Repurposing drugs to treat neurological diseases

Journal of Neurology, Jan 2018

T. H. Massey, N. P. Robertson

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Repurposing drugs to treat neurological diseases

Journal of Neurology https://doi.org/10.1007/s00415 Repurposing drugs to treat neurological diseases T. H. Massey 0 N. P. Robertson 0 0 Division of Psychological Medicine and Clinical Neuroscience, Department of Neurology, Cardiff University, University Hospital of Wales , Heath Park, Cardiff CF14 4XN , UK 1 N. P. Robertson Vol.:(011233456789) Introduction The development of new drugs can be expensive: on average, it costs over $2 billion to take a medication from inception to clinical practice. Drug discovery is particularly difficult in neuropsychiatric diseases as targets are often poorly defined, inaccessible, and not easily assayed. Furthermore, many neurological diseases progress slowly over many years, often requiring clinical trials examining efficacy to be large and have complex end points. However, one way of expediting drug development is to repurpose drugs from their original use to a new indication. Multiple examples exist in clinical medicine: sildenafil was an ineffective angina drug repurposed for erectile dysfunction; minoxidil was a hypertension drug repurposed for hair loss. These unexpected therapeutic discoveries were made serendipitously, and often as sideeffects in clinical trials. Unbiased, high-throughput screens are now being used systematically to test libraries of clinically approved drugs in areas of medicine away from their usual indications. These screens can generate novel therapeutic avenues, shed light on molecular pathology, and lead directly to clinical trials. This month’s journal club explores three papers relating to drug repurposing in Neurology. The first two papers use unbiased cell-based screens of drug/compound libraries to search for potential therapeutic activities relating to either Parkinson’s disease or Zika virus infection of neurons, respectively. The third paper reports a clinical trial of clemastine, commonly used as an antihistamine, in the remyelination of optic nerves in multiple sclerosis. β2A‑drenoreceptor is a regulator of the α‑synuclein gene driving risk of Parkinson’s disease Intraneuronal aggregates of phosphorylated α-synuclein (Lewy bodies) are found in the brains of patients with Parkinson’s disease (PD). Disease severity correlates with Lewy body formation, although there is debate about whether these aggregates are directly toxic to neurons. Overexpression of wild-type α-synuclein, either as a result of SNCA gene duplication/triplication in familial PD or from gene regulatory variants in sporadic disease, can drive PD. Furthermore, decreased α-synuclein production correlates with clinical improvement. This paper reported a high-throughput screening assay for compounds that could reduce SNCA gene expression in human neuroblastoma cell lines. Cells were grown in multiwell plates, treated with one of 1126 drugs previously tested for safety in humans, and then harvested for gene expression analysis. Optimisation and replication of the screen ultimately identified four drugs that significantly reduced SNCA mRNA and protein levels in a dose-dependent manner: three β2-adrenoceptor (β2AR) agonists, including the common asthma medication salbutamol, and riluzole, a drug licensed in amyotrophic lateral sclerosis. Conversely, β2AR inhibition by propranolol, a non-specific β-blocker, led to increased SNCA mRNA and protein levels. Extending the observations to animal models, intraperitoneal administration of β2AR agonist clenbuterol to wild-type mice significantly reduced SNCA expression in the substantia nigra. Similar clenbuterol administration to a mouse model of PD prevented nigral neuronal loss. Finally, the study took advantage of the Norwegian Prescription Database (NorPD) which contains all information about individual prescriptions in Norway since 2004. Interestingly, if an individual had ever used salbutamol (n = 619,863), they had a significantly lower incidence of PD (rate ratio = 0.66, 95% confidence interval 0.58–0.76), and, conversely, if they had ever used propranolol for at least 1 year (n = 14,794), they had a significantly increased risk of PD (rate ratio = 2.20, 95% confidence interval 1.62–3.00). Adjustments were made for age, sex, and level of education, as well as attempts to control for other potential confounders such as smoking and essential tremor. Comment. This study used a well-designed unbiased screen to discover compounds that can regulate α-synuclein gene expression. Unexpectedly, these included β2AR agonists widely used as asthma medications. The correlation of β2AR agonist use and reduced incidence of PD in the large Norwegian population fitted in well with the cellular and animal work presented, although whether SNCA expression is the critical driver of pathology in sporadic PD is unknown. Further work is needed to elucidate molecular mechanisms, but this should not prevent clinical trials of β2AR agonists in PD being fast-tracked. Mittal S et al (2017) Science 357: 891–898. Identification of small‑molecule i (...truncated)


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T. H. Massey, N. P. Robertson. Repurposing drugs to treat neurological diseases, Journal of Neurology, 2018, pp. 1-3, DOI: 10.1007/s00415-018-8732-z