Current Neuropharmacology (v.15, #4)

Meet Our Editorial Board Member by Cristine Alves da Costa (457-457).

Background: In recent decades, the interest in behavioral interventions has been growing due to the higher prevalence of age-related cognitive impairments. Hence, behavioral interventions, such as cognitive stimulation and physical activity, and along with these, our lifestyle (education level, work position, frequency of cognitive and social activities) have shown important benefits during the cognitive impairment, dementia and even recovery after brain injury. This is due to the fact that this type of intervention and activities promote the formation of a cognitive and brain reserve that allows tolerating brain damage during a long period of time without the appearance of cognitive symptoms. With regard to this, animal models have proved very useful in providing information about the brain mechanisms involved in the development of these cognitive and brain reserves and how they interact with each other.

Methods: We summarize several studies showing the positive effects of Environmental Enrichment (EE), understood as a housing condition in which animals benefit from the sensory, physical, cognitive and social stimulation provided, on brain and cognitive functions usually impaired during aging.

Results: Most of studies have shown that EE is a successful protocol to improve cognitive functions and reduce anxiety-related behaviors across the lifespan, as well as in animal models of neurodegenerative diseases.

Conclusion: Therefore, EE is a laboratory condition in which some aspects of an active lifestyle are reproduced.

Chlorogenic Acid and Mental Diseases: From Chemistry to Medicine by Seyed Fazel Nabavi, Silvia Tejada, William N. Setzer, Olga Gortzi, Antoni Sureda, Nady Braidy, Maria Daglia, Azadeh Manayi, Seyed Mohammad Nabavi (471-479).
Background: At present, much attention has been focused on the beneficial effects of natural products on the human health due to their high efficacy and low adverse effects. Among them, polyphenolic compounds are known as one of the most important and common classes of natural products, which possess multiple range of health-promotion effects including anti-inflammatory and antioxidant activities. A plethora of scientific evidence has shown that polyphenolic compounds possess beneficial effects on the central nervous system.

Methods: Data were collected from Web of Science (ISI Web of Knowledge), Medline, Pubmed, Scopus, Embase, and BIOSIS Previews (from 1950 to 2015), through searching of these keywords: “chlorogenic acid and mental diseases” and “chlorogenic acid and neuroprotection”.

Results: Chlorogenic acid is known as one of the most common polyphenolic compounds, and is found in different types of fruits and vegetables, spices, wine, olive oil, as well as coffee. The potential neuroprotective effects of chlorogenic acid have been highlighted in several in vitro and in vivo studies. This review critically analyses the available scientific evidence regarding the neuroprotective effects of chlorogenic acid, and its neuropharmacological mechanisms of action. In addition, we also discuss its biosynthesis, sources, bioavailability and metabolism, to provide a broad perspective of the therapeutic implications of this compound in brain health and disease.

Conclusion: The present review showed that chlorogenic acid possesses neuroprotective effects under the both in vitro and in vivo models.

Cholinergic System and Post-translational Modifications: An Insight on the Role in Alzheimer';s Disease by Touqeer Ahmed, Saadia Zahid, Aamra Mahboob, Syeda Mehpara Farhat (480-494).
Background: Alzheimer's disease (AD) is the most common form of old age dementia. The formation of amyloid plaques (A?), neurofibrillary tangles and loss of basal forebrain cholinergic neurons are the hallmark events in the pathology of AD.

Literature Review: Cholinergic system is one of the most important neurotransmitter system involved in learning and memory which preferentially degenerates in the initial stages of AD. Activation of cholinergic receptors (muscarinic and nicotinic) activates multiple pathways which result in post translational modifications (PTMs) in multiple proteins which bring changes in nervous system. Cholinergic receptors-mediated PTMs “in-part” substantially affect the biosynthesis, proteolysis, degradation and expression of many proteins and in particular, amyloid precursor protein (APP). APP is subjected to several PTMs (proteolytic processing, glycosylation, sulfation, and phosphorylation) during its course of processing, resulting in A? deposition, leading to AD. A? also alters the PTMs of tau which is a microtubule associated protein. Therefore, post-translationally modified tau and A? collectively aggravate the neuronal loss that leads to cholinergic hypofunction.

Conclusion: Despite the accumulating evidences, the interaction between cholinergic neurotransmission and the physiological significance of PTM events remain speculative and still needs further exploration. This review focuses on the role of cholinergic system and discusses the significance of PTMs in pathological progression of AD and highlights some important future directions.

Neuroprotective Effects of Exercise Treatments After Injury: The Dual Role of Neurotrophic Factors by Stefano Cobianchi, Ariadna Arbat-Plana, Víctor M. Lopez-Alvarez, Xavier Navarro (495-518).
Background: Shared connections between physical activity and neuroprotection have been studied for decades, but the mechanisms underlying this effect of specific exercise were only recently brought to light. Several evidences suggest that physical activity may be a reasonable and beneficial method to improve functional recovery in both peripheral and central nerve injuries and to delay functional decay in neurodegenerative diseases. In addition to improving cardiac and immune functions, physical activity may represent a multifunctional approach not only to improve cardiocirculatory and immune functions, but potentially modulating trophic factors signaling and, in turn, neuronal function and structure at times that may be critical for neurodegeneration and regeneration.

Methods: Research content related to the effects of physical activity and specific exercise programs in normal and injured nervous system have been reviewed.

Results: Sustained exercise, particularly if applied at moderate intensity and early after injury, exerts anti-inflammatory and pro-regenerative effects, and may boost cognitive and motor functions in aging and neurological disorders. However, newest studies show that exercise modalities can differently affect the production and function of brain-derived neurotrophic factor and other neurotrophins involved in the generation of neuropathic conditions. These findings suggest the possibility that new exercise strategies can be directed to nerve injuries with therapeutical benefits.

Conclusion: Considering the growing burden of illness worldwide, understanding of how modulation of neurotrophic factors contributes to exercise-induced neuroprotection and regeneration after peripheral nerve and spinal cord injuries is a relevant topic for research, and represents the beginning of a new non-pharmacological therapeutic approach for better rehabilitation of neural disorders.

The Long Run: Neuroprotective Effects of Physical Exercise on Adult Neurogenesis from Youth to Old Age by Daniele Saraulli, Marco Costanzi, Valentina Mastrorilli, Stefano Farioli-Vecchioli (519-533).
Background: The rapid lengthening of life expectancy has raised the problem of providing social programs to counteract the age-related cognitive decline in a growing number of older people. Physical activity stands among the most promising interventions aimed at brain wellbeing, because of its effective neuroprotective action and low social cost. The purpose of this review is to describe the neuroprotective role exerted by physical activity in different life stages. In particular, we focus on adult neurogenesis, a process which has proved being highly responsive to physical exercise and may represent a major factor of brain health over the lifespan.

Methods: The most recent literature related to the subject has been reviewed. The text has been divided into three main sections, addressing the effects of physical exercise during childhood/ adolescence, adulthood and aging, respectively. For each one, the most relevant studies, carried out on both human participants and rodent models, have been described.

Results: The data reviewed converge in indicating that physical activity exerts a positive effect on brain functioning throughout the lifespan. However, uncertainty remains about the magnitude of the effect and its biological underpinnings. Cellular and synaptic plasticity provided by adult neurogenesis are highly probable mediators, but the mechanism for their action has yet to be conclusively established.

Conclusion: Despite alternative mechanisms of action are currently debated, age-appropriate physical activity programs may constitute a large-scale, relatively inexpensive and powerful approach to dampen the individual and social impact of age-related cognitive decline.

Background: Omega-3 polyunsaturated fatty acids (n-3 PUFA) are structural components of the brain and are indispensable for neuronal membrane synthesis. Along with decline in cognition, decreased synaptic density and neuronal loss, normal aging is accompanied by a reduction in n-3 PUFA concentration in the brain in both humans and rodents. Recently, many clinical and experimental studies have demonstrated the importance of n-3 PUFA in counteracting neurodegeneration and agerelated dysfunctions.

Methods: This review will focus on the neuroprotective effects of n-3 PUFA on cognitive impairment, neuroinflammation and neurodegeneration during normal aging. Multiple pathways of n-3 PUFA preventive action will be examined.

Results: Namely, n-3 PUFA have been shown to increase the levels of several signaling factors involved in synaptic plasticity, thus leading to the increase of dendritic spines and synapses as well as the enhancement of hippocampal neurogenesis even at old age. In elderly subjects n-3 PUFA exert anti-inflammatory effects associated with improved cognitive functions. Interestingly, growing evidence highlights n-3 PUFA efficacy in preventing the loss of both gray and white matter volume and integrity.

Conclusion: This review shows that n-3 PUFA are essential for a successful aging and appear as ideal cognitive enhancers to be implemented in nutritional interventions for the promotion of healthy aging.

In recent years, a growing interest has emerged in the beneficial effects of positive social interactions on health. The present work aims to review animal and human studies linking social interactions and health throughout the lifespan, with a focus on current knowledge of the possible mediating role of opioids and oxytocin. During the prenatal period, a positive social environment contributes to regulating maternal stress response and protecting the fetus from exposure to maternal active glucocorticoids. Throughout development, positive social contact with the caregiver acts as a “hidden regulator” and promotes infant neuroaffective development. Postnatal social neuroprotection interventions involving caregiver-infant physical contact seem to be crucial for rescuing preterm infants at risk for neurodevelopmental disorders. Attachment figures and friendships in adulthood continue to have a protective role for health and brain functioning, counteracting brain aging. In humans, implementation of meditative practices that promote compassionate motivation and prosocial behavior appears beneficial for health in adolescents and adults. Human and animal studies suggest the oxytocinergic and opioidergic systems are important mediators of the effects of social interactions. However, most of the studies focus on a specific phase of life (i.e., adulthood). Future studies should focus on the role of opioids and oxytocin in positive social interactions adopting a lifespan perspective.

Polyphenols Beyond Barriers: A Glimpse into the Brain by Ines Figueira, Regina Menezes, Diana Macedo, Ines Costa, Claudia Nunes dos Santos (562-594).
Background: Ageing can be simply defined as the process of becoming older, which is genetically determined but also environmentally modulated. With the continuous increase of life expectancy, quality of life during ageing has become one of the biggest challenges of developed countries. The quest for a healthy ageing has led to the extensive study of plant polyphenols with the aim to prevent age-associated deterioration and diseases, including neurodegenerative diseases. The world of polyphenols has fascinated researchers over the past decades, and in vitro, cell-based, animal and human studies have attempted to unravel the mechanisms behind dietary polyphenols neuroprotection.

Methods: In this review, we compiled some of the extensive and ever-growing research in the field, highlighting some of the most recent trends in the area.

Results: The main findings regarding polypolyphenols neuroprotective potential performed using in vitro, cellular and animal studies, as well as human trials are covered in this review. Concepts like bioavailability, polyphenols biotransformation, transport of dietary polyphenols across barriers, including the blood-brain barrier, are here explored.

Conclusion: The diversity and holistic properties of polypolyphenol present them as an attractive alternative for the treatment of multifactorial diseases, where a multitude of cellular pathways are disrupted. The underlying mechanisms of polypolyphenols for nutrition or therapeutic applications must be further consolidated, however there is strong evidence of their beneficial impact on brain function during ageing. Nevertheless, only the tip of the iceberg of nutritional and pharmacological potential of dietary polyphenols is hitherto understood and further research needs to be done to fill the gaps in pursuing a healthy ageing.

Background: Microglia are the resident immunocompetent cells of the CNS and also constitute a unique cell type that contributes to neural network homeostasis and function. Understanding microglia cell-signaling not only will reveal their diverse functions but also will help to identify pharmacological and non-pharmacological tools to modulate the activity of these cells.

Methods: We undertook a search of bibliographic databases for peer-reviewed research literature to identify microglial activators and their cell-specificity. We also looked for their effects on neural network function and dysfunction.

Results: We identified several pharmacological targets to modulate microglial function, which are more or less specific (with the proper control experiments). We also identified pharmacological targets that would require the development of new potent and specific modulators. We identified a wealth of evidence about the participation of microglia in neural network function and their alterations in pathological conditions.

Conclusion: The identification of specific microglia-activating signals provides experimental tools to modulate the activity of this heterogeneous cell type in order to evaluate its impact on other components of the nervous system, and it also helps to identify therapeutic approaches to ease some pathological conditions related to microglial dysfunction.

Tumour-Derived Glutamate: Linking Aberrant Cancer Cell Metabolism to Peripheral Sensory Pain Pathways by Jennifer Fazzari, Katja Linher-Melville, Gurmit Singh (620-636).
Background: Chronic pain is a major symptom that develops in cancer patients, most commonly emerging during advanced stages of the disease. The nature of cancer-induced pain is complex, and the efficacy of current therapeutic interventions is restricted by the dose-limiting sideeffects that accompany common centrally targeted analgesics.

Methods: This review focuses on how up-regulated glutamate production and export by the tumour converge at peripheral afferent nerve terminals to transmit nociceptive signals through the transient receptor cation channel, TRPV1, thereby initiating central sensitization in response to peripheral disease-mediated stimuli.

Results: Cancer cells undergo numerous metabolic changes that include increased glutamine catabolism and over-expression of enzymes involved in glutaminolysis, including glutaminase. This mitochondrial enzyme mediates glutaminolysis, producing large pools of intracellular glutamate. Upregulation of the plasma membrane cystine/glutamate antiporter, system xc -, promotes aberrant glutamate release from cancer cells. Increased levels of extracellular glutamate have been associated with the progression of cancer-induced pain and we discuss how this can be mediated by activation of TRPV1.

Conclusion: With a growing population of patients receiving inadequate treatment for intractable pain, new targets need to be considered to better address this largely unmet clinical need for improving their quality of life. A better understanding of the mechanisms that underlie the unique qualities of cancer pain will help to identify novel targets that are able to limit the initiation of pain from a peripheral source-the tumour.

Acetylcholinesterase Inhibitors and Drugs Acting on Muscarinic Receptors- Potential Crosstalk of Cholinergic Mechanisms During Pharmacological Treatment by Ondrej Soukup, Michael Winder, Uday Kumar Killi, Vladimir Wsol, Daniel Jun, Kamil Kuca, Gunnar Tobin (637-653).
Background: Pharmaceuticals with targets in the cholinergic transmission have been used for decades and are still fundamental treatments in many diseases and conditions today. Both the transmission and the effects of the somatomotoric and the parasympathetic nervous systems may be targeted by such treatments. Irrespective of the knowledge that the effects of neuronal signalling in the nervous systems may include a number of different receptor subtypes of both the nicotinic and the muscarinic receptors, this complexity is generally overlooked when assessing the mechanisms of action of pharmaceuticals.

Methods: We have search of bibliographic databases for peer-reviewed research literature focused on the cholinergic system. Also, we have taken advantage of our expertise in this field to deduce the conclusions of this study.

Results: Presently, the life cycle of acetylcholine, muscarinic receptors and their effects are reviewed in the major organ systems of the body. Neuronal and non-neuronal sources of acetylcholine are elucidated. Examples of pharmaceuticals, in particular cholinesterase inhibitors, affecting these systems are discussed. The review focuses on salivary glands, the respiratory tract and the lower urinary tract, since the complexity of the interplay of different muscarinic receptor subtypes is of significance for physiological, pharmacological and toxicological effects in these organs.

Conclusion: Most pharmaceuticals targeting muscarinic receptors are employed at such large doses that no selectivity can be expected. However, some differences in the adverse effect profile of muscarinic antagonists may still be explained by the variation of expression of muscarinic receptor subtypes in different organs. However, a complex pattern of interactions between muscarinic receptor subtypes occurs and needs to be considered when searching for selective pharmaceuticals. In the development of new entities for the treatment of for instance pesticide intoxication, the muscarinic receptor selectivity needs to be considered. Reactivators generally have a muscarinic M2 receptor acting profile. Such a blockade may engrave the situation since it may enlarge the effect of the muscarinic M3 receptor effect. This may explain why respiratory arrest is the major cause for deaths by esterase blocking.