmisartan, and dabigatran, the anti-diabetic agent pioglitazone, the anti-cancer agents nilotinib and bexarotene, and immunomodulatory agents.

Moreover, several drugs are under preclinical investigation for repositioning in both neurodegenerative diseases, such as the beta-lactam antibiotic ceftriaxone and several immunomodulatory agents.

In Parkinson's disease, the investigational repurposing of potential disease-modifying drugs embraces agents with various therapeutic indications such as the anti-cancer nilotinib, the antidiabetic drugs pioglitazone and exenatide, the anti‐hypertensives isradipine, and food supplements such as inosine.

The abuse of substances is among the most prevalent neurological disorders worldwide, especially in developed countries, and is associated with high mortality and burden of disease. Despite this recognized social plague, the number of medications approved for treating drugs of abuse-related disorders is still small.

Recently, Baclofen has been approved for repositioning in the treatment of alcohol abuse in Europe, whereas the cardiovascular agents prazosin and doxazosin are being considered for the treatment of alcohol and cocaine dependence, and modafinil for cocaine abuse.

Depression is a devastating mood disorder prevalent in Western countries and impacting 300 million people globally - according to the World Health Organization. It causes multiple symptoms such as sadness, anxiety, low self-esteem, lack of motivation, anhedonia, and a loss of appetite among others. Several neurobiological factors are known to contribute to the etiology of depression, including altered neurotransmission and, more recently, a recognized vascular insufficiency and inflammation. Accordingly, many drugs with variate mechanisms of action have been proposed or have been tested for the treatment of depression, ranging from the anesthetic ketamine, cough-suppressant Dextromethorphan, to the anti-inflammatory agents Infliximab or etanercept, as well as antidiabetic drugs such as pioglitazone.

Additionally, depression is well documented in neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease, as well as in neurological disorders with aberrant vascular inflammatory response, such as stroke and traumatic brain injury, thus depression may serve as a key co-morbidity factor in pathological conditions that may be responsive to anti-depressive drugs.

This topic aims at collecting original research and review articles focusing on drug repurposing in the following neurological disorders:
- Parkinson’s disease;
- Alzheimer’s disease;
- Huntington’s disease;
- Neuropsychiatric disorders including drugs of abuse-related disorders and depression.

Keywords: Parkinson, Alzheimer, depression, drugs of abuse, Huntington

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