Frontiers in Clinical Drug Research - CNS and Neurological Disorders

A high incidence of people suffering from depression displays a disrupted sleep and, in particular, insomnia. Persistent sleep loss can significantly worsen the quality of life and prognosis of patients, by increasing the risk of relapse during remission and even suicidality. Moreover, an ever emerging issue in the management of depressed patients is the possible arise of poor sleep during an antidepressant treatment. This presumably results from the complex interweave between mood and sleep physiology, which can make it considerably difficult to apply suitable diagnoses and interventions for psychiatrists and physicians. Beside behavioral/psychotherapy approaches, pro-hypnotic drugs are considered preferential overall for treating geriatric depressive patients with insomnia or cases showing refractory poor-quality sleep. Among elective pro-hypnotic compounds, some antidepressants acting on multiple pharmacological targets, also called atypical, have been found particularly effective and well tolerated for these patients. In this book chapter, we will thus present some aspects of the neurobiology of sleep, current focuses concerning the interlaces between sleep and mood, as well as sleep physiology alterations present in depression subtypes, also in respect to their onset as an antidepressant side-effect. Afterwards, we will discuss the effectiveness and advantages of atypical antidepressants on hypnotic and antidepressant responses, overall on those acting on the serotonin and melatonin systems, together with our specific aims in this search field. A deeper knowledge of the mechanisms of action of these drugs could indeed help to elucidate, on the one hand, the physiopathology of sleep, while, on the other, would better define their usefulness in the clinical practice and stimulate the discovery of new drugs.

Perinatal brain injury remains a leading cause of mortality and morbidity in children. Neonatal encephalopathy (NE), which is primarily caused by hypoxicischemic (HI) events known as hypoxic-ischemic encephalopathy (HIE), is the predominant form of brain injury in term infants. NIE leads to high mortality and high incidence of sustained childhood disabilities among survivors. The past three decades witnessed significant progress towards a deep understanding of cellular and molecular mechanisms underlying HI-induced brain injury, yet basic research findings remain to be translated into clinical practice. Currently, the only available treatment option for HIE is therapeutic hypothermia, also known as targeted temperature management (TTM). Despite the successful translation from basic research into clinical use, TTM has several serious limitations including a narrow window of opportunity and a moderate efficacy leaving about 40-50% of treated infants still die or suffer from a significant neurologic disability. Hence, there is an urgent need to explore combined therapies which should broaden the therapeutic window and/or enhance therapeutic efficacy. In this chapter, we discussed several classes of neuroprotectants that showed promise in pre- and/or clinical settings. The first half of this chapter reviews advances in recent development of basic and clinical research in TTM, including major clinical trials. The second half focuses on potential candidate therapies to be combined with hypothermia.

The time is right for the development and implementation of a powerful new method to treat tinnitus. The necessity for this advancement centers on the observation that over 50 million individuals are affected by this condition, ~3 million are seriously disabled, effective treatments remain elusive, and there is no cure. To address this formidable problem, we describe a theranostic nanoparticle-based drug-delivery platform to localize and treat tinnitus by attenuating hyperactive neural activity in regions of the brain affected by this condition. The driving force underlying this approach centers on the multi-functionality of nanoparticles (NPs). Specifically, their exterior surfaces can be decorated with multiple ligands designed to cross the bloodbrain- barrier (BBB), target specific receptors in brain regions responsible for tinnitusrelated hyperactivity, have the ability to encapsulate contrast agents so that tinnitusrelated neural activity can be spatially localized in the brain using magnetic resonance imaging (MRI), and have their central core loaded with a pharmacological agent, enabling a payload of drugs to be delivered to those regions of the brain affected by this condition. In theory, this approach will attenuate and/or eliminate tinnitus-related hyperactivity; hence, markedly reduce or remove the tinnitus percept from consciousness. To date, an ex vivo model and in vivo animal experiments suggest that capsid-based NPs are able to cross the BBB, which is an essential first step for this technology to succeed. Optimization of NP concentrations, loading therapeutic and imaging agents, and further exploring over expressed receptor targets for delivery to specific brain regions are currently underway.

Dexmedetomidine is a highly selective α2-adrenergic receptor agonist with anxiolysis and analgesic properties as well as benefit on neuroprotection. While initially used solely as a sedative agent in ICU, recent studies also looked into the potential use of dexmedetomidine as an anaesthetic adjunct, an opioid sparing analgesic and as a neuroprotective agent, with some promising results. One particular research focus is its use in postoperative delirium; a common yet potentially serious condition associated with high incidence of postoperative complications, and lead to adverse outcomes in patients as well as increased health care costs. Currently, the pharmacotherapies in use are mostly symptom orientated are associated with a number of side effects. Dexmedetomidine has been demonstrated to reverse the pathological changes associated with postoperative delirium, and shown benefits in a number of human trials. In this chapter we will review the pharmacological properties of Dexmedetomidine and its potential clinical uses, in particular, focusing on postoperative delirium.

Protein folding is a complex process that occurs via a series of intermediates which fold further to give rise to the unique three-dimensional structure, a conformation which is usually biologically functional. In protein misfolding and aggregation, protein molecule acquires an abnormal conformation of the tertiary structure, which interacts with other similar structures thereby forming dimers, oligomers, protofibrils and finally mature fibrils. Further, research on aggregates led to grouping of aggregates into two different structures: random amorphous structures and well-ordered amyloid fibril structures. The fibrillar aggregates of Aβ peptide, α- synuclein, huntingtin, PrP, are either deposited in the tissues as intracellular inclusions or extracellular plaques (amyloid) leading to manifestation of various neurodegenerative diseases including Alzheimer's disease, Parkinson’s disease, Huntington’s disease and Prion disease respectively. Now, accumulating evidence suggests that amyloid oligomers or amyloid beta intermediates rather than fibrils constituting the deposits are more toxic thereby different types of neurodegenerative diseases occur. Amyloid species have been generally considered as pathological entities, now studies indicate that it may also play a functional role. Keeping the above views in mind, in this chapter we have focussed on protein aggregation phenomenon that starts from the very first event, protein misfolding to fibril aggregate formation steps. We have also reviewed different mechanisms of aggregation, the role of amyloids in different neurodegenerative diseases and amyloid cascade hypothesis. To treat these devastating disorders several novel therapeutic approaches have been discussed in detail.