Current Neuropharmacology - Volume 20, Issue 11, 2022

The role of the immune system in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) has become clear in recent decades, as evidenced by the presence of activated microglia and astrocytes and numerous soluble mediators in the brain and peripheral tissues of affected patients. Among inflammatory mediators, chemokines play a central role in neuroinflammation due to their dual function as chemoattractants for immune cells and molecular messengers in crosstalk among CNS-resident cells. The chemokine Bv8/Prokineticin 2 (PK2) has recently emerged as an important player in many age-related and chronic diseases that are either neurodegenerative or systemic. In this perspective paper, we briefly discuss the role that PK2 and its cognate receptors play in AD and PD animal models and in patients. Given the apparent changes in PK2 blood levels in both AD and PD patients, the potential clinical value of PK2 either as a disease biomarker or as a therapeutic target for these disorders is discussed.

Cocaine Use Disorder (CUD) is one of the diseases with the greatest social and health impact, due to the high cost of rehabilitation management and the high risk of dangerous behavior and relapse. This pathology frequently leads to unsuccessful attempts to interrupt the consumption, resulting in relapses and a vicious cycle of binge/intoxication, withdrawal/negative affect, and preoccupation/ anticipation (craving). The alternation of these phases in addiction was well illustrated by Koob and colleagues in the so-called “addictive cycle”, which nowadays represents a landmark in the addiction field. Recently, there has been a surge of interest in the worldwide literature for biomarkers that might explain the different stages of addiction, and one of the most studied biomarkers is, without a doubt, Brain-derived Neurotrophic Factor (BDNF). In this perspective article, we discuss the potential role of BDNF as biomarker of the CUD phases described in the “Addictive Cycle”, speculating about the close relationship between BDNF fluctuations and the clinical course of CUD. We also discuss BDNF’s potential role as “staging” biomarker, predicting the progression of the disease. Finding valuable biomarkers of CUD severity and disease stage could shift clinicians' focus away from behavioral symptomatic treatment and toward a novel brain-based approach, allowing for the development of mo

The literature on epileptic seizures in Alzheimer's disease has significantly increased over the past decades. Remarkably, several studies suggest a bi-directional link between these two common neurological diseases, with either condition carrying a nearly 2-fold risk of contracting the other in comparison to healthy subjects. In this respect, evidence from both clinical and preclinical studies indicates that epileptogenesis and neurodegeneration possibly share common underlying mechanisms. However, the precise association between epileptogenesis and neurodegeneration still needs to be fully elucidated. Targeted intervention to reduce abnormal network hyperexcitability might constitute a therapeutic strategy to postpone the onset of later neurodegenerative changes and consequent cognitive decline by many years in patients. By virtue of this, an early diagnosis and treatment of seizures in patients with Alzheimer’s disease should be pursued. To date, no guidelines are available for treating epileptic activity in this context, largely due to the paucity of studies sufficient to answer the related questions. Accordingly, clinical trials are mandatory, not only to inform clinicians about symptomatic management of seizures in Alzheimer’s disease patients but also to detect if treatment with antiseizure medications could have disease-modifying effects. Moreover, it will be fundamental to expand the application of animal models of Alzheimer’s disease to comorbid conditions, such as epilepsy both to reveal the mechanisms underlying seizure onset and to better define their role in cognitive decline. Such models could also be useful to identify pharmacological compounds having therapeutically effectiveness as well as reliable early biomarkers for seizures in Alzheimer’s disease.

A high-fat diet with appropriate protein and low carbohydrate content, widely known as the ketogenic diet (KD), is considered as an effective non-pharmacotherapeutic treatment option for certain types of epilepsies. Several preclinical and clinical studies have been carried out to elucidate its mechanism of antiepileptic action. Ketone bodies produced after KD's breakdown interact with cellular excito-inhibitory processes and inhibit abnormal neuronal firing. The generated ketone bodies decrease glutamate release by inhibiting the vesicular glutamate transporter 1 and alter the transmembrane potential by hyperpolarization. Apart from their effect on the well-known pathogenic mechanisms of epilepsy, some recent studies have shown the interaction of KD metabolites with novel neuronal targets, particularly adenosine receptors, adenosine triphosphate-sensitive potassium channel, mammalian target of rapamycin, histone deacetylase, hydroxycarboxylic acid receptors, and the NLR family pyrin domain containing 3 inflammasomes to suppress seizures. The role of KD in augmenting gut microbiota as a potential mechanism for epileptic seizure suppression has been established. Furthermore, some recent findings also support the beneficial effect of KD against epilepsy- associated comorbidities. Despite several advantages of the KD in epilepsy management, its use is also associated with a wide range of side effects. Hypoglycemia, excessive ketosis, acidosis, renal stones, cardiomyopathies, and other metabolic disturbances are the primary adverse effects observed with the use of KD. However, in some recent studies, modified KD has been tested with lesser side effects and better tolerability. The present review discusses the molecular mechanism of KD and its role in managing epilepsy and its associated comorbidities.

Microglia are the resident immune cells of the brain and play a crucial role in housekeeping and maintaining homeostasis of the brain microenvironment. Upon injury or disease, microglial cells become activated, at least partly, via signals initiated by injured neurons. Activated microglia, thereby, contribute to both neuroprotection and neuroinflammation. However, sustained microglial activation initiates a chronic neuroinflammatory response which can disturb neuronal health and disrupt communications between neurons and microglia. Thus, microglia-neuron crosstalk is critical in a healthy brain as well as during states of injury or disease. As most studies focus on how neurons and microglia act in isolation during neurotrauma, there is a need to understand the interplay between these cells in brain pathophysiology. This review highlights how neurons and microglia reciprocally communicate under physiological conditions and during brain injury and disease. Furthermore, the modes of microglia-neuron communication are exposed, focusing on cell-contact dependent signaling and communication by the secretion of soluble factors like cytokines and growth factors. In addition, it has been discussed that how microglia-neuron interactions could exert either beneficial neurotrophic effects or pathologic proinflammatory responses. We further explore how aberrations in microglia-neuron crosstalk may be involved in central nervous system (CNS) anomalies, namely traumatic brain injury (TBI), neurodegeneration, and ischemic stroke. A clear understanding of how the microglia-neuron crosstalk contributes to the pathogenesis of brain pathologies may offer novel therapeutic avenues of brain trauma treatment.

Microglial activation is one of the common hallmarks shared by various central nervous system (CNS) diseases. Based on surrounding circumstances, activated microglia play either detrimental or neuroprotective effects. Galectin-3 (Gal-3), a group of β-galactoside-binding proteins, has been cumulatively revealed to be a crucial biomarker for microglial activation after injuries or diseases. In consideration of the important role of Gal-3 in the regulation of microglial activation, it might be a potential target for the treatment of CNS diseases. Recently, Gal-3 expression has been extensively investigated in numerous pathological processes as a mediator of neuroinflammation, as well as in cell proliferation. However, the underlying mechanisms of Gal-3 involved in microgliamediated neuroinflammation in various CNS diseases remain to be further investigated. Moreover, several clinical studies support that the levels of Gal-3 are increased in the serum or cerebrospinal fluid of patients with CNS diseases. Thus, we summarized the roles and underlying mechanisms of Gal-3 in activated microglia, thus providing a better insight into its complexity expression pattern, and contrasting functions in CNS diseases.

Neurodegenerative diseases affect over 30 million people worldwide with an ascending trend. Most individuals suffering from these irreversible brain damages belong to the elderly population, with onset between 50 and 60 years. Although the pathophysiology of such diseases is partially known, it remains unclear upon which point a disease turns degenerative. Moreover, current therapeutics can treat some of the symptoms but often have severe side effects and become less effective in long-term treatment. For many neurodegenerative diseases, the involvement of G proteincoupled receptors (GPCRs), which are key players of neuronal transmission and plasticity, has become clearer and holds great promise in elucidating their biological mechanism. With this review, we introduce and summarize class A and class C GPCRs, known to form heterodimers or oligomers to increase their signalling repertoire. Additionally, the examples discussed here were shown to display relevant alterations in brain signalling and had already been associated with the pathophysiology of certain neurodegenerative diseases. Lastly, we classified the heterodimers into two categories of crosstalk, positive or negative, for which there is known evidence.

P2X7 receptors (Rs) are prominent members of the P2XR family, which after binding ATP, open non-selective cationic channels, thereby allowing the transmembrane passage of Na+, Ca²⁺, and K+. Long-lasting and repetitive stimulation of the receptor by its agonist leads to the formation of large membrane pores permeable for organic cations of up to 900 Da molecular size. These pores are believed to play a role in apoptosis and inflammation. P2X7Rs are located primarily at peripheral macrophages and microglial cells, the resident macrophages of the CNS. The coactivation of toll-like receptors 4 (TLR4) by lipopolysaccharide, a constituent of the cell membrane of gram-negative bacteria, and the P2X7R by ATP leads to the generation and release of the proinflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α. Together with the microglial release of chemokines, reactive oxygen and nitrogen species, proteases, and excitotoxic glutamate, these cytokines result in neurodegeneration. P2X7Rs were found not only to amplify various neurodegenerative illnesses, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, but also to participate in a range of psychiatric diseases, such as major depression, bipolar disorder, schizophrenia, and autism spectrum disorder. Based on the prevention/reversal of neuroinflammation, pharmacological antagonists of P2X7Rs and their genetic deletion in animal experiments counteract these deleterious psychiatric conditions. Hence, brain penetrant P2X7R antagonists are potential therapeutics for psychiatric diseases, although the available evidence still needs to be extended and validated by further clinical data.

Neuroinflammation is a trigger for several neurodegenerative and neuropsychiatric disorders. Exposure to noxious external stimuli induces homeostatic disturbances resulting in morphological changes in microglia, their activation, and elaboration of pro-inflammatory mediators. This leads to neuroinflammation with the progressive loss of neurons. Nutraceuticals such as anthocyanins are a class of brightly colored bioactive compounds present in fruits and vegetables with purported health benefits. They interfere with the activation of several signaling cascades that have a prominent role in preventing neuroinflammation. More importantly, anthocyanins can cross the blood-brain barrier and are safe. Hence, the current review focuses on the bioavailability of anthocyanins, clinical and in vitro evidence on their role in impeding the activation of transcription factors, modulating the immune milieu within the central nervous system, preventing the activation of microglia, and averting neuroinflammation.

Background: Tobacco use in humans is a long-standing public health concern. Flavors are common additives in tobacco and alternative tobacco products, added to mask nicotine’s harsh orosensory effects and increase the appeal of these products. Animal models are integral for investigating nicotine use and addiction and are helpful for understanding the effects of flavor additives on the use of nicotine delivery products. Objective: This review focuses on preclinical models to evaluate the contribution of flavor additives to nicotine addiction. Materials and Methods: An electronic literature search was conducted by authors up to May 2022. Original articles were selected. Results: The behavioral models of rodents described here capture multiple dimensions of human flavored nicotine use behaviors, including advantages and disadvantages. Conclusion: The consensus of the literature search was that human research on nicotine use behavior has not caught up with fast-changing product innovations, marketing practices, and federal regulations. Animal models are therefore needed to investigate mechanisms underlying nicotine use and addiction. This review provides a comprehensive overvie

Brain-derived neurotrophic factor (BDNF) is a crucial brain signaling protein that is integral to many signaling pathways. This neurotrophin has shown to be highly involved in brain plastic processes such as neurogenesis, synaptic plasticity, axonal growth, and neurotransmission, among others. In the first part of this review, we revise the role of BDNF in different neuroplastic processes within the central nervous system. On the other hand, its deficiency in key neural circuits is associated with the development of psychiatric disorders, including alcohol abuse disorder. Many people begin to drink alcohol during adolescence, and it seems that changes in BDNF are evident after the adolescent regularly consumes alcohol. Therefore, the second part of this manuscript addresses the involvement of BDNF during adolescent brain maturation and how this process can be negatively affected by alcohol abuse. Finally, we propose different BNDF enhancers, both behavioral and pharmacological, which should be considered in the treatment of problematic alcohol consumption initiated during the adolescence.

Background: High mobility group box 1 (HMGB1) protein is a damage-associated molecular pattern (DAMP) that plays an important role in the repair and regeneration of tissue injury. It also acts as a pro-inflammatory cytokine through the activation of toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), to elicit the neuroinflammatory response. HMGB1 may aggravate several cellular responses, which may lead to pathological inflammation and cellular death. Thus, there have been a considerable amount of research into the pathological role of HMGB1 in diseases. However, whether the mechanism of action of HMGB1 is similar in all neurodegenerative disease pathology remains to be determined. Objective: Therefore, this systematic review aimed to critically evaluate and elucidate the role of HMGB1 in the pathology of neurodegeneration based on the available literature. Methods: A comprehensive literature search was performed on four databases; EMBASE, PubMed, Scopus, and CINAHL Plus. Results: A total of 85 articles were selected for critical appraisal, after subjecting to the inclusion and exclusion criteria in this study. The selected articles revealed that HMGB1 levels were found elevated in most neurodegeneration except in Huntington’s disease and Spinocerebellar ataxia, where the levels were found decreased. This review also showcased that HMGB1 may act on distinctive pathways to elicit its pathological response leading to the various neurodegeneration processes/ diseases. Conclusion: While there have been promising findings in HMGB1 intervention research, further studies may still be required before any HMGB1 intervention may be recommended as a therapeutic target for neurodegenerative diseases.