Frontiers in Clinical Drug Research- Central Nervous System

The development of nucleic acid-based therapeutics has recently aroused an increasing interest due to the great promise they hold for the treatment of a wide range of both inherited and acquired disorders. A prominent part in this field is played by neurodegenerative diseases, for which therapeutic interventions are currently limited to palliative and symptomatic treatment. Advances in the elucidation of the molecular mechanisms involved in these disorders provide the basis for developing nucleic acid-based treatment strategies able to address the molecular cause of the disease.

Several types of nucleic acid-based therapeutics have been proposed. All those therapeutics may be grouped into two main classes, i.e., protein coding nucleic acids (DNA molecules) and regulatory nucleic acids (DNA or RNA molecules). The use of nucleic acids belonging to the first class is aimed at providing the relevant cells with a protein that either permits to rescue a missing function or supplies a new function able to counteract or alleviate the disease. Regulatory nucleic acids are used in order to counteract the harmful effects of a specific gene in the relevant cells. They include several types of molecules that allow virtually any step of gene expression to be controlled. Regulation at transcriptional and post-transcriptional levels can be achieved by the means of oligonucleotides, catalytic nucleic acids, siRNAs and antisense RNAs, while protein synthesis and protein function can be inhibited by siRNAs and aptamers or decoys, respectively.

The delivery of genes coding for neurotrophic factors as neuroprotective/ neurorestorative agents is a favored strategy for the treatment of neurodegenerative diseases, but a number of alternative strategies have also been proposed, such as the use of aromatic-L-amino decarboxylase (AADC) encoding gene for Parkinson’s disease. More recently, advances in gene silencing technology have led to the evaluation of strategies aimed at selectively interfering with the pathogenetic mechanisms underlying disease phenotype, as in the case of Huntington’s disease where RNA interference technology could provide a tool to target the mutant HTT allele.

A prerequisite for the successful clinical application of nucleic acid-based therapeutics to the treatment of neurodegenerative diseases is the availability of safe and efficient systems for nucleic acid delivery to the central nervous system, or better to the relevant neuronal subpopulations depending on the specific disease. A few viral vectors, those based on the adeno-associated virus or lentiviruses in particular, have shown promise as neuron-targeted nucleic acid carriers and the clinical trials undertaken to date have employed viral vectors almost exclusively. However, viral vectors have several drawbacks, such as those resulting from a non-complete safety, that significantly limit their widespread clinical use. Consequently, a great deal of efforts to develop non-viral vectors for nucleic acid delivery to the central nervous system has been made in the recent years. Non-viral vectors offer several advantages including improved safety profiles, lower production costs and ability to target specific neuronal subpopulations, but their delivery efficiency has to be improved in order to thoroughly realize their potential in clinical settings.

This chapter illustrates the rationale and current status of nucleic acid-based strategies for the treatment of two neurodegenerative movement disorders, Huntington’s disease and Parkinson’s disease.

Reactive species have been regarded as by-products of cellular metabolism that cause oxidative damage contributing to aging, cancer and neurodegenerative diseases. However, accumulated evidence support the notion that reactive species mediate intracellular signals that regulate physiological functions including posttranslational protein modifications with important functional implications. Cysteine thiol groups of proteins are particularly susceptible to oxidative modifications by oxygen, nitrogen and sulfur species and they can be oxidized to several different products, including disulfide, sulfenic acid, sulfinic acid, sulfonic acid, S-nitrosothiols and S-glutathione, which have critical roles in cellular redox homeostasis. Since there are many cysteine-bearing proteins and cysteine-dependent enzymes susceptible to oxidative modifications that may contribute to cellular function and dysfunction, this chapter reviews the role of oxidative-changed proteins at cysteine residues in aging and some frequent neurodegenerative diseases. The concept of a cellular cysteine network (CYSTEINET) is advanced as a functional and structural matrix of interconnected proteins that in conjunction with reactive species and glutathione can regulate the cellular bioenergetic metabolism, the redox homeostasis, and the cellular survival. This network may represent an ancestral down-top system composed by a complex matrix of proteins with very different cellular functions, but bearing the same regulatory thiol radical. In this context and based on scientific evidences, current therapeutic and potential mechanism of action of some particular thiol bearing substances are revised.

Parkinson's disease (PD) is typically characterized by its motor symptoms, namely rigidity, resting tremor, bradykinesia and postural instability. However, non-motor symptoms (NMS) such as sleep disturbance, pain, constipation, urinary problems and fatigue are integral to PD and are the leading cause of poor quality of life for both people with PD and their caregivers. Although NMS affect almost every patient, they remain under-recognized and under-treated. An evaluation of the treatment consequences of NMS in over 60% of patients revealed that NMS such as apathy, pain, sexual difficulties, bowel incontinence and sleep disorders may not be revealed to health care professionals because the patients are either embarrassed or unaware that the symptoms are linked to PD. This mini-review provides an overview of NMS in PD along with possible drug therapies.

Recent clinical trials indicate the importance of the agonists at the alpha 7 nicotinic receptor (a7nAChR) in the modulation of cognitive deficits in both Alzheimer's disease and schizophrenia. Such benefits have been modelled on the effects of the a7nAChR agonists in neurons. However, it is of note that the a7nAChR is also a powerful immune and glia regulator, suggesting that some of a7nAChR agonist benefits may be mediated by the suppression of immune and glia reactivity, which is in line with more recent conceptualizations of these disorders that have emphasized the role of these cells. Notably, melatonin, also efficacious across an array of medical conditions, is a significant regulator of a7nAChR levels and activity, with the a7nAChR mediating many of the beneficial effects of melatonin, including in the regulation of mitochondrial functioning.

This chapter focuses on the wide-ranging benefits that may arise from melatonin interactions with the a7nAChR, especially as to how such interactions may impact on the cellular mechanisms of an array of medical conditions. Such interactions are likely to have relevance across a host of neurodegenerative and psychiatric conditions.

Antidepressant medications have been available for more than fifty years, yet the proportion of patients helped by the various classes of these agents has hardly changed at all. This despite greater insight into the disorder at a biological level based on knowledge derived from contemporary advances in neuroscience. Two fundamental issues may lie at the heart of this apparent paradox. First, depression is a highly heterogeneous disorder and almost certainly is not a single ‘disease’ entity. The diagnosis is based on the clustering of a discrete set of symptoms, within a defined time frame and as such is best described as a syndrome or disorder. The cause(s) of depression remain unknown and are, in all probability, multi-factorial. The identification of bio-marker defined depression sub-groups may aid both more precise diagnoses and better treatment outcomes. Secondly, the development of pharmacological treatments has been limited by the prevailing aetiological hypothesis of the disorder, the monoamine hypothesis. While it is now well recognised that such a postulate is limited in its explanatory power, both for aetiology and treatment, it has, nevertheless, driven drug development for well over five decades. Clearly, while monoamines surely are important in mediating responses to antidepressant medication, they are almost certainly not the only important driver. Thus the shortcomings in such agents have been well recognised almost since their inception. Principal among these drawbacks has been speed of onset of action with full recovery and remission taking several weeks if not months. Additionally, the relative lack of efficacy of medications in all likelihood reflects the heterogeneity of the disorder and the inability to define predictive factors such as symptom patterns, personality variables or biomarkers, which are responsive to particular pharmacological properties of individual medications. Serious adverse events, side effects, cardiovascular safety and multiple potential drug interactions have also been cited as drawbacks of the existing plethora of antidepressant medications. While few medications have yet emerged into clinical practice based on the insights gleaned from recent basic studies, the notion of targeting multiple, relevant sites in the central nervous system to improve treatment outcomes in major depression has produced some new agents. These so called multi-modal antidepressants simultaneously interact with several different receptors and transporter molecules thought to contribute to antidepressant responses. Expanding the effects on central monoamine activity through the development of so-called triple reuptake inhibitors has been one multi-modal approach to the treatment of depression. Amitifiadine is the first triple reuptake exemplar to reach early clinical trials. To date clinical outcomes could be described as mixed. Vilazodone and vortioxetine are multi-modal agents which target reuptake mechanisms as well as other neurotransmitter receptors. This review examines the pharmacological properties of these new agents and critically evaluates their efficacy in clinical trials with a particular emphasis on whether the multi-modal approach obviates some of the perceived shortcomings of existing medications. Achievement of high remission rates in depression is increasingly recognised as the bench mark of an efficacious drug. The extent to which these new agents achieve better remission rates can be regarded as a measure of the extent to which the multi-modal hypothesis is realized and may guide treatment approaches into the future.