Table of Content

15 October 2019, Volume 14 Issue 10 Previous Issue    Next Issue

For Selected:

Download Citations EndNote Reference Manager ProCite BibTeX RefWorks

Toggle Thumbnails

Select

Physiological effects of amyloid precursor protein and its derivatives on neural stem cell biology and signaling pathways involved Raquel Coronel, Charlotte Palmer, Adela Bernabeu-Zornoza, María Monteagudo, Andreea Rosca, Alberto Zambrano, Isabel Liste 2019, 14 (10):  1661-1671.  doi: 10.4103/1673-5374.257511 Abstract ( 94 )   PDF (1020KB) ( 173 )   Save The pathological implication of amyloid precursor protein (APP) in Alzheimer’s disease has been widely documented due to its involvement in the generation of amyloid-β peptide. However, the physiological functions of APP are still poorly understood. APP is considered a multimodal protein due to its role in a wide variety of processes, both in the embryo and in the adult brain. Specifically, APP seems to play a key role in the proliferation, differentiation and maturation of neural stem cells. In addition, APP can be processed through two canonical processing pathways, generating different functionally active fragments: soluble APP-α, soluble APP-β, amyloid-β peptide and the APP intracellular C-terminal domain. These fragments also appear to modulate various functions in neural stem cells, including the processes of proliferation, neurogenesis, gliogenesis or cell death. However, the molecular mechanisms involved in these effects are still unclear. In this review, we summarize the physiological functions of APP and its main proteolytic derivatives in neural stem cells, as well as the possible signaling pathways that could be implicated in these effects. The knowledge of these functions and signaling pathways involved in the onset or during the development of Alzheimer’s disease is essential to advance the understanding of the pathogenesis of Alzheimer’s disease, and in the search for potential therapeutic targets. Related Articles | Metrics

Select

Challenges in microRNAs’ targetome prediction and validation Jesus Eduardo Rojo Arias, Volker Busskamp 2019, 14 (10):  1672-1677.  doi: 10.4103/1673-5374.257514 Abstract ( 105 )   PDF (195KB) ( 198 )   Save MicroRNAs (miRNAs) are small RNA molecules with important roles in post-transcriptional regulation of gene expression. In recent years, the predicted number of miRNAs has skyrocketed, largely as a consequence of high-throughput sequencing technologies becoming ubiquitous. This dramatic increase in miRNA candidates poses multiple challenges in terms of data deposition, curation, and validation. Although multiple databases containing miRNA annotations and targets have been developed, ensuring data quality by validating miRNA-target interactions requires the efforts of the research community. In order to generate databases containing biologically active miRNAs, it is imperative to overcome a multitude of hurdles, including restricted miRNA expression patterns, distinct miRNA biogenesis machineries, and divergent miRNA-mRNA interaction dynamics. In the present review, we discuss recent advances and limitations in miRNA prediction, identification, and validation. Lastly, we focus on the most enriched neuronal miRNA, miR-124, and its gene regulatory network in human neurons, which has been revealed using a combined computational and experimental approach. Related Articles | Metrics

Select

Can we further optimize therapeutic hypothermia for hypoxic-ischemic encephalopathy? Anthony Davies, Guido Wassink, Laura Bennet, Alistair J. Gunn, Joanne O. Davidson 2019, 14 (10):  1678-1683.  doi: 10.4103/1673-5374.257512 Abstract ( 88 )   PDF (377KB) ( 108 )   Save Perinatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal death and disability. Therapeutic hypothermia significantly reduces death and major disability associated with HIE; however, many infants still experience lifelong disabilities to movement, sensation and cognition. Clinical guidelines, based on strong clinical and preclinical evidence, recommend therapeutic hypothermia should be started within 6 hours of birth and continued for a period of 72 hours, with a target brain temperature of 33.5 ± 0.5°C for infants with moderate to severe HIE. The clinical guidelines also recommend that infants be rewarmed at a rate of 0.5°C per hour, but this is not based on strong evidence. There are no randomized controlled trials investigating the optimal rate of rewarming after therapeutic hypothermia for infants with HIE. Preclinical studies of rewarming are conflicting and results were confounded by treatment with sub-optimal durations of hypothermia. In this review, we evaluate the evidence for the optimal start time, duration and depth of hypothermia, and whether the rate of rewarming after treatment affects brain injury and neurological outcomes. Related Articles | Metrics

Select

P2X7 receptor signaling during adult hippocampal neurogenesis Hannah C. Leeson, Tailoi Chan-Ling, Michael D. Lovelace, Jeremy C. Brownlie, Ben J. Gu, Michael W. Weible II 2019, 14 (10):  1684-1694.  doi: 10.4103/1673-5374.257510 Abstract ( 109 )   PDF (1826KB) ( 102 )   Save Neurogenesis is a persistent and essential feature of the adult mammalian hippocampus. Granular neurons generated from resident pools of stem or progenitor cells provide a mechanism for the formation and consolidation of new memories. Regulation of hippocampal neurogenesis is complex and multifaceted, and numerous signaling pathways converge to modulate cell proliferation, apoptosis, and clearance of cellular debris, as well as synaptic integration of newborn immature neurons. The expression of functional P2X7 receptors in the central nervous system has attracted much interest and the regulatory role of this purinergic receptor during adult neurogenesis has only recently begun to be explored. P2X7 receptors are exceptionally versatile: in their canonical role they act as adenosine triphosphate-gated calcium channels and facilitate calcium-signaling cascades exerting control over the cell via calcium-encoded sensory proteins and transcription factor activation. P2X7 also mediates transmembrane pore formation to regulate cytokine release and facilitate extracellular communication, and when persistently stimulated by high extracellular adenosine triphosphate levels large P2X7 pores form, which induce apoptotic cell death through cytosolic ion dysregulation. Lastly, as a scavenger receptor P2X7 directly facilitates phagocytosis of the cellular debris that arises during neurogenesis, as well as during some disease states. Understanding how P2X7 receptors regulate the physiology of stem and progenitor cells in the adult hippocampus is an important step towards developing useful therapeutic models for regenerative medicine. This review considers the relevant aspects of adult hippocampal neurogenesis and explores how P2X7 receptor activity may influence the molecular physiology of the hippocampus, and neural stem and progenitor cells. Related Articles | Metrics

Select

Gamma-aminobutyric acid (GABA) promotes recovery from spinal cord injury in lampreys: role of GABA receptors and perspective on the translation to mammals Daniel Romaus-Sanjurjo, María Celina Rodicio, Antón Barreiro-Iglesias 2019, 14 (10):  1695-1696.  doi: 10.4103/1673-5374.257515 Abstract ( 150 )   PDF (320KB) ( 112 )   Save In mammals, spinal cord injury (SCI) is a devastating event that can lead to a permanent loss of motor, sensory and autonomic functions below the site of injury. In the last years, the role of different neurotransmitter systems on regeneration and recovery from SCI has been deciphered. For example, studies in lampreys have shown that eurotransmitters play a key role in modulating the survival and regeneration of brainstem descending neurons after SCI. Glutamate is known to play a prominent role after SCI since it causes excitotoxicity to non-injured neurons during the secondary phase after a traumatic injury both in mammals and lampreys. In contrast, recent work in lampreys has shown that γ-aminobutyric acid (GABA) can play a neuroprotective and pro-regenerative role after SCI. GABA is the main inhibitory neurotransmitter in the central nervous system (CNS) of vertebrates, and acts through both metabotropic G-protein-coupled GABAB receptors, and ionotropic ligand-gated chloride channel GABAA receptors. Here, we discuss recent work from our group and others on the possible role of different GABA eceptors in neuronal survival and regeneration after SCI and provide a perspective on future work in this field. Related Articles | Metrics

Select

Modulating neuronal plasticity with choline Eunice W. M. Chin, Eyleen L.K. Goh 2019, 14 (10):  1697-1698.  doi: 10.4103/1673-5374.257516 Abstract ( 111 )   PDF (535KB) ( 113 )   Save The American psychologist William James once wrote that nervous tissue seems to be endowed with a “very extraordinary” degree of plasticity. To be plastic means to be capable of being molded, receiving shape, or being made to assume a desired form. This can be achieved consequential to changes in the internal and/or external environment. Being plastic, neurons are highly able to amend their structural and functional output, through alteration of their morphology, activation of ntracellular signaling cascades, regulation of synaptic density and neurotransmitter release, or a combination of these events. This can all be accomplished without compromising the stability and integrity of the entire neuronal network. Neuronal plasticity can be affected by many factors. For instance, the behaviour of the organism can influence neuronal plasticity, where dendritic spine density increases following learning. And, exposure to biochemicals in the environment can result in changes to neurotransmitter release and dendritic spine shape. From an altruistic standpoint, the question arises as to whether plasticity-modulating compounds can be harnessed for therapeutic purposes. Related Articles | Metrics

Select

Human neural stem cell transplants to address multiple pathologies associated with traumatic brain injury Helene Clervius, Mirza Baig, Anil Mahavadi, Shyam Gajavelli 2019, 14 (10):  1699-1700.  doi: 10.4103/1673-5374.255620 Abstract ( 91 )   PDF (379KB) ( 103 )   Save Traumatic brain injury (TBI), an unmet need: TBI is an alteration in brain function caused by an external force with evidence of brain pathology. It could be from a bump, blow, blast or jolt to the head including penetrating the cranium. TBI is a public health concern worldwide due to its economic impact. Most TBIs are survivable, do not need hospitalization but may influence productivity. A smaller percentage of TBI due to falls or penetrating TBI (PTBI) needs hospitalization and accounts for largest fraction of TBI care costs. PTBI especially that involving firearm injury is an increasingly serious issue. In the United States, PTBI is an issue both in the military and civilian context costing more than $70–75 billion annually. PTBI has become increasingly survivable including previously lethal midline crossing of projectile due to brain trauma foundation guidelines as well as timely neurosurgical intervention. The extent of recovery is proportional to initial damage; injuries limited to single hemisphere stabilize earlier than those crossing the midline do. However, currently the consequence of surviving a PTBI is most likely to be permanent disability. Rate of disability has not changed over the past 5 decades. Almost 3.2 million Americans live with neurobehavioral disability i.e., chronic cognitive and functional impairment requiring support from their families and the State, with lifetime costs of millions of dollars per patient. The TBI lesion is dynamic with continued brain atrophy, which correlates with persistent neurological deficit and overall social outcome. Observations of post-TBI tissue loss by pathologists were confirmed by longitudinal imaging studies in living TBI survivors. Progressive volume loss was coincident with persistent neuroinflammation thought to be due to chronic microglial activation. In a study of veterans living with TBI spanning4 decades, loss of tissue following PTBI was approximately 56 mL. Magnification of the primary injury via secondary mechanism underlies such volume loss and consequent disability. The PTBI penumbra (tissue surrounding the PTBI injury core) is render vulnerable by pyroptosis of chronically activated microglia. Continued pyroptosis of microglia and adjacent cells facilitate the lesion expansion into otherwise intact remote regions. Spontaneous recovery in TBI generally takes place within the first 3 months after injury and is mainly due to neural plasticity but not endogenous reparative neurogenesis. Success in restoring an injured brain with current therapies is limited by inability of central nervous system to regenerate spontaneously. Hence, current medical treatments albeit unsuccessfully, have sought to (i) prevent neuroinflammation driven deterioration and (ii) replace lost cells. The historical failure of acute neuroprotective trials has led to alternate approachesi.e., recruit endogenous neural stem cells (NSCs) or replace via transplantation of exogenous NSCs with a goal to rebuild circuitry. Both preclinical and clinical attempts to boost endogenous NSCs have failed to repair injured brains. In addition, the concept of recruiting endogenous NSCs to repair injured brain developed in rodents may have limited scope in humans given the differences in neurogenesis rate and recruitment distances. Could precise stereotactic placement of NSCs help address the unmet need and repair an injured brain? Related Articles | Metrics

Select

Remodeling dendritic spines for treatment of traumatic brain injury Lilia Koza, Daniel A. Linseman 2019, 14 (10):  1701-1702.  doi: 10.4103/1673-5374.257520 Abstract ( 150 )   PDF (255KB) ( 136 )   Save In the United States, approximately one-third of all injury-related deaths are due to traumatic brain injury (TBI). Anyone is at risk for TBI; however, the risk is higher for athletes in contact sports, military personnel, children, and the elderly. TBI is characterized by a mild, moderate, or severe mechanical force to the head which can be further classified as blast, blunt, or ballistic. The sheer mechanical force of the impact to the head results in the primary injury including diffuse axonal injury, internal bleeding, swelling, and neuronal cell death. Secondary injury occurs over time, often weeks to months post-TBI, and is characterized by neuroinflammation, blood-brain-barrier disruption, oxidative stress, mitochondrial dysfunction, neuronal apoptosis, and other deleterious effects in the brain. Recent research indicates that secondary injury from TBI may be considered a risk factor for neurodegenerative diseases occurring later in life, such as Alzheimer’s disease and chronic traumatic encephalopathy. A key molecular mechanism that contributes to secondary injury after TBI is free radical damage which is induced by the aberrant production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Related Articles | Metrics

Select

Delayed peripheral treatment with neurotrophin-3 improves sensorimotor recovery after central nervous system injury Sotiris G. Kakanos, Lawrence D.F. Moon 2019, 14 (10):  1703-1704.  doi: 10.4103/1673-5374.257518 Abstract ( 106 )   PDF (340KB) ( 121 )   Save Neurotrophin-3 (NT3) is a growth factor found in many body tissues including the heart, intestines, skin, nervous system and in skeletal muscles including muscle spindles. NT3 is required for the survival, correct connectivity and function of sensory (“proprioceptive”) afferents that innervate muscle spindles; these neurons express receptors for NT3 including tropomyocin receptor kinase C. These proprioceptive afferents are important for normal movement and signals from muscle spindles are important for recovery of limb movement (e.g., after spinal cord lateral hemisection). The level of NT3 declines in most tissues during postnatal development; its level is low in adult and elderly humans and other mammals. Elevation of NT3 has been shown to improve outcome in various animal models of neurological disease and injury. For example, many groups have shown that delivery of NT3 directly into the central nervous system promotes recovery after spinal cord injury but this often involved invasive routes or gene therapy. Related Articles | Metrics

Select

Diterpenes and the crosstalk with the arachidonic acid pathways, relevance in neurodegeneration Juan M. Zolezzi,Nibaldo C. Inestrosa 2019, 14 (10):  1705-1706.  doi: 10.4103/1673-5374.257521 Abstract ( 97 )   PDF (220KB) ( 120 )   Save Dementia has emerged as one of the main threats to human health in the modern civilization. Increased aging of world population and unhealthy lifestyle habits have been identified as critical factors able to facilitate dementia establishment. In this context, according to the Alzheimer’s Research International, Alzheimer’s disease (AD) constitutes the primary cause of dementia worldwide and its numbers are expected to grow during the following years. Clinically, AD is characterized by the progressive decline in the cognitive performance as well as by an altered social behavior. Initially affecting the short-term memory, the long-term memory becomes compromised as the pathology progresses. Relevantly, the severe cognitive impairment observed in AD reflects the dramatic effects of the pathology to the hippocampus and to the brain cortex circuitry, characterized by synaptic damage and neuronal loss. Histopathologically, AD displays two pathognomonic lesions within the brain parenchyma: the extraneuronal senile plaques, which are constituted by aggregated forms of the amyloid-β (Aβ) peptide, and the intraneuronal formation of neurofibrillary tangles (NFTs), constituted mainly of hyperphosphorylated tau protein. As reported elsewhere, it is important to note that additional features develop during AD, playing a critical role in its pathophysiology. Severe neuroinflammation, represented by glial reactivity and increased levels of pro-inflammatory mediators, vascular disease, mitochondrial dysfunction, calcium dyshomeostasis, and oxidative stress, are some of the most relevant alterations observed during AD. Regrettably, despite significant resources committed to the study of AD, no effective therapy is currently available to improve patient’s outcome. Thus, the evaluation of potentially useful molecules able to modulate the progression of the disease remains an urgent need to be satisfied in the context of AD research. Related Articles | Metrics

Select

Are the mechanisms involved in astrocyte and lymphocyte death during HIV infection similar? Diego S. Ojeda, Andreas Till, Jorge Quarleri 2019, 14 (10):  1707-1708.  doi: 10.4103/1673-5374.257519 Abstract ( 86 )   PDF (268KB) ( 89 )   Save Acquired immune deficiency syndrome is associated with the death of CD4+ T lymphocytes. The entry of the human immunodeficiency virus (HIV) into the central nervous system leads to a broad spectrum of HIV-associated neurocognitive disorders (HAND) ranging from mild to severe dementia. Inside the central nervous system, HIV establishes infection in astrocytes – the predominant cell type in the brain, thus causing neuropathology, but the underlying mechanisms remain unknown. Much research has been focused on the role of innate immune activation, prompted by abundance of soluble viral factors, abortive infection, or cytokines secreted by neighboring microglia and associated with euroinflammation and HAND. However, the mechanisms that prime and activate the inflammatory process during HIV infection have not been unraveled. Related Articles | Metrics

Select

Can leukocyte telomere shortening be a possible biomarker to track Huntington’s diseaseprogression? Elide Mantuano，artina Peconi1，aniela Scarabino 2019, 14 (10):  1709-1710.  doi: 10.4103/1673-5374.257522 Abstract ( 91 )   PDF (241KB) ( 168 )   Save Huntington’s disease (HD): HD is an autosomal dominant neurodegenerative disease, caused by a CAG trinucleotide repeat expansion in the first exon of the HTT gene encoding the huntingtin protein. The mutant protein contains an expanded polyglutamine sequence that confers a toxic gain-of-function and causes neurodegeneration. Moreover, several studies indicate that loss of the normal protein beneficial functions, contribute to the pathology. Triplet expansion over 40 repeats are fully penetrant and invariably lead to manifest HD in the fourth or fifth decade of life. Related Articles | Metrics

Select

The local mammalian target of rapamycin (mTOR) modulation: a promising strategy to counteract neurodegeneration Diego Dolcetta,Roberto Dominici 2019, 14 (10):  1711-1712.  doi: 10.4103/1673-5374.257524 Abstract ( 85 )   PDF (237KB) ( 121 )   Save Alzheimer’s disease (AD) and the evolution of the “Amyloid Hypothesis”: The primary risk factor for dementia is aging, as the overwhelming majority of individuals who have the disease (~95%) are 65 years old or older, and the rate of development of AD doubles roughly every five years from that age, peaking at a nearly 50% population prevalence by the age of 85. The disease is progressive and irreversible, with an average time course of 8 to 10 years. Regardless of catastrophic forecasts for the next decades, its actual prevalence has huge family and social costs. The exact mechanisms leading to AD remain unknown, limiting the identification of effective disease-modifying therapies. The two principal neuropathological hallmarks of AD are extracellular β-amyloid (Aβ) peptide deposition (senile plaques, SPs) and intracellular neurofibrillary tangles, containing hyperphosphorylated tau protein. In 1999, with a pioneering work, Dale and Hardy (2016) opened the way to the “era” of the so-called “Amyloid Hypothesis”. It supports the concept that an imbalance between production and clearance of Aβ42 and related Aβ neurotoxic peptides may be the initiating factor in AD, with consequent accumulation and deposition of oligomeric or fibrillar forms of Aβ. Since then, many therapies have focused on the removal of extracellular Aβ (eAβ). All these have given good cognitive benefits on animal models, but, as far as we know, none of them allowed the recovery to the cognitive starting point in all respects. The predominant role that the Aβ has in the development of AD is now widely accepted. While eAβ has historically garnered the greatest attention, the intracellular Aβ (iAβ) is receiving increasing consideration for its pathophysiological contributions to AD. Similarly to Caccamo et al. we also consider our approach more efficacious on iAβ than on neurofibrillary tangle removal . We therefore moved towards the latest version of the “Amyloid Hypothesis”, aiming to set up a fully and readily translational protocol. Related Articles | Metrics

Select

The role of LRRK2 on PKA-NFκB pathway in microglia cells: implications for Parkinson’s disease Isabella Russo 2019, 14 (10):  1713-1714.  doi: 10.4103/1673-5374.257523 Abstract ( 90 )   PDF (319KB) ( 154 )   Save Leucine-rich repeat kinase 2 (LRRK2), a gene linked to autosomal-dominantly inherited and sporadic Parkinson’s disease (PD) as a risk factor, encodes a large and complex protein with a dual enzymatic activity. LRRK2 contains several domains involved in protein-protein interactions, however, the presence of both a kinase and GTPase domain points to intracellular signaling functions (Marín, 2006). While LRRK2 has been linked to several molecular pathways important for neuronal activity, the observation that its expression is high in microglia has attracted the attention of different groups to understand whether LRRK2 dysfunctions in these cells may impact neuronal activity as secondary event. In this regard, since 2012 numerous studies have demonstrated that LRRK2 controls microglia activation and plays important roles in these cells. Microglia are highly specialized macrophages responsible for mediating innate immune defense in the brain and scavenging debris or misfolded/aggregated proteins. They are considered main actors upon an inflammatory stimulus, and although a well-regulated inflammatory response is crucial for tissue repair and brain homeostasis, an excessive and prolonged neuroinflammation can lead to overproduction of toxic molecules, which results in deleterious cellular damage, as observed in different neurodegenerative diseases including PD. Related Articles | Metrics

Select

New ex vivo demyelination/remyelination models to defeat multiple sclerosis and neuromyelitis optica Yiting Liu 2019, 14 (10):  1715-1716.  doi: 10.4103/1673-5374.257525 Abstract ( 131 )   PDF (453KB) ( 117 )   Save Multiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory diseases of the central nervous system (CNS) resulting in CNS inflammation, infiltration of peripheral immune cells, loss of myelin and oligodendrocytes, interruption of axonal communication, and neurologic deficits. Following oligodendrocyte injury, newly generated myelinating oligodendrocytes derived from oligodendrocyte progenitors (OPCs) may produce new myelin sheaths around denuded axons (remyelination) restoring neuronal function. While remyelination is apparent in MS lesions, the process is often inefficient; in NMO, remyelination is even more limited. Currently, there are no restorative therapies for MS and NMO. Understanding the mechanisms underlying driving disease-specific myelin damage and repair is critical to identify remyelination barriers and develop new treatments promoting remyelination. Current studies to understand the molecular and cellular events regulating demyelination and remyelination processes have employed developmental, toxic, and caustic models of oligodendrocyte injury. These models cannot replicate the inflammatory pathology of demyelination in MS and NMO, and fail to replicate the milieu that may inhibit repair. Related Articles | Metrics

Select

A different view on the pathophysiology of Parkinson’s disease: a descendent neurochemical hypothesis? Burak Yulug,Mehmet Ozansoy, Seyda Cankaya 2019, 14 (10):  1717-1718.  doi: 10.4103/1673-5374.257527 Abstract ( 97 )   PDF (164KB) ( 88 )   Save It has been already shown that Parkinson’s disease (PD) is characterized by a prominent degeneration in substantia nigra (SN) neurons. Growing evidence suggests that there is a latent period of PD associated with slight non-motor findings such as olfactory dysfunction . However, the potential biomarker role of olfactory dysfunction in PD has been a topic of great interest in the last years. The classical hypothesis of Braak suggests that PD begins as a synucleinopathy in the lower brainstem or in the olfactory bulb (OB) that progresses rostrally to the SN and amygdala to cause parkinsonism at a later stage of the disease. However, Braak’s hypothesis should be cautiously interpreted since this scheme is not based on the distribution of neuronal cell loss, but on the distribution of the accumulation of abnormal α-synuclein aggregates which leaves unanswered how it relates to the progression of neurochemical changes. Related Articles | Metrics

Select

Fine-tuning the response of growth cones to guidance cues: a perspective on the role of microRNAs Sarah E. Walker, Gaynor E. Spencer, Robert L. Carlone 2019, 14 (10):  1719-1720.  doi: 10.4103/1673-5374.257517 Abstract ( 92 )   PDF (202KB) ( 111 )   Save In the development and regeneration of the nervous system, neurons face the complex task of establishing and/or repairing neuronal connections and contacts. The formation of these neuronal circuits is largely coordinated by tightly regulated temporal and spatial changes in mRNA translation, which enables incredibly precise control over protein expression and localization. Local mRNA translation in specific cellular compartments appears to play a role in many processes that are important to nervous system development and regeneration, including: cell survival, migration, growth cone guidance, and synaptogenesis. Related Articles | Metrics

Select

Potential preventive disease-modifying pharmacological strategies to delay late onset Alzheimer’s disease Miren Ettcheto, Oriol Busquets, Antoni Camins 2019, 14 (10):  1721-1725.  doi: 10.4103/1673-5374.257513 Abstract ( 107 )   PDF (419KB) ( 129 )   Save Alzheimer’s disease (AD) is a progressive neurodegenerative disease that was histopathologically characterized in the brain by the presence of extracellular senile plaques made of amyloid β peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated Tau protein. Over the years, AD has been classified in two subgroups: early onset or familial AD and late onset or sporadic AD. On the one hand, familial AD has been described to be the result of genetic mutations that cause, in some cases, for the overproduction of amyloid β. On the other, the cause of late onset or sporadic AD is still unclear even though several hypotheses have been proposed to explain the process of severe and progressive memory and cognitive loss. In the present review, some of the current hypotheses that try to explain the origin of late onset or sporadic AD have been summarized. Also, their potential implication in the development of new drugs for the presymptomatic treatment of late onset or sporadic AD has been considered. Related Articles | Metrics

Select

Vascular endothelial growth factor A promotes platelet adhesion to collagen IV and causes early brain injury after subarachnoid hemorrhage Zun-Wei Liu, Jun-Jie Zhao, Hong-Gang Pang, Jin-Ning Song 2019, 14 (10):  1726-1733.  doi: 10.4103/1673-5374.257530 Abstract ( 105 )   PDF (1671KB) ( 116 )   Save The role of vascular endothelial growth factor A in platelet adhesion in cerebral microvessels in the early stage of subarachnoid hemorrhage remains unclear. In this study, the endovascular puncture method was used to produce a rat model of subarachnoid hemorrhage. Then, 30 minutes later, vascular endothelial growth factor A antagonist anti-vascular endothelial growth factor receptor 2 antibody, 10 μg, was in¬jected into the right ventricle. Immunohistochemistry and western blot assay were used to assess expression of vascular endothelial growth factor A, occludin and claudin-5. Immunohistochemical double labeling was conducted to examine co-expression of GP Ia-II integrin and type IV collagen. TUNEL was used to detect apoptosis in the hippocampus. Neurological score was used to assess behavioral performance. After subarachnoid hemorrhage, the expression of vascular endothelial growth factor A increased in the hippocampus, while occludin and claudin-5 expression levels decreased. Co-expression of GP Ia-II integrin and type IV collagen and the number of apoptotic cells increased, whereas behavioral performance was markedly impaired. After treatment with anti-vascular endothelial growth factor receptor 2 antibody, occludin and claudin-5 expression recovered, while co-expression of GP Ia-II integrin and type IV collagen and the number of apoptotic cells decreased. Furthermore, behavioral performance improved notably. Our findings suggest that increased vascular endothelial growth factor A levels promote platelet adhesion and contribute to early brain injury after subarachnoid hemorrhage. This study was approved by the Biomedical Ethics Committee, Medical College of Xi’an Jiaotong University, China in December 2015 (SYXK [Shaan] 2015-002). Related Articles | Metrics

Select

Resveratrol reduces brain injury after subarachnoid hemorrhage by inhibiting oxidative stress and endoplasmic reticulum stress Yun-Kai Xie, Xin Zhou, Hong-Tao Yuan, Jie Qiu, Dan-Qing Xin, Xi-Li Chu, Da-Chuan Wang, Zhen Wang 2019, 14 (10):  1734-1742.  doi: 10.4103/1673-5374.257529 Abstract ( 139 )   PDF (15710KB) ( 73 )   Save Previous studies have shown that resveratrol, a bioactive substance found in many plants, can reduce early brain injury after subarach¬noid hemorrhage, but how it acts is still unclear. This study explored the mechanism using the experimental subarachnoid hemorrhage rat model established by injecting autologous blood into the cerebellomedullary cistern. Rat models were treated with an intraperitoneal injection of 60 mg/kg resveratrol 2, 6, 24 and 46 hours after injury. At 48 hours after injury, their neurological function was assessed using a modified Garcia score. Brain edema was measured by the wet-dry method. Neuronal apoptosis in the prefrontal cortex was detected by terminal deoxyribonucleotidyl transferase-mediated biotin-16-dUTP nick-end labeling assay. Levels of reactive oxygen species and malondialdehyde in the prefrontal cortex were determined by colorimetry. CHOP, glucose-regulated protein 78, nuclear factor-erythroid 2-related factor 2 and heme oxygenase-1 mRNA expression levels in the prefrontal cortex were measured by reverse transcription poly¬merase chain reaction. Tumor necrosis factor-alpha content in the prefrontal cortex was detected by enzyme linked immunosorbent assay. Immunohistochemical staining was used to detect the number of positive cells of nuclear factor-erythroid 2-related factor 2, heme oxygen¬ase 1, glucose-regulated protein 78, CHOP and glial fibrillary acidic protein. Western blot assay was utilized to analyze the expression levels of nuclear factor-erythroid 2-related factor 2, heme oxygenase 1, glucose-regulated protein 78 and CHOP protein expression levels in the prefrontal cortex. The results showed that resveratrol treatment markedly alleviated neurological deficits and brain edema in experimental subarachnoid hemorrhage rats, and reduced neuronal apoptosis in the prefrontal cortex. Resveratrol reduced the levels of reactive oxygen species and malondialdehyde, and increased the expression of nuclear factor-erythroid 2-related factor 2, heme oxygenase-1 mRNA and protein in the prefrontal cortex. Resveratrol decreased glucose-regulated protein 78, CHOP mRNA and protein expression and tumor necrosis factor-alpha level. It also activated astrocytes. The results suggest that resveratrol exerted neuroprotective effect on subarachnoid hemorrhage by reducing oxidative damage, endoplasmic reticulum stress and neuroinflammation. The study was approved by the Animals Ethics Committee of Shandong University, China on February 22, 2016 (approval No. LL-201602022). Related Articles | Metrics

Select

Constraint-induced movement therapy enhances angiogenesis and neurogenesis after cerebral ischemia/ reperfusion Zhi-Yong Zhai, Juan Feng 2019, 14 (10):  1743-1754.  doi: 10.4103/1673-5374.257528 Abstract ( 268 )   PDF (1825KB) ( 128 )   Save Constraint-induced movement therapy after cerebral ischemia stimulates axonal growth by decreasing expression levels of Nogo-A, RhoA, and Rho-associated kinase (ROCK) in the ischemic boundary zone. However, it remains unclear if there are any associations between the Nogo-A/RhoA/ROCK pathway and angiogenesis in adult rat brains in pathological processes such as ischemic stroke. In addition, it has not yet been reported whether constraint-induced movement therapy can promote angiogenesis in stroke in adult rats by overcoming Nogo-A/RhoA/ROCK signaling. Here, a stroke model was established by middle cerebral artery occlusion and reperfusion. Seven days after stroke, the following treatments were initiated and continued for 3 weeks: forced limb use in constraint-induced movement therapy rats (constraint-induced movement therapy group), intraperitoneal infusion of fasudil (a ROCK inhibitor) in fasudil rats (fasudil group), or lateral ventricular injection of NEP1–40 (a specific antagonist of the Nogo-66 receptor) in NEP1–40 rats (NEP1–40 group). Immunohistochemistry and western blot assay results showed that, at 2 weeks after middle cerebral artery occlusion, expression levels of RhoA and ROCK were lower in the ischemic boundary zone in rats treated with NEP1–40 compared with rats treated with ischemia/reperfusion or constraint-induced movement therapy alone. However, at 4 weeks after middle cerebral artery occlusion, expression levels of RhoA and ROCK in the ischemic boundary zone were markedly decreased in the NEP1–40 and constraint-induced movement therapy groups, but there was no difference between these two groups. Compared with the ischemia/reperfusion group, modified neurological severity scores and foot fault scores were lower and time taken to locate the platform was shorter in the constraint-induced movement therapy and fasudil groups at 4 weeks after middle cerebral artery occlusion, especially in the constraint-induced movement therapy group. Immunofluorescent staining demonstrated that fasudil promoted an immune response of nerve-regeneration-related markers (BrdU in combination with CD31 (platelet endothelial cell adhesion molecule), Nestin, doublecortin, NeuN, and glial fibrillary acidic protein) in the subventricular zone and ischemic boundary zone ipsilateral to the infarct. After 3 weeks of constraint-induced movement therapy, the number of regenerated nerve cells was noticeably increased, and was accompanied by an increased immune response of tight junctions (claudin-5), a pericyte marker (α-smooth muscle actin), and vascular endothelial growth factor receptor 2. Taken together, the results demonstrate that, compared with fasudil, constraint-induced movement therapy led to stronger angiogenesis and nerve regeneration ability and better nerve functional recovery at 4 weeks after cerebral ischemia/reperfusion. In addition, constraint-induced movement therapy has the same degree of inhibition of RhoA and ROCK as NEP1–40. Therefore, constraint-induced movement therapy promotes angiogenesis and neurogenesis after cerebral ischemia/reperfusion injury, at least in part by overcoming the Nogo-A/RhoA/ROCK signaling pathway. All protocols were approved by the Institutional Animal Care and Use Committee of China Medical University, China on December 9, 2015 (approval No. 2015PS326K). Related Articles | Metrics

Select

Soluble Nogo receptor 1 fusion protein protects neural progenitor cells in rats with ischemic stroke Hai-Wei He, Yue-Lin Zhang, Bao-Qi Yu, Gen Ye, Wei You, Kwok-fai So, Xin Li 2019, 14 (10):  1755-1764.  doi: 10.4103/1673-5374.257531 Abstract ( 96 )   PDF (3629KB) ( 144 )   Save Soluble Nogo66 receptor-Fc protein (sNgR-Fc) enhances axonal regeneration following central nervous system injury. However, the underlying mechanisms remain unclear. In this study, we investigated the effects of sNgR-Fc on the proliferation and differentiation of neural progenitor cells. The photothrombotic cortical injury model of ischemic stroke was produced in the parietal cortex of Sprague-Dawley rats. The rats with photothrombotic cortical injury were randomized to receive infusion of 400 μg/kg sNgR-Fc (sNgR-Fc group) or an equal volume of phosphate-buffered saline (photothrombotic cortical injury group) into the lateral ventricle for 3 days. The effects of sNgR-Fc on the proliferation and differentiation of endogenous neural progenitor cells were examined using BrdU staining. Neurological function was evaluated with the Morris water maze test. To further examine the effects of sNgR-Fc treatment on neural progenitor cells, photothrombotic cortical injury was produced in another group of rats that received transplantation of neural progenitor cells from the hippocampus of embryonic Sprague-Dawley rats. The animals were then given an infusion of phosphate-buffered saline (neural progenitor cells group) or sNgR-Fc (sNgR-Fc + neural progenitor cells group) into the lateral ventricle for 3 days. sNgR-Fc enhanced the proliferation of cultured neural progenitor cells in vitro as well as that of endogenous neural progenitor cells in vivo, compared with phosphate-buffered saline, and it also induced the differentiation of neural progenitor cells into neurons. Compared with the photothrombotic cortical injury group, escape latency in the Morris water maze and neurological severity score were greatly reduced, and distance traveled in the target quadrant was considerably increased in the sNgR-Fc group, indicating a substantial improvement in neurological function. Furthermore, compared with phosphate-buffered saline infusion, sNgR-Fc infusion strikingly improved the survival and differentiation of grafted neural progenitor cells. Our findings show that sNgR-Fc regulates neural progenitor cell proliferation, migration and differentiation. Therefore, sNgR-Fc is a potential novel therapy for stroke and neurodegenerative diseases, The protocols were approved by the Committee on the Use of Live Animals in Teaching and Research of the University of Hong Kong (approval No. 4560-17) in November, 2015. Related Articles | Metrics

Select

TrkA regulates the regenerative capacity of bone marrow stromal stem cells in nerve grafts Mei-Ge Zheng, Wen-Yuan Sui, Zhen-Dan He, Yan Liu, Yu-Lin Huang, Shu-Hua Mu, Xin-Zhong Xu, Ji-Sen Zhang, Jun-Le Qu, Jian Zhang, Dong Wang 2019, 14 (10):  1765-1771.  doi: 10.4103/1673-5374.257540 Abstract ( 116 )   PDF (1970KB) ( 143 )   Save We previously demonstrated that overexpression of tropomyosin receptor kinase A (TrkA) promotes the survival and Schwann cell-like differentiation of bone marrow stromal stem cells in nerve grafts, thereby enhancing the regeneration and functional recovery of the peripheral nerve. In the present study, we investigated the molecular mechanisms underlying the neuroprotective effects of TrkA in bone marrow stromal stem cells seeded into nerve grafts. Bone marrow stromal stem cells from Sprague-Dawley rats were infected with recombinant lentivirus vector expressing rat TrkA, TrkA-shRNA or the respective control. The cells were then seeded into allogeneic rat acellular nerve allografts for bridging a 1-cm right sciatic nerve defect. Then, 8 weeks after surgery, hematoxylin and eosin staining showed that compared with the control groups, the cells and fibers in the TrkA overexpressing group were more densely and uniformly arranged, whereas they were relatively sparse and arranged in a disordered manner in the TrkA-shRNA group. Western blot assay showed that compared with the control groups, the TrkA overexpressing group had higher expression of the myelin marker, myelin basic protein and the axonal marker neurofilament 200. The TrkA overexpressing group also had higher levels of various signaling molecules, including TrkA, pTrkA (Tyr490), extracellular signal-regulated kinases 1/2 (Erk1/2), pErk1/2 (Thr202/Tyr204), and the anti-apoptotic proteins Bcl-2 and Bcl-xL. In contrast, these proteins were downregulated, while the pro-apoptotic factors Bax and Bad were upregulated, in the TrkA-shRNA group. The levels of the TrkA effectors Akt and pAkt (Ser473) were not different among the groups. These results suggest that TrkA enhances the survival and regenerative capacity of bone marrow stromal stem cells through upregulation of the Erk/Bcl-2 pathway. All procedures were approved by the Animal Ethical and Welfare Committee of Shenzhen University, China in December 2014 (approval No. AEWC- 2014-001219). Related Articles | Metrics

Select

Eosinopenia is a predictive factor for the severity of acute ischemic stroke Hui-Min Zhao, Wen-Qian Qin, Pei-Ji Wang, Zhong-Min Wen 2019, 14 (10):  1772-1779.  doi: 10.4103/1673-5374.258411 Abstract ( 134 )   PDF (1167KB) ( 624 )   Save Previous data have revealed an association between eosinopenia and mortality of acute ischemic stroke. However, the relationship of eosinopenia with infarct volume, infection rate, and poor outcome of acute ischemic stroke is still unknown. The retrospective study included 421 patients (273 males, 65%; mean age, 68.0 ± 13.0 years) with first acute ischemic stroke who were hospitalized in the Second Affiliated Hospital of Soochow University, China, from January 2017 to February 2018. Laboratory data, neuroimaging results, and modified Rankin Scale scores were collected. Patients were divided into four groups according to their eosinophil percentage level (< 0.4%, 0.4–1.1%, 1.1–2.3%, ≥ 2.3%). Spearman’s correlation analysis showed that the percentage of eosinophils was negatively correlated with infarct volume (rs = −0. 514, P < 0.001). Receiver operating characteristic analysis demonstrated that eosinopenia predicted a large infarct volume more accurately than neutrophilia; the area under curve was 0.906 and 0.876, respectively; a large infarct was considered as that with a diameter larger than 3 cm and involving more than two major arterial blood supply areas. Logistic regression analysis revealed that eosinophil percentage was an independent risk factor for acute ischemic stroke (P = 0.002). Moreover, eosinophil percentage was significantly associated with large infarct volume, high infection rate (pulmonary and urinary tract infections), and poor outcome (modified Rankin Scale score > 3) after adjusting for potential confounding factors (P-trend < 0.001). These findings suggest that eosinopenia has the potential to predict the severity of acute ischemic stroke. This study was approved by the Ethics Committee of the Second Affiliated Hospital of Soochow University, China (approval number: K10) on November 10, 2015. Related Articles | Metrics

Select

Collagen-chitosan scaffold impregnated with bone marrow mesenchymal stem cells for treatment of traumatic brain injury Feng Yan, Ming Li, Hong-Qi Zhang, Gui-Lin Li, Yang Hua, Ying Shen, Xun-Ming Ji, Chuan-Jie Wu, Hong An, Ming Ren 2019, 14 (10):  1780-1786.  doi: 10.4103/1673-5374.257533 Abstract ( 107 )   PDF (1757KB) ( 140 )   Save Combinations of biomaterials and cells can effectively target delivery of cells or other therapeutic factors to the brain to rebuild damaged nerve pathways after brain injury. Porous collagen-chitosan scaffolds were prepared by a freeze-drying method based on brain tissue engineering. The scaffolds were impregnated with rat bone marrow mesenchymal stem cells. A traumatic brain injury rat model was estab¬lished using the 300 g weight free fall impact method. Bone marrow mesenchymal stem cells/collagen-chitosan scaffolds were implanted into the injured brain. Modified neurological severity scores were used to assess the recovery of neurological function. The Morris water maze was employed to determine spatial learning and memory abilities. Hematoxylin-eosin staining was performed to measure pathologi¬cal changes in brain tissue. Immunohistochemistry was performed for vascular endothelial growth factor and for 5-bromo-2-deoxyuridine (BrdU)/neuron specific enolase and BrdU/glial fibrillary acidic protein. Our results demonstrated that the transplantation of bone marrow mesenchymal stem cells and collagen-chitosan scaffolds to traumatic brain injury rats remarkably reduced modified neurological severity scores, shortened the average latency of the Morris water maze, increased the number of platform crossings, diminished the degeneration of damaged brain tissue, and increased the positive reaction of vascular endothelial growth factor in the transplantation and surround¬ing areas. At 14 days after transplantation, increased BrdU/glial fibrillary acidic protein expression and decreased BrdU/neuron specific enolase expression were observed in bone marrow mesenchymal stem cells in the injured area. The therapeutic effect of bone marrow mesenchymal stem cells and collagen-chitosan scaffolds was superior to stereotactic injection of bone marrow mesenchymal stem cells alone. To test the biocompatibility and immunogenicity of bone marrow mesenchymal stem cells and collagen-chitosan scaffolds, im¬munosuppressive cyclosporine was intravenously injected 12 hours before transplantation and 1–5 days after transplantation. The above indicators were similar to those of rats treated with bone marrow mesenchymal stem cells and collagen-chitosan scaffolds only. These findings indicate that transplantation of bone marrow mesenchymal stem cells in a collagen-chitosan scaffold can promote the recovery of neuropathological injury in rats with traumatic brain injury. This approach has the potential to be developed as a treatment for traumatic brain injury in humans. All experimental procedures were approved by the Institutional Animal Investigation Committee of Capital Medi¬cal University, China (approval No. AEEI-2015-035) in December, 2015. Related Articles | Metrics

Select

Melatonin modifies SOX2+ cell proliferation in dentate gyrus and modulates SIRT1 and MECP2 in long-term sleep deprivation Alan Hinojosa-Godínez, Luis F. Jave-Suarez, Mario Flores-Soto, Alma Y. Gálvez-Contreras, Sonia Luquín, Edith Oregon-Romero, Oscar González-Pérez, Rocio E. González-Castañeda 2019, 14 (10):  1787-1795.  doi: 10.4103/1673-5374.257537 Abstract ( 193 )   PDF (2420KB) ( 407 )   Save Melatonin is a pleiotropic molecule that, after a short-term sleep deprivation, promotes the proliferation of neural stem cells in the adult hippocampus. However, this effect has not been observed in long-term sleep deprivation. The precise mechanism exerted by melatonin on the modulation of neural stem cells is not entirely elucidated, but evidence indicates that epigenetic regulators may be involved in this process. In this study, we investigated the effect of melatonin treatment during a 96-hour sleep deprivation and analyzed the expression of epigenetic modulators predicted by computational text mining and keyword clusterization. Our results showed that the administration of melatonin under sleep-deprived conditions increased the MECP2 expression and reduced the SIRT1 expression in the dentate gyrus. We observed that let-7b, mir-132, and mir-124 were highly expressed in the dentate gyrus after melatonin administration, but they were not modified by sleep deprivation. In addition, we found more Sox2+/5-bromo-2′-deoxyuridine (BrdU)+ cells in the subgranular zone of the sleep-deprived group treated with melatonin than in the untreated group. These findings may support the notion that melatonin modifies the expression of epigenetic mediators that, in turn, regulate the proliferation of neural progenitor cells in the adult dentate gyrus under long-term sleep-deprived conditions. All procedures performed in this study were approved by the Animal Ethics Committee of the University of Guadalajara, Mexico (approval No. CI-16610) on January 2, 2016. Related Articles | Metrics

Select

Differences in pathological changes between two rat models of severe traumatic brain injury Yi-Ming Song, Yu Qian, Wan-Qiang Su, Xuan-Hui Liu, Jin-Hao Huang, Zhi-Tao Gong, Hong-Liang Luo, Chuang Gao, Rong-Cai Jiang 2019, 14 (10):  1796-1804.  doi: 10.4103/1673-5374.257534 Abstract ( 151 )   PDF (1913KB) ( 101 )   Save The rat high-impact free weight drop model mimics the diffuse axonal injury caused by severe traumatic brain injury in humans, while severe controlled cortical impact can produce a severe traumatic brain injury model using precise strike parameters. In this study, we compare the pathological mechanisms and pathological changes between two rat severe brain injury models to identify the similarities and differences. The severe controlled cortical impact model was produced by an electronic controlled cortical impact device, while the severe free weight drop model was produced by dropping a 500 g free weight from a height of 1.8 m through a plastic tube. Body temperature and mortality were recorded, and neurological deficits were assessed with the modified neurological severity score. Brain edema and blood-brain barrier damage were evaluated by assessing brain water content and Evans blue extravasation. In addition, a cytokine array kit was used to detect inflammatory cytokines. Neuronal apoptosis in the brain and brainstem was quantified by immunofluorescence staining. Both the severe controlled cortical impact and severe free weight drop models exhibited significant neurological impairments and body temperature fluctuations. More severe motor dysfunction was observed in the severe controlled cortical impact model, while more severe cognitive dysfunction was observed in the severe free weight drop model. Brain edema, inflammatory cytokine changes and cortical neuronal apoptosis were more substantial and blood-brain barrier damage was more focal in the severe controlled cortical impact group compared with the severe free weight drop group. The severe free weight drop model presented with more significant apoptosis in the brainstem and diffused blood-brain barrier damage, with higher mortality and lower repeatability compared with the severe controlled cortical impact group. Severe brainstem damage was not found in the severe controlled cortical impact model. These results indicate that the severe controlled cortical impact model is relatively more stable, more reproducible, and shows obvious cerebral pathological changes at an earlier stage. Therefore, the severe controlled cortical impact model is likely more suitable for studies on severe focal traumatic brain injury, while the severe free weight drop model may be more apt for studies on diffuse axonal injury. All experimental procedures were approved by the Ethics Committee of Animal Experiments of Tianjin Medical University, China (approval number: IRB2012-028-02) in February, 2012. Related Articles | Metrics

Select

Brain networks modeling for studying the mechanism underlying the development of Alzheimer’s disease Shuai-Zong Si, Xiao Liu, Jin-Fa Wang, Bin Wang, Hai Zhao 2019, 14 (10):  1805-1813.  doi: 10.4103/1673-5374.257538 Abstract ( 123 )   PDF (1276KB) ( 221 )   Save Alzheimer’s disease is a primary age-related neurodegenerative disorder that can result in impaired cognitive and memory functions. Al¬though connections between changes in brain networks of Alzheimer’s disease patients have been established, the mechanisms that drive these alterations remain incompletely understood. This study, which was conducted in 2018 at Northeastern University in China, included data from 97 participants of the Alzheimer’s Disease Neuroimaging Initiative dataset covering genetics, imaging, and clinical data. All participants were divided into two groups: normal control (n = 52; 20 males and 32 females; mean age 73.90 ± 4.72 years) and Alzheimer’s disease (n = 45, 23 males and 22 females; mean age 74.85 ± 5.66). To uncover the wiring mechanisms that shaped changes in the topology of human brain networks of Alzheimer’s disease patients, we proposed a local naïve Bayes brain network model based on graph theory. Our results showed that the proposed model provided an excellent fit to observe networks in all properties examined, including cluster¬ing coefficient, modularity, characteristic path length, network efficiency, betweenness, and degree distribution compared with empirical methods. This proposed model simulated the wiring changes in human brain networks between controls and Alzheimer’s disease patients. Our results demonstrate its utility in understanding relationships between brain tissue structure and cognitive or behavioral functions. Related Articles | Metrics

Select

Ginsenoside Rb1 protects dopaminergic neurons from inflammatory injury induced by intranigral lipopolysaccharide injection Da-Wei Li, Fa-Zhan Zhou, Xian-Chang Sun, Shu-Chen Li, Jin-Bin Yang, Huan-Huan Sun, Ai-Hua Wang 2019, 14 (10):  1814-1822.  doi: 10.4103/1673-5374.257536 Abstract ( 106 )   PDF (1687KB) ( 159 )   Save Accumulating studies suggest that neuroinflammation characterized by microglial overactivation plays a pivotal role in the pathogenesis of Parkinson’s disease. As such, inhibition of microglial overactivation might be a promising treatment strategy to delay the onset or slow the progression of Parkinson’s disease. Ginsenoside Rb1, the most active ingredient of ginseng, reportedly exerts neuroprotective effects by suppressing inflammation in vitro. The present study aimed to evaluate the neuroprotective and anti-inflammatory effects of ginsenoside Rb1 in a lipopolysaccharide-induced rat Parkinson’s disease model. Rats were divided into four groups. In the control group, sham-operated rats were intraperitoneally administered normal saline for 14 consecutive days. In the ginsenoside Rb1 group, ginsenoside Rb1 (20 mg/kg) was intraperitoneally injected for 14 consecutive days after sham surgery. In the lipopolysaccharide group, a single dose of lipopolysaccharide was unilaterally microinjected into the rat substantial nigra to establish the Parkinson’s disease model. Lipopolysaccharide-injected rats were treated with normal saline for 14 consecutive days. In the ginsenoside Rb1 + lipopolysaccharide group, lipopolysaccharide was unilaterally microinjected into the rat substantial nigra. Subsequently, ginsenoside Rb1 was intraperitoneally injected for 14 consecutive days. To investigate the therapeutic effects of ginsenoside Rb1, behavioral tests were performed on day 15 after lipopolysaccharide injection. We found that ginsenoside Rb1 treatment remarkably reduced apomorphine-induced rotations in lipopolysaccharide-treated rats compared with the lipopolysaccharide group. To investigate the neurotoxicity of lipopolysaccharide and potential protective effect of ginsenoside Rb1, contents of dopamine and its metabolites in the striatum were measured by high-performance liquid chromatography. Compared with the lipopolysaccharide group, ginsenoside Rb1 obviously attenuated the lipopolysaccharide-induced depletion of dopamine and its metabolites in the striatum. To further explore the neuroprotective effect of ginsenoside Rb1 against lipopolysaccharide-induced neurotoxicity, immunohistochemistry and western blot assay of tyrosine hydroxylase were performed to evaluate dopaminergic neuron degeneration in the substantial nigra par compacta. The results showed that lipopolysaccharide injection caused a large loss of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra and a significant decrease in overall tyrosine hydroxylase expression. However, ginsenoside Rb1 noticeably reversed these changes. To investigate whether the neuroprotective effect of ginsenoside Rb1 was associated with inhibition of lipopolysaccharide-induced microglial activation, we examined expression of the microglia marker Iba-1. Our results confirmed that lipopolysaccharide injection induced a significant increase in Iba-1 expression in the substantia nigra; however, ginsenoside Rb1 effectivelysuppressed lipopolysaccharide-induced microglial overactivation. To elucidate the inhibitory mechanism of ginsenoside Rb1, we examined expression levels of inflammatory mediators (tumor necrosis factor-α, interleukin-1β, inducible nitric oxide synthase, and cyclooxygenase 2) and phosphorylation of nuclear factor kappa B signaling-related proteins (IκB, IKK) in the substantia nigra with enzyme-linked immunosorbent and western blot assays. Our results revealed that compared with the control group, phosphorylation and expression of inflammatory mediators IκB and IKK in the substantia nigra of lipopolysaccharide group rats were significantly increased; whereas, ginsenoside Rb1 obviously reduced lipopolysaccharide-induced changes on the lesioned side of the substantial nigra par compacta. These findings confirm that ginsenoside Rb1 can inhibit inflammation induced by lipopolysaccharide injection into the substantia nigra and protect dopaminergic neurons, which may be related to its inhibition of the nuclear factor kappa B signaling pathway. This study was approved by the Experimental Animal Ethics Committee of Shandong University of China in April, 2016 (approval number: KYLL-2016-0148). Related Articles | Metrics

Select

Mapping theme trends and knowledge structures for human neural stem cells: a quantitative and co-word biclustering analysis for the 2013–2018 period Wen-Juan Wei, Bei Shi, Xin Guan, Jing-Yun Ma, Ya-Chen Wang, Jing Liu 2019, 14 (10):  1823-1832.  doi: 10.4103/1673-5374.257535 Abstract ( 75 )   PDF (5153KB) ( 238 )   Save Neural stem cells, which are capable of multi-potential differentiation and self-renewal, have recently been shown to have clinical potential for repairing central nervous system tissue damage. However, the theme trends and knowledge structures for human neural stem cells have not yet been studied bibliometrically. In this study, we retrieved 2742 articles from the PubMed database from 2013 to 2018 using “Neural Stem Cells” as the retrieval word. Co-word analysis was conducted to statistically quantify the characteristics and popular themes of human neural stem cell-related studies. Bibliographic data matrices were generated with the Bibliographic Item Co-Occurrence Matrix Builder. We identified 78 high-frequency Medical Subject Heading (MeSH) terms. A visual matrix was built with the repeated bisection method in gCLUTO software. A social network analysis network was generated with Ucinet 6.0 software and GraphPad Prism 5 software. The analyses demonstrated that in the 6-year period, hot topics were clustered into five categories. As suggested by the constructed strategic diagram, studies related to cytology and physiology were well-developed, whereas those related to neural stem cell applications, tissue engineering, metabolism and cell signaling, and neural stem cell pathology and virology remained immature. Neural stem cell therapy for stroke and Parkinson’s disease, the genetics of microRNAs and brain neoplasms, as well as neuroprotective agents, Zika virus, Notch receptor, neural crest and embryonic stem cells were identified as emerging hot spots. These undeveloped themes and popular topics are potential points of focus for new studies on human neural stem cells. Related Articles | Metrics

Select

Sciatic nerve injury alters the spatial arrangement of neurons and glial cells in the anterior horn of the spinal cord Ali Rashidiani-Rashidabadi, Mohammad Hassan Heidari, Ensieh Sajadi, Fatemeh Hejazi, Fatemeh Fadaei Fathabady,Yousef Sadeghi, Abbas Aliaghaei, Amir Raoofi, Mohammad-Amin Abdollahifar, Reza Mastery Farahni 2019, 14 (10):  1833-1840.  doi: 10.4103/1673-5374.257539 Abstract ( 191 )   PDF (3189KB) ( 162 )   Save The spatial arrangement of the cell is important and considered as underlying mechanism for mathematical modeling of cell to cell interaction. The ability of cells to take on the characteristics of other cells in an organism, it is important to understand the dynamical behavior of the cells. This method implements experimental parameters of the cell-cell interaction into the mathematical simulation of cell arrangement. The purpose of this research was to explore the three-dimensional spatial distribution of anterior horn cells in the rat spinal cord to examine differences after sciatic nerve injury. Sixteen Sprague-Dawley male rats were assigned to control and axotomy groups. Twelve weeks after surgery, the anterior horn was removed for first- and second-order stereological studies. Second-order stereological techniques were applied to estimate the pair correlation and cross-correlation functions using a dipole probe superimposed onto the spinal cord sections. The findings revealed 7% and 36% reductions in the mean volume and total number of motoneurons, respectively, and a 25% increase in the neuroglial cell number in the axotomized rats compared to the control rats. In contrast, the anterior horn volume remained unchanged. The results also indicated a broader gap in the pair correlation curve for the motoneurons and neuroglial cells in the axotomized rats compared to the control rats. This finding shows a negative correlation for the distribution of motoneurons and neuroglial cells in the axotomized rats. The cross-correlation curve shows a negative correlation between the motoneurons and neuroglial cells in the axotomized rats. These findings suggest that cellular structural and functional changes after sciatic nerve injury lead to the alterations in the spatial arrangement of motoneurons and neuroglial cells, finally affecting the normal function of the central nervous system. The experimental protocol was reviewed and approved by the Animal Ethics Committee of Shahid Beheshti University of Medical Sciences (approval No. IR.SBMU.MSP.REC1395.375) on October 17, 2016.  Related Articles | Metrics