Extracellular matrix and biomimetic engineering microenvironment for neuronal differentiation Deepak Jain, Sabrina Mattiassi, Eyleen L Goh, Evelyn K.F. Yim Neural Regeneration Research 2020 15(4):573-585 Extracellular matrix (ECM) influences cell differentiation through its structural and biochemical properties. In nervous system, neuronal behavior is influenced by these ECMs structures which are present in a meshwork, fibrous, or tubular forms encompassing specific molecular compositions. In addition to contact guidance, ECM composition and structures also exert its effect on neuronal differentiation. This short report reviewed the native ECM structure and composition in central nervous system and peripheral nervous system, and their impact on neural regeneration and neuronal differentiation. Using topographies, stem cells have been differentiated to neurons. Further, focussing on engineered biomimicking topographies, we highlighted the role of anisotropic topographies in stem cell differentiation to neurons and its recent temporal application for efficient neuronal differentiation.

Extracellular vesicles in the diagnosis and treatment of central nervous system diseases Alisa A Shaimardanova, Valeriya V Solovyeva, Daria S Chulpanova, Victoria James, Kristina V Kitaeva, Albert A Rizvanov Neural Regeneration Research 2020 15(4):586-596 Extracellular vesicles, including exosomes and microvesicles, play a fundamental role in the activity of the nervous system, participating in signal transmission between neurons and providing the interaction of central nervous system with all body systems. In many neurodegenerative diseases, neurons pack toxic substances into vesicles and release them into the extracellular space, which leads to the spread of misfolded neurotoxic proteins. The contents of neuron-derived extracellular vesicles may indicate pathological changes in the central nervous system, and the analysis of extracellular vesicle molecular content contributes to the development of non-invasive methods for the diagnosis of many central nervous system diseases. Extracellular vesicles of neuronal origin can be isolated from various biological fluids due to their ability to cross the blood-brain barrier. Today, the diagnostic potential of almost all toxic proteins involved in nervous system disease pathogenesis, specifically α-synuclein, tau protein, superoxide dismutase 1, FUS, leucine-rich repeat kinase 2, as well as some synaptic proteins, has been well evidenced. Special attention is paid to extracellular RNAs mostly associated with extracellular vesicles, which are important in the onset and development of many neurodegenerative diseases. Depending on parental cell type, extracellular vesicles may have different therapeutic properties, including neuroprotective, regenerative, and anti-inflammatory. Due to nano size, biosafety, ability to cross the blood-brain barrier, possibility of targeted delivery and the lack of an immune response, extracellular vesicles are a promising vehicle for the delivery of therapeutic substances for the treatment of neurodegenerative diseases and drug delivery to the brain. This review describes modern approaches of diagnosis and treatment of central nervous system diseases using extracellular vesicles.

Evidence and explanation for the involvement of the nucleus accumbens in pain processing Haley N Harris, Yuan B Peng Neural Regeneration Research 2020 15(4):597-605 The nucleus accumbens (NAc) is a subcortical brain structure known primarily for its roles in pleasure, reward, and addiction. Despite less focus on the NAc in pain research, it also plays a large role in the mediation of pain and is effective as a source of analgesia. Evidence for this involvement lies in the NAc’s cortical connections, functions, pharmacology, and therapeutic targeting. The NAc projects to and receives information from notable pain structures, such as the prefrontal cortex, anterior cingulate cortex, periaqueductal gray, habenula, thalamus, etc. Additionally, the NAc and other pain-modulating structures share functions involving opioid regulation and motivational and emotional processing, which each work beyond simply the rewarding experience of pain offset. Pharmacologically speaking, the NAc responds heavily to painful stimuli, due to its high density of μ opioid receptors and the activation of several different neurotransmitter systems in the NAc, such as opioids, dopamine, calcitonin gene-related peptide, γ-aminobutyric acid, glutamate, and substance P, each of which have been shown to elicit analgesic effects. In both preclinical and clinical models, deep brain stimulation of the NAc has elicited successful analgesia. The multi-functional NAc is important in motivational behavior, and the motivation for avoiding pain is just as important to survival as the motivation for seeking pleasure. It is possible, then, that the NAc must be involved in both pleasure and pain in order to help determine the motivational salience of positive and negative events.

MicroRNAs in blood and cerebrospinal fluid as diagnostic biomarkers of multiple sclerosis and to monitor disease progression Bridget Martinez, Philip V Peplow Neural Regeneration Research 2020 15(4):606-619 Multiple sclerosis is a chronic autoimmune disease of the central nervous system. It is the main cause of non-traumatic neurological disability in young adults. Multiple sclerosis mostly affects people aged 20–50 years; however, it can occur in young children and much older adults. Factors identified in the distribution of MS include age, gender, genetics, environment, and ethnic background. Multiple sclerosis is usually associated with progressive degrees of disability. The disease involves demyelination of axons of the central nervous system and causes brain and spinal cord neuronal loss and atrophy. Diagnosing multiple sclerosis is based on a patient’s medical history including symptoms, physical examination, and various tests such as magnetic resonance imaging, cerebrospinal fluid and blood tests, and electrophysiology. The disease course of multiple sclerosis is not well correlated with the biomarkers presently used in clinical practice. Blood-derived biomarkers that can detect and distinguish the different phenotypes in multiple sclerosis may be advantageous in personalized treatment with disease-modifying drugs and to predict response to treatment. The studies reviewed have shown that the expression levels of a large number of miRNAs in peripheral blood, serum, exosomes isolated from serum, and cerebrospinal fluid are altered in multiple sclerosis and can distinguish the disease phenotypes from each other. Further studies are warranted to independently validate these findings so that individual or pairs of miRNAs in serum or cerebrospinal fluid can be used as potential diagnostic markers for adult and pediatric multiple sclerosis and for monitoring disease progression and response to therapy.

Urokinase-type plasminogen activator is a modulator of synaptic plasticity in the central nervous system: implications for neurorepair in the ischemic brain Manuel Yepes Neural Regeneration Research 2020 15(4):620-624 The last two decades have witnessed a rapid decrease in mortality due to acute cerebral ischemia that paradoxically has led to a rapid increase in the number of patients that survive an acute ischemic stroke with various degrees of disability. Unfortunately, the lack of an effective therapeutic strategy to promote neurological recovery among stroke survivors has led to a rapidly growing population of disabled patients. Thus, understanding the mechanisms of neurorepair in the ischemic brain is a priority with wide scientific, social and economic implications. Cerebral ischemia has a harmful effect on synaptic structure associated with the development of functional impairment. In agreement with these observations, experimental evidence indicates that synaptic repair underlies the recovery of neurological function following an ischemic stroke. Furthermore, it has become evident that synaptic plasticity is crucial not only during development and learning, but also for synaptic repair after an ischemic insult. The plasminogen activating system is assembled by a cascade of enzymes and their inhibitors initially thought to be solely involved in the generation of plasmin. However, recent work has shown that in the brain this system has an important function regulating the development of synaptic plasticity via mechanisms that not always require plasmin generation. Urokinase-type plasminogen activator (uPA) is a serine proteinase and one of the plasminogen activators, that upon binding to its receptor (uPAR) not only catalyzes the conversion of plasminogen into plasmin on the cell surface, but also activates cell signaling pathways that promote cell migration, proliferation and survival. The role of uPA is the brain is not fully understood. However, it has been reported while uPA and uPAR are abundantly found in the developing central nervous system, in the mature brain their expression is restricted to a limited group of cells. Remarkably, following an ischemic injury to the mature brain the expression of uPA and uPAR increases to levels comparable to those observed during development. More specifically, neurons release uPA during the recovery phase from an ischemic injury, and astrocytes, axonal boutons and dendritic spines recruit uPAR to their plasma membrane. Here we will review recent evidence indicating that binding of uPA to uPAR promotes the repair of synapses damaged by an ischemic injury, with the resultant recovery of neurological function. Furthermore, we will discuss data indicating that treatment with recombinant uPA is a potential therapeutic strategy to promote neurological recovery among ischemic stroke survivors.

Neuroinflammation and oxidative stress act in concert to promote neurodegeneration in the diabetic retina and optic nerve: galectin-3 participation Henrique Rocha Mendonca, Raul Carpi-Santos, Karin da Costa Calaza, Ana Maria Blanco Martinez Neural Regeneration Research 2020 15(4):625-635 Diabetes is a lifelong disease characterized by glucose metabolic imbalance, in which low insulin levels or impaired insulin signaling lead to hyperglycemic state. Within 20 years of diabetes progression, 95% of patients will have diabetic retinopathy, the leading cause of visual defects in working-age people worldwide. Although diabetes is considered a microvascular disease, recent studies have shown that neurodegeneration precedes vascular changes within the diabetic visual system, albeit its mechanisms are still under investigation. Neuroinflammation and oxidative stress are intrinsically related phenomena, since macrophage/microglia and astrocytes are the main sources of reactive oxygen species during central nervous system chronic degenerative diseases, and both pathological processes are increased in the visual system during diabetes. The present review will focus on recent findings of the contribution of oxidative stress derived from neuroinflammation in the early neurodegenerative aspects of the diabetic visual system and their relationship with galectin-3.

Unfolded protein response in myelin disorders Wensheng Lin, Sarrabeth Stone Neural Regeneration Research 2020 15(4):636-645 Activation of the unfolded protein response in response to endoplasmic reticulum stress preserves cell viability and function under stressful conditions. Nevertheless, persistent, unresolvable activation of the unfolded protein response can trigger apoptosis to eliminate stressed cells. Recent studies show that the unfolded protein response plays an important role in the pathogenesis of various disorders of myelin, including multiples sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease, vanishing white matter disease, spinal cord injury, tuberous sclerosis complex, and hypoxia-induced perinatal white matter injury. In this review we summarize the current literature on the unfolded protein response and the evidence for its role in the pathogenesis of myelin disorders.

Relationship between MRI perfusion and clinical severity in multiple sclerosis Maria Marcella Lagana, Laura Pelizzari, Francesca Baglio Neural Regeneration Research 2020 15(4):646-652 Perfusion alterations within several brain regions have been shown in multiple sclerosis patients using different magnetic resonance imaging (MRI) techniques. Furthermore, MRI-derived brain perfusion metrics have been investigated in association with multiple sclerosis phenotypes, physical disability, and cognitive impairment. However, a review focused on these aspects is still missing. Our aim was to review all the studies investigating the relationship between perfusion MRI and clinical severity during the last fifteen years to understand the clinical relevance of these findings. Perfusion differences among phenotypes were observed both with 1.5T and 3T scanners, with progressive multiple sclerosis presenting with lower perfusion values than relapsing-remitting multiple sclerosis patients. However, only 3T scanners showed a statistically significant distinction. Controversial results about the association between MRI-derived perfusion metrics and physical disability scores were found. However, the majority of the studies showed that lower brain perfusion and longer transit time are associated with more severe physical disability and worse cognitive performances.

Therapeutic importance of hydrogen sulfide in age-associated neurodegenerative diseases Rubaiya Tabassum, Na Young Jeong, Junyang Jung Neural Regeneration Research 2020 15(4):653-662 Hydrogen sulfide (H2S) is a gasotransmitter that acts as an antioxidant and exhibits a wide variety of cytoprotective and physiological functions in age-associated diseases. One of the major causes of age-related diseases is oxidative stress. In recent years, the importance of H2S has become clear, although its antioxidant function has not yet been fully explored. The enzymes cystathionine β-synthase, cystathionine γ-lya-se, and 3-mercaptopyruvate sulfurtransferase are involved in the enzymatic production of H2S. Previously, H2S was considered a neuromodulator, given its role in long-term hippocampal potentiation, but it is now also recognized as an antioxidant in age-related neurodegeneration. Due to aerobic metabolism, the central nervous system is vulnerable to oxidative stress in brain aging, resulting in age-associated degenerative diseases. H2S exerts its antioxidant effect by limiting free radical reactions through the activation of antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase, which protect against the effects of aging by regulating apoptosis-related genes, including p53, Bax, and Bcl-2. This review explores the implications and mechanisms of H2S as an antioxidant in age-associated neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Down syndrome.

Role of CD20+ T cells in multiple sclerosis: implications for treatment with ocrelizumab Stefan Gingele, Thomas Skripuletz, Roland Jacobs Neural Regeneration Research 2020 15(4):663-664