Current Medicinal Chemistry - Volume 26, Issue 20, 2019

Background: Aging is an unavoidable, physiological process that reduces the complexity and the plasticity of the synaptic contacts in Central Nervous System (CNS), having profound implications for human well-being. The term “cognitive reserve” refers to central cellular adaptations that augment the resilience of human brain to damage and aging. The term “Cognitive training” indicates the cultural, social and physical stimulations proposed as add-on therapy for the cure of central neurological diseases. “Cognitive training” reinforces the “cognitive reserve” permitting to counteract brain impairments and rejuvenating synaptic complexity. The research has begun investigating the clinical impact of the “cognitive training” in aged people, but additional work is needed to definitively assess its effectiveness. In particular, there is a need to understand, from a preclinical point of view, whether “cognitive training” promotes compensatory effects or, alternatively, if it elicits genuine recovery of neuronal defects. Although the translation from rodent studies to the clinical situation could be difficult, the results from pre-clinical models are of high clinical relevance, since they should allow a better understanding of the effects of environmental interventions in aging-associated chronic derangements in mammals. Conclusion: Data in literature and the recent results obtained in our laboratory concerning the impact of environmental stimulation on the presynaptic release of noradrenaline, glutamate and gamma amino butyric acid (GABA) suggest that these neurotransmitters undergo different adaptations during aging and that they are differently tuned by “cognitive training”. The impact of “cognitive training” on neurotransmitter exocytosis might account for the cellular events involved in reinforcement of “cognitive reserve” in young and old animals.

Population aging is accelerating rapidly worldwide, from 461 million people older than 65 years in 2004 to an estimated 2 billion people by 2050, leading to critical implications for the planning and delivery of health and social care. The most problematic expression of population aging is the clinical condition of frailty, which is a state of increased vulnerability that develops as a consequence of the accumulation of microscopic damages in many physiological systems that lead to a striking and disproportionate change in health state, even after an apparently small insult. Since little is known about the biology of frailty, an important perspective to understand this phenomenon is to establish how the alterations that physiologically occur during a condition of healthy aging may instead promote cumulative decline with subsequent depletion of homoeostatic reserve and increase the vulnerability also after minor stressor events. In this context, the present review aims to provide a description of the molecular mechanisms that, by having a critical impact on behavior and neuronal function in aging, might be relevant for the development of frailty. Moreover, since these biological systems are also involved in the coping strategies set in motion to respond to environmental challenges, we propose a role for lifestyle stress as an important player to drive frailty in aging.

Autophagy is an essential catabolic mechanism that delivers misfolded proteins and damaged organelles to the lysosome for degradation. Autophagy pathways include macroautophagy, chaperone-mediated autophagy and microautophagy, each involving different mechanisms of substrate delivery to lysosome. Defects of these pathways and the resulting accumulation of protein aggregates represent a common pathobiological feature of neurodegenerative disorders such as Alzheimer, Parkinson and Huntington disease. This review provides an overview of the role of autophagy in Parkinson’s disease (PD) by summarizing the most relevant genetic and experimental evidence showing how this process can contribute to disease pathogenesis. Given lysosomes take part in the final step of the autophagic process, the role of lysosomal defects in the impairment of autophagy and their impact on disease will also be discussed. A glance on the role of non-neuronal autophagy in the pathogenesis of PD will be included. Moreover, we will examine novel pharmacological targets and therapeutic strategies that, by boosting autophagy, may be theoretically beneficial for PD. Special attention will be focused on natural products, such as phenolic compounds, that are receiving increasing consideration due to their potential efficacy associated with low toxicity. Although many efforts have been made to elucidate autophagic process, the development of new therapeutic interventions requires a deeper understanding of the mechanisms that may lead to autophagy defects in PD and should take into account the multifactorial nature of the disease as well as the phenotypic heterogeneity of PD patients.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder among elderly population, characterized by the progressive degeneration of dopaminergic neurons in the midbrain. To date, exact cause remains unknown and the mechanism of neurons death uncertain. It is typically considered as a disease of central nervous system (CNS). Nevertheless, numerous evidence has been accumulated in several past years testifying undoubtedly about the principal role of neuroinflammation in progression of PD. Neuroinflammation is mainly associated with presence of activated microglia in brain and elevated levels of cytokine levels in CNS. Nevertheless, active participation of immune system as well has been noted, such as, elevated levels of cytokine levels in blood, the presence of auto antibodies, and the infiltration of T cell in CNS. Moreover, infiltration and reactivation of those T cells could exacerbate neuroinflammation to greater neurotoxic levels. Hence, peripheral inflammation is able to prime microglia into pro-inflammatory phenotype, which can trigger stronger response in CNS further perpetuating the on-going neurodegenerative process. In the present review, the interplay between neuroinflammation and the peripheral immune response in the pathobiology of PD will be discussed. First of all, an overview of regulation of microglial activation and neuroinflammation is summarized and discussed. Afterwards, we try to collectively analyze changes that occurs in peripheral immune system of PD patients, suggesting that these peripheral immune challenges can exacerbate the process of neuroinflammation and hence the symptoms of the disease. In the end, we summarize some of proposed immunotherapies for treatment of PD.

Recent literature agrees that neurodegenerative processes involve both the retina and the central nervous system, which are two strictly related anatomical structures. However, the causal mechanisms of this dual involvement are still uncertain. To date, anterograde transsynaptic neurodegeneration, triggered by retinal ganglion cells’ death, and retrograde transsynaptic neurodegeneration, induced by neurodegenerative processes of the central nervous system, has been considered the major possible causal mechanisms. The development of novel neuroimaging techniques has recently supported both the study of the central stations of the visual pathway as well as the study of the retina which is possibly an open window to the central nervous system.

Background: Alzheimer’s Disease (AD) accounts for approximately 50% of all cases of dementia and, in spite of the great effort for the development of disease-modifying drugs, a definitive treatment of cognitive impairment is not available yet. A perfect adherence to the current therapy of cognitive decline is needed for a better control of the disease and this is proven to reduce, though not completely abolish, the associated Behavioural and Psychological Symptoms of Dementia (BPSDs) from occurring. This cluster of symptoms, remarkably affecting patients’ health-related quality of life (HRQL), is tightly associated with pain states. Antipsychotics are the only treatment for BPSDs. However, these drugs are more effective and safer in the short-term (6-12 weeks), they are able to manage aggression but not agitation and they cannot control pain. Aromatherapy with Melissa officinalis and Lavandula officinalis has been employed to handle BPSDs, but it has not provided strong evidence to offer relief from pain. Objective: Bergamot Essential Oil (BEO) exerts antinociceptive activity through several pharmacological mechanisms: in particular, it is able to enhance autophagy, a process undergoing derangement in chronic pain. Thus, the sound pharmacological basis for clinical translation of aromatherapy with BEO in the treatment of BPSDs has been pointed out. Conclusion: The antinociceptive effects elicited by BEO in experimental pain models make it a possible candidate for the pharmacological management of pain-related BPSDs.

Background: Major depressive disorder (MDD) is a multifactorial chronic and debilitating mood disease with high lifetime prevalence and associated with excess mortality. Treatments for this disease are not effective in all patients showing the need to find new therapeutic targets. Objective: This review aims to update our knowledge on the involvement of astroglial gap junctions and hemichannels in MDD and to show how they have become potential targets for the treatment of this pathology. Methods: The method applied in this review includes a systematic compilation of the relevant literature. Results and Conclusion: The use of rodent models of depression, gene analysis of hippocampal tissues of MDD patients and post-mortem studies on the brains from MDD patients suggest that astrocytic gap junction dysfunction may be a part of MDD etiologies. Chronic antidepressant treatments of rats, rat cultured cortical astrocytes and human astrocytoma cell lines support the hypothesis that the up-regulation of gap junctional coupling between astrocytes could be an underlying mechanism for the therapeutic effect of antidepressants. However, two recent functional studies suggest that connexin43 hemichannel activity is a part of several antidepressants’ mode of action and that astrocyte gap junctional intercellular communication and hemichannels exert different effects on antidepressant drug response. Even if they emerge as new therapeutic targets for new and more active treatments, further studies are needed to decipher the sophisticated and respective role of astrocytic gap junctions and hemichannels in MDD.

Background: Neuronal α4β2 nAChRs are receptors involved in the role of neurotransmitters regulation and release, and this ionic channel participates in biological process of memory, learning and attention. This work aims to review the structure and functioning of the α4β2 nAChR emphasizing its role in the treatment of associated diseases like nicotine addiction and underlying pathologies such as cognition, depression and attention-deficit hyperactivity disorder. Methods: The authors realized extensive bibliographic research using the descriptors “Nicotine Receptor α4β2” and “cognition”, “depression”, “attention-deficit hyperactivity disorder”, besides cross-references of the selected articles and after analysis of references in the specific literature. Results: As results, it was that found 179 relevant articles presenting the main molecules with affinity to nAChR α4β2 related to the cited diseases. The α4β2 nAChR subtype is a remarkable therapeutic target since this is the most abundant receptor in the central nervous system. Conclusion: In summary, this review presents perspectives on the pharmacology and therapeutic targeting of α4β2 nAChRs for the treatment of cognition and diseases like nicotine dependence, depression and attention-deficit hyperactivity disorder.

Filamentous ascomycetes (Neurospora and Monascus) have been studied for a long time because of their production of secondary metabolites such as microbial pigments. The ascomycetes represent an interesting group of compounds with high potential for medicinal applications. Many recent studies have shown their efficacy in the treatment of serious pathological states such as oncological diseases, neurodegenerative diseases and hyperlipidaemia. Nevertheless, the clinical usability of ascomycetes is still limited. However, this problem can be solved by the use of these compounds with combinations of other therapeutic agents. This strategy can suppress their side effects and improve their therapeutic efficacy. Moreover, their co-application can significantly enhance conventional therapies that are used. This review summarizes and discusses the general principles of this approach, introduced and supported by numerous examples. In addition, the prediction of the future potential application of this methodology is included.