The use of multi-target drugs in the treatment of neurodegenerative diseases

Neurodegenerative disorders lead to increased mortality and morbidity in older patients, and are a great burden on society, where there is currently no approved treatment to prevent the progression of these diseases. Many neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), Lewy body disease, cerebrovascular disease, frontotemporal dementias and neuronal deterioration following stroke, often display comorbidity with neurodegenerative symptoms and behavioral alterations. These include depressive illness and delusional characteristics often associated with schizophrenia [1,2]. Several studies employing a variety of methodological approaches have led to the identification of specific molecular mechanisms underlying cell death and consequential behavioral changes in neurodegenerative disorders [3]. It has thus become increasingly clear that these alterations must be addressed through strategies aimed at the development of therapeutic agents for neurodegenerative diseases that apply entirely novel concepts [4]. Current therapeutic approaches for the treatment of neurodegenerative diseases merely offer limited, and even worse, transient symptomatic benefits to patients, with no mitigation of the insidious loss of neuronal cells encountered in these conditions [5]. Neurodegenerative diseases have a multifactorial pathoetio logical origin [6], and it is not surprising that conventional drug-discovery approaches that embrace a ‘one gene, one drug, one disease’ philosophy may not offer the best pathway towards the development of much needed disease-modifying therapeutics for these diseases [7,8]. Drugs that target only one protein are susceptible to resistance, one reason (among several others) being that even a single mutation in the target active site often substantially reduces compound binding affinity and, hence, efficacy. On the other hand, resistance to drugs that target multiple proteins would require the unlikely event of concurrent mutations appearing in multiple protein targets. In view of these concerns, many clinicians and basic scientists have become persuaded that a strategy aimed at the simultaneous targeting of multiple proteins (and therefore etiologies) involved in the development of a disease should be more beneficial than the currently accepted ‘silver bullet’ approach. This approach may be useful in designing drug treatments for a range of diseases [9]. Diseases of the CNS for which such an approach has been suggested include, among others, movement disorders, cognitive deficit disorders, negative symptoms in schizophrenia, Lewy body disease and depressive illness [10–13]. Cornelis J Van der Schyf