Molecular Mechanisms Underlying the Beneficial Effects of Exercise on Brain Function and Neurological Disorders

As life expectancy has increased, particularly in developed countries, due to medical advances and increased prosperity, age-related neurological diseases and mental health disorders have become more prevalent health issues, reducing the well-being and quality of life of sufferers and their families. In recent decades, due to reduced work-related levels of physical activity, and key research insights, prescribing adequate exercise has become an innovative strategy to prevent or delay the onset of these pathologies and has been demonstrated to have therapeutic benefits when used as a sole or combination treatment. Recent evidence suggests that the beneficial effects of exercise on the brain are related to several underlying mechanisms related to muscle–brain, liver–brain and gut–brain crosstalk. Therefore, this review aims to summarize the most relevant current knowledge of the impact of exercise on mood disorders and neurodegenerative diseases, and to highlight the established and potential underlying mechanisms involved in exercise–brain communication and their benefits for physiology and brain function.     

The Role of Gut Microbiota and Gut–Brain Interplay in Selected Diseases of the Central Nervous System

The gut microbiome has attracted increasing attention from researchers in recent years. The microbiota can have a specific and complex cross-talk with the host, particularly with the central nervous system (CNS), creating the so-called “gut–brain axis”. Communication between the gut, intestinal microbiota, and the brain involves the secretion of various metabolites such as short-chain fatty acids (SCFAs), structural components of bacteria, and signaling molecules. Moreover, an imbalance in the gut microbiota composition modulates the immune system and function of tissue barriers such as the blood–brain barrier (BBB). Therefore, the aim of this literature review is to describe how the gut–brain interplay may contribute to the development of various neurological disorders, combining the fields of gastroenterology and neuroscience. We present recent findings concerning the effect of the altered microbiota on neurodegeneration and neuroinflammation, including Alzheimer’s and Parkinson’s diseases, as well as multiple sclerosis. Moreover, the impact of the pathological shift in the microbiome on selected neuropsychological disorders, i.e., major depressive disorders (MDD) and autism spectrum disorder (ASD), is also discussed. Future research on the effect of balanced gut microbiota composition on the gut–brain axis would help to identify new potential opportunities for therapeutic interventions in the presented diseases.     

Shared Inflammatory Pathology of Stroke and COVID-19

Though COVID-19 is primarily characterized by symptoms in the periphery, it can also affect the central nervous system (CNS). This has been established by the association between stroke and COVID-19. However, the molecular mechanisms that cause stroke related to a COVID-19 infection have not been fully explored. More specifically, stroke and COVID-19 exhibit an overlap of molecular mechanisms. These similarities provide a way to better understand COVID-19 related stroke. We propose here that peripheral macrophages upregulate inflammatory proteins such as matrix metalloproteinases (MMPs) in response to SARS-CoV-2 infection. These inflammatory molecules and the SARS-CoV-2 virus have multiple negative effects related to endothelial dysfunction that results in the disruption of the blood–brain barrier (BBB). Finally, we discuss how the endothelial blood–brain barrier injury alters central nervous system function by leading to astrocyte dysfunction and inflammasome activation. Our goal is to elucidate such inflammatory pathways, which could provide insight into therapies to combat the negative neurological effects of COVID-19.     

Microglial Activation Damages Dopaminergic Neurons through MMP-2/-9-Mediated Increase of Blood-Brain Barrier Permeability in a Parkinson’s Disease Mouse Model

Chronic neuroinflammation has been considered to be involved in the progressive dopaminergic neurodegeneration in Parkinson’s disease (PD). However, the mechanisms remain unknown. Accumulating evidence indicated a key role of the blood–brain barrier (BBB) dysfunction in neurological disorders. This study is designed to elucidate whether chronic neuroinflammation damages dopaminergic neurons through BBB dysfunction by using a rotenone-induced mouse PD model. Results showed that rotenone dose-dependently induced nigral dopaminergic neurodegeneration, which was associated with increased Evans blue content and fibrinogen accumulation as well as reduced expressions of zonula occludens-1 (ZO-1), claudin-5 and occludin, three tight junction proteins for maintaining BBB permeability, in mice, indicating BBB disruption. Rotenone also induced nigral microglial activation. Depletion of microglia or inhibition of microglial activation by PLX3397 or minocycline, respectively, greatly attenuated BBB dysfunction in rotenone-lesioned mice. Mechanistic inquiry revealed that microglia-mediated activation of matrix metalloproteinases-2 and 9 (MMP-2/-9) contributed to rotenone-induced BBB disruption and dopaminergic neurodegeneration. Rotenone-induced activation of MMP-2/-9 was significantly attenuated by microglial depletion and inactivation. Furthermore, inhibition of MMP-2/-9 by a wide-range inhibitor, SB-3CT, abrogated elevation of BBB permeability and simultaneously increased tight junctions expression. Finally, we found that microglial depletion and inactivation as well as inhibition of MMP-2/-9 significantly ameliorated rotenone-elicited nigrostriatal dopaminergic neurodegeneration and motor dysfunction in mice. Altogether, our findings suggested that microglial MMP-2/-9 activation-mediated BBB dysfunction contributed to dopaminergic neurodegeneration in rotenone-induced mouse PD model, providing a novel view for the mechanisms of Parkinsonism.     

Melatonin and the Brain–Heart Crosstalk in Neurocritically Ill Patients—From Molecular Action to Clinical Practice

Brain injury, especially traumatic brain injury (TBI), may induce severe dysfunction of extracerebral organs. Cardiac dysfunction associated with TBI is common and well known as the brain–heart crosstalk, which broadly refers to different cardiac disorders such as cardiac arrhythmias, ischemia, hemodynamic insufficiency, and sudden cardiac death, which corresponds to acute disorders of brain function. TBI-related cardiac dysfunction can both worsen the brain damage and increase the risk of death. TBI-related cardiac disorders have been mainly treated symptomatically. However, the analysis of pathomechanisms of TBI-related cardiac dysfunction has highlighted an important role of melatonin in the prevention and treatment of such disorders. Melatonin is a neurohormone released by the pineal gland. It plays a crucial role in the coordination of the circadian rhythm. Additionally, melatonin possesses strong anti-inflammatory, antioxidative, and antiapoptotic properties and can modulate sympathetic and parasympathetic activities. Melatonin has a protective effect not only on the brain, by attenuating its injury, but on extracranial organs, including the heart. The aim of this study was to analyze the molecular activity of melatonin in terms of TBI-related cardiac disorders. Our article describes the benefits resulting from using melatonin as an adjuvant in protection and treatment of brain injury-induced cardiac dysfunction.     

The Therapeutic Role of Exercise and Probiotics in Stressful Brain Conditions

Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurological disorders such as Parkinson’s disease, Alzheimer’s dementia, ischemic stroke, and head and spinal cord injury. The increased production of reactive oxygen species (ROS) has been associated with mitochondrial dysfunction, altered metal homeostasis, and compromised brain antioxidant defence. All these changes have been reported to directly affect synaptic activity and neurotransmission in neurons, leading to cognitive dysfunction. In this context two non-invasive strategies could be employed in an attempt to improve the aforementioned stressful brain status. In this regard, it has been shown that exercise could increase the resistance against oxidative stress, thus providing enhanced neuroprotection. Indeed, there is evidence suggesting that regular physical exercise diminishes BBB permeability as it reinforces antioxidative capacity, reduces oxidative stress, and has anti-inflammatory effects. However, the differential effects of different types of exercise (aerobic exhausted exercise, anaerobic exercise, or the combination of both types) and the duration of physical activity will be also addressed in this review as likely determinants of therapeutic efficacy. The second proposed strategy is related to the use of probiotics, which can also reduce some biomarkers of oxidative stress and inflammatory cytokines, although their underlying mechanisms of action remain unclear. Moreover, various probiotics produce neuroactive molecules that directly or indirectly impact signalling in the brain. In this review, we will discuss how physical activity can be incorporated as a component of therapeutic strategies in oxidative stress-based neurological disorders along with the augmentation of probiotics intake.     

Diabetes and Ischemic Stroke: An Old and New Relationship an Overview of the Close Interaction between These Diseases

Diabetes mellitus is a comprehensive expression to identify a condition of chronic hyperglycemia whose causes derive from different metabolic disorders characterized by altered insulin secretion or faulty insulin effect on its targets or often both mechanisms. Diabetes and atherosclerosis are, from the point of view of cardio- and cerebrovascular risk, two complementary diseases. Beyond shared aspects such as inflammation and oxidative stress, there are multiple molecular mechanisms by which they feed off each other: chronic hyperglycemia and advanced glycosylation end-products (AGE) promote ‘accelerated atherosclerosis’ through the induction of endothelial damage and cellular dysfunction. These diseases impact the vascular system and, therefore, the risk of developing cardio- and cerebrovascular events is now evident, but the observation of this significant correlation has its roots in past decades. Cerebrovascular complications make diabetic patients 2–6 times more susceptible to a stroke event and this risk is magnified in younger individuals and in patients with hypertension and complications in other vascular beds. In addition, when patients with diabetes and hyperglycemia experience an acute ischemic stroke, they are more likely to die or be severely disabled and less likely to benefit from the one FDA-approved therapy, intravenous tissue plasminogen activator. Experimental stroke models have revealed that chronic hyperglycemia leads to deficits in cerebrovascular structure and function that may explain some of the clinical observations. Increased edema, neovascularization, and protease expression as well as altered vascular reactivity and tone may be involved and point to potential therapeutic targets. Further study is needed to fully understand this complex disease state and the breadth of its manifestation in the cerebrovasculature.     

Colocalization and Interaction Study of Neuronal JNK3, JIP1, and β-Arrestin2 Together with PSD95

c-Jun N-terminal kinases (JNKs) are stress-activated serine/threonine protein kinases belonging to the mitogen-activated protein kinase (MAPK) family. Among them, JNK3 is selectively expressed in the central nervous system, cardiac smooth muscle, and testis. In addition, it is the most responsive JNK isoform to stress stimuli in the brain, and it is involved in synaptic dysfunction, an essential step in neurodegenerative processes. JNK3 pathway is organized in a cascade of amplification in which signal transduction occurs by stepwise, highly controlled phosphorylation. Since different MAPKs share common upstream activators, pathway specificity is guaranteed by scaffold proteins such as JIP1 and β-arrestin2. To better elucidate the physiological mechanisms regulating JNK3 in neurons, and how these interactions may be involved in synaptic (dys)function, we used (i) super-resolution microscopy to demonstrate the colocalization among JNK3–PSD95–JIP1 and JNK3–PSD95–β-arrestin2 in cultured hippocampal neurons, and (ii) co-immunoprecipitation techniques to show that the two scaffold proteins and JNK3 can be found interacting together with PSD95. The protein-protein interactions that govern the formation of these two complexes, JNK3–PSD95–JIP1 and JNK3–PSD95–β-arrestin2, may be used as targets to interfere with their downstream synaptic events.     

Secondary Metabolites of Plants as Modulators of Endothelium Functions

According to the World Health Organization, cardiovascular diseases are the main cause of death worldwide. They may be caused by various factors or combinations of factors. Frequently, endothelial dysfunction is involved in either development of the disorder or results from it. On the other hand, the endothelium may be disordered for other reasons, e.g., due to infection, such as COVID-19. The understanding of the role and significance of the endothelium in the body has changed significantly over time—from a simple physical barrier to a complex system encompassing local and systemic regulation of numerous processes in the body. Endothelium disorders may arise from impairment of one or more signaling pathways affecting dilator or constrictor activity, including nitric oxide–cyclic guanosine monophosphate activation, prostacyclin–cyclic adenosine monophosphate activation, phosphodiesterase inhibition, and potassium channel activation or intracellular calcium level inhibition. In this review, plants are summarized as sources of biologically active substances affecting the endothelium. This paper compares individual substances and mechanisms that are known to affect the endothelium, and which subsequently may cause the development of cardiovascular disorders.     

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel K_v1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.     

Melatonin for Neonatal Encephalopathy: From Bench to Bedside

Neonatal encephalopathy is a leading cause of morbidity and mortality worldwide. Although therapeutic hypothermia (HT) is now standard practice in most neonatal intensive care units in high resource settings, some infants still develop long-term adverse neurological sequelae. In low resource settings, HT may not be safe or efficacious. Therefore, additional neuroprotective interventions are urgently needed. Melatonin’s diverse neuroprotective properties include antioxidant, anti-inflammatory, and anti-apoptotic effects. Its strong safety profile and compelling preclinical data suggests that melatonin is a promising agent to improve the outcomes of infants with NE. Over the past decade, the safety and efficacy of melatonin to augment HT has been studied in the neonatal piglet model of perinatal asphyxia. From this model, we have observed that the neuroprotective effects of melatonin are time-critical and dose dependent. Therapeutic melatonin levels are likely to be 15–30 mg/L and for optimal effect, these need to be achieved within the first 2–3 h after birth. This review summarises the neuroprotective properties of melatonin, the key findings from the piglet and other animal studies to date, and the challenges we face to translate melatonin from bench to bedside.     

The Gut-Brain Axis in Inflammatory Bowel Disease—Current and Future Perspectives

The gut–brain axis is a bidirectional communication system driven by neural, hormonal, metabolic, immunological, and microbial signals. Signaling events from the gut can modulate brain function and recent evidence suggests that the gut–brain axis may play a pivotal role in linking gastrointestinal and neurological diseases. Accordingly, accumulating evidence has suggested a link between inflammatory bowel diseases (IBDs) and neurodegenerative, as well as neuroinflammatory diseases. In this context, clinical, epidemiological and experimental data have demonstrated that IBD predisposes a person to pathologies of the central nervous system (CNS). Likewise, a number of neurological disorders are associated with changes in the intestinal environment, which are indicative for disease-mediated gut–brain inter-organ communication. Although this axis was identified more than 20 years ago, the sequence of events and underlying molecular mechanisms are poorly defined. The emergence of precision medicine has uncovered the need to take into account non-intestinal symptoms in the context of IBD that could offer the opportunity to tailor therapies to individual patients. The aim of this review is to highlight recent findings supporting the clinical and biological link between the gut and brain, as well as its clinical significance for IBD as well as neurodegeneration and neuroinflammation. Finally, we focus on novel human-specific preclinical models that will help uncover disease mechanisms to better understand and modulate the function of this complex system.     

Extracellular Vesicles as an Index for Endothelial Injury and Cardiac Dysfunction in a Rodent Model of GDM

Gestational diabetes mellitus (GDM) increases risk of adverse pregnancy outcomes and maternal cardiovascular complications. It is widely believed that maternal endothelial dysfunction is a critical determinant of these risks, however, connections to maternal cardiac dysfunction and mechanisms of pathogenesis are unclear. Circulating extracellular vesicles (EVs) are emerging biomarkers that may provide insights into the pathogenesis of GDM. We examined the impact of GDM on maternal cardiac and vascular health in a rat model of diet-induced obesity-associated GDM. We observed a >3-fold increase in circulating levels of endothelial EVs (p < 0.01) and von Willebrand factor (p < 0.001) in GDM rats. A significant increase in mitochondrial DNA (mtDNA) within circulating extracellular vesicles was also observed suggesting possible mitochondrial dysfunction in the vasculature. This was supported by nicotinamide adenine dinucleotide deficiency in aortas of GDM mice. GDM was also associated with cardiac remodeling (increased LV mass) and a marked impairment in maternal diastolic function (increased isovolumetric relaxation time [IVRT], p < 0.01). Finally, we observed a strong positive correlation between endothelial EV levels and IVRT (r = 0.57, p < 0.05). In summary, we observed maternal vascular and cardiac dysfunction in rodent GDM accompanied by increased circulating endothelial EVs and EV-associated mitochondrial DNA. Our study highlights a novel method for assessment of vascular injury in GDM and highlights vascular mitochondrial injury as a possible therapeutic target.     

Induction of Oxidative Stress and Mitochondrial Dysfunction by Juglone Affects the Development of Bovine Oocytes

Juglone, a major naphthalenedione component of walnut trees, has long been used in traditional medicine as an antimicrobial and antitumor agent. Nonetheless, its impact on oocyte and preimplantation embryo development has not been entirely clarified. Using the bovine model, we sought to elucidate the impact of juglone treatment during the in vitro maturation (IVM) of oocytes on their maturation and development of embryos. Results showed a severe reduction in oocyte nuclear maturation and cumulus expansion and a significant increase in mitochondrial dysfunction and reactive oxygen species (ROS) levels in cumulus–oocyte complexes (COCs) treated with juglone (12.5, 25.0, and 50.0 µM). In addition, RT–qPCR showed downregulation of the expansion-related (HAS2, TNFAIP6, PTX3, and PTGS2) and mitochondrial (ATPase6 and ATP5F1E) genes in juglone-treated COCs. Moreover, the development rates of day 4 total cleavage and 8–16 cell stage embryos, as well as day 8 blastocysts, were significantly reduced following exposure to juglone. Using immunofluorescence, the apoptotic marker caspase-9 was overexpressed in oocytes exposed to juglone (25.0 µM) compared to the untreated control. In conclusion, our study reports that exposing bovine oocytes to 12.5–50.0 µM of juglone can reduce their development through the direct induction of ROS accumulation, apoptosis, and mitochondrial dysfunction.     

Electroconvulsive Therapy in Psychiatric Disorders: A Narrative Review Exploring Neuroendocrine–Immune Therapeutic Mechanisms and Clinical Implications

Electroconvulsive therapy (ECT) is based on conducting an electrical current through the brain to stimulate it and trigger generalized convulsion activity with therapeutic ends. Due to the efficient use of ECT during the last years, interest in the molecular bases involved in its mechanism of action has increased. Therefore, different hypotheses have emerged. In this context, the goal of this review is to describe the neurobiological, endocrine, and immune mechanisms involved in ECT and to detail its clinical efficacy in different psychiatric pathologies. This is a narrative review in which an extensive literature search was performed on the Scopus, Embase, PubMed, ISI Web of Science, and Google Scholar databases from inception to February 2022. The terms “electroconvulsive therapy”, “neurobiological effects of electroconvulsive therapy”, “molecular mechanisms in electroconvulsive therapy”, and “psychiatric disorders” were among the keywords used in the search. The mechanisms of action of ECT include neurobiological function modifications and endocrine and immune changes that take place after ECT. Among these, the decrease in neural network hyperconnectivity, neuroinflammation reduction, neurogenesis promotion, modulation of different monoaminergic systems, and hypothalamus–hypophysis–adrenal and hypothalamus–hypophysis–thyroid axes normalization have been described. The majority of these elements are physiopathological components and therapeutic targets in different mental illnesses. Likewise, the use of ECT has recently expanded, with evidence of its use for other pathologies, such as Parkinson’s disease psychosis, malignant neuroleptic syndrome, post-traumatic stress disorder, and obsessive–compulsive disorder. In conclusion, there is sufficient evidence to support the efficacy of ECT in the treatment of different psychiatric disorders, potentially through immune, endocrine, and neurobiological systems.     

Mitochondria and Calcium Homeostasis: Cisd2 as a Big Player in Cardiac Ageing

The ageing of human populations has become a problem throughout the world. In this context, increasing the healthy lifespan of individuals has become an important target for medical research and governments. Cardiac disease remains the leading cause of morbidity and mortality in ageing populations and results in significant increases in healthcare costs. Although clinical and basic research have revealed many novel insights into the pathways that drive heart failure, the molecular mechanisms underlying cardiac ageing and age-related cardiac dysfunction are still not fully understood. In this review we summarize the most updated publications and discuss the central components that drive cardiac ageing. The following characters of mitochondria-related dysfunction have been identified during cardiac ageing: (a) disruption of the integrity of mitochondria-associated membrane (MAM) contact sites; (b) dysregulation of energy metabolism and dynamic flexibility; (c) dyshomeostasis of Ca²⁺ control; (d) disturbance to mitochondria–lysosomal crosstalk. Furthermore, Cisd2, a pro-longevity gene, is known to be mainly located in the endoplasmic reticulum (ER), mitochondria, and MAM. The expression level of Cisd2 decreases during cardiac ageing. Remarkably, a high level of Cisd2 delays cardiac ageing and ameliorates age-related cardiac dysfunction; this occurs by maintaining correct regulation of energy metabolism and allowing dynamic control of metabolic flexibility. Together, our previous studies and new evidence provided here highlight Cisd2 as a novel target for developing therapies to promote healthy ageing     

Copper,Iron, and Manganese Toxicity in Neuropsychiatric Conditions

Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and “prion-like disease”, amyotrophic lateral sclerosis, Huntington’s disease, Friedreich’s ataxia, and depression.