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15 April 2022, Volume 17 Issue 4 Previous Issue   

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Towards a comprehensive understanding of p75 neurotrophin receptor functions and interactions in the brain Joel F. Ritala, Seán B. Lyne, Antti Sajanti, Romuald Girard, Janne Koskimäki 2022, 17 (4):  701-704.  doi: 10.4103/1673-5374.314291 Abstract ( 508 )   PDF (844KB) ( 181 )   Save The role of neurotrophins in neuronal plasticity has recently become a strong focus in neuroregeneration research field to elucidate the biological mechanisms by which these molecules modulate synapses, modify the response to injury, and alter the adaptation response. Intriguingly, the prior studies highlight the role of p75 neurotrophin receptor (p75NTR) in various injuries and diseases such as central nervous system injuries, Alzheimer’s disease and amyotrophic lateral sclerosis. More comprehensive elucidation of the mechanisms, and therapies targeting these molecular signaling networks may allow for neuronal tissue regeneration following an injury. Due to a diverse role of the p75NTR in biology, the body of evidence comprising its biological role is diffusely spread out over numerous fields. This review condenses the main evidence of p75NTR for clinical applications and presents new findings from published literature how data mining approach combined with bioinformatic analyses can be utilized to gain new hypotheses in a molecular and network level. Related Articles | Metrics

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Microglia regulation of synaptic plasticity and learning and memory Jessica Cornell, Shelbi Salinas, Hou-Yuan Huang, Miou Zhou 2022, 17 (4):  705-716.  doi: 10.4103/1673-5374.322423 Abstract ( 896 )   PDF (680KB) ( 265 )   Save Microglia are the resident macrophages of the central nervous system. Microglia possess varied morphologies and functions. Under normal physiological conditions, microglia mainly exist in a resting state and constantly monitor their microenvironment and survey neuronal and synaptic activity. Through the C1q, C3 and CR3 “Eat Me” and CD47 and SIRPα “Don’t Eat Me” complement pathways, as well as other pathways such as CX3CR1 signaling, resting microglia regulate synaptic pruning, a process crucial for the promotion of synapse formation and the regulation of neuronal activity and synaptic plasticity. By mediating synaptic pruning, resting microglia play an important role in the regulation of experience-dependent plasticity in the barrel cortex and visual cortex after whisker removal or monocular deprivation, and also in the regulation of learning and memory, including the modulation of memory strength, forgetfulness, and memory quality. As a response to brain injury, infection or neuroinflammation, microglia become activated and increase in number. Activated microglia change to an amoeboid shape, migrate to sites of inflammation and secrete proteins such as cytokines, chemokines and reactive oxygen species. These molecules released by microglia can lead to synaptic plasticity and learning and memory deficits associated with aging, Alzheimer’s disease, traumatic brain injury, HIV-associated neurocognitive disorder, and other neurological or mental disorders such as autism, depression and post-traumatic stress disorder. With a focus mainly on recently published literature, here we reviewed the studies investigating the role of resting microglia in synaptic plasticity and learning and memory, as well as how activated microglia modulate disease-related plasticity and learning and memory deficits. By summarizing the function of microglia in these processes, we aim to provide an overview of microglia regulation of synaptic plasticity and learning and memory, and to discuss the possibility of microglia manipulation as a therapeutic to ameliorate cognitive deficits associated with aging, Alzheimer’s disease, traumatic brain injury, HIV-associated neurocognitive disorder, and mental disorders. Related Articles | Metrics

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Stroke recovery enhancing therapies: lessons from recent clinical trials Andreas Rogalewski, Wolf-Rüdiger Schäbitz 2022, 17 (4):  717-720.  doi: 10.4103/1673-5374.314287 Abstract ( 140 )   PDF (315KB) ( 107 )   Save Poststroke recovery processes include restoration or compensation of function, respectively functions initially lost or new functions acquired after an injury. Therapeutic interventions can enhance these processes and/or reduce processes impeding regeneration. Numerous experimental studies suggest great opportunities for such treatments, but the results from recent large clinical trials using neuromodulators such as dopamine and fluoxetine are disappointing. The reasons for this are manifold affecting forward translation of results from animals models into the human situation. This “translational road block” is defined by differences between animals and humans with regard to the genetic and epigenetic background, size and anatomy of the brain, cerebral vascular anatomy, immune system, as well as clinical function and behavior. Backward blockade includes the incompatible adaption of targets and outcomes in clinical trials with regard to prior preclinical findings. For example, the design of clinical recovery trials varies widely and was characterized by the selection of different clinical endpoints, the inclusion a broad spectrum of stroke subtypes and clinical syndromes as well as different time windows for treatment initiation after infarct onset. This review will discuss these aspects based on the results of the recent stroke recovery trials with the goal to contribute to the currently biggest unmet need in stroke research - the development of a recovery enhancing therapy that improves the functional outcome of a chronic stroke patient.  Related Articles | Metrics

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Functional and immunological peculiarities of peripheral nerve allografts Kelly C.S. Roballo, Jason P. Gigley, Tyler A. Smith, George D. Bittner, Jared S. Bushman 2022, 17 (4):  721-727.  doi: 10.4103/1673-5374.322445 Abstract ( 220 )   PDF (388KB) ( 135 )   Save This review addresses the accumulating evidence that live (not decellularized) allogeneic peripheral nerves are functionally and immunologically peculiar in comparison with many other transplanted allogeneic tissues. This is relevant because live peripheral nerve allografts are very effective at promoting recovery after segmental peripheral nerve injury via axonal regeneration and axon fusion. Understanding the immunological peculiarities of peripheral nerve allografts may also be of interest to the field of transplantation in general. Three topics are addressed: The first discusses peripheral nerve injury and the potential utility of peripheral nerve allografts for bridging segmental peripheral nerve defects via axon fusion and axon regeneration. The second reviews evidence that peripheral nerve allografts elicit a more gradual and less severe host immune response allowing for prolonged survival and function of allogeneic peripheral nerve cells and structures. Lastly, potential mechanisms that may account for the immunological differences of peripheral nerve allografts are discussed.  Related Articles | Metrics

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MicroRNA expression in animal models of amyotrophic lateral sclerosis and potential therapeutic approaches Bridget Martinez, Philip V. Peplow 2022, 17 (4):  728-740.  doi: 10.4103/1673-5374.322431 Abstract ( 333 )   PDF (652KB) ( 155 )   Save A review of recent animal models of amyotrophic lateral sclerosis showed a large number of miRNAs had altered levels of expression in the brain and spinal cord, motor neurons of spinal cord and brainstem, and hypoglossal, facial, and red motor nuclei and were mostly upregulated. Among the miRNAs found to be upregulated in two of the studies were miR-21, miR-155, miR-125b, miR-146a, miR-124, miR-9, and miR-19b, while those downregulated in two of the studies included miR-146a, miR-29, miR-9, and miR-125b. A change of direction in miRNA expression occurred in some tissues when compared (e.g., miR-29b-3p in cerebellum and spinal cord of wobbler mice at 40 days), or at different disease stages (e.g., miR-200a in spinal cord of SOD1(G93A) mice at 95 days vs. 108 and 112 days). In the animal models, suppression of miR-129-5p resulted in increased lifespan, improved muscle strength, reduced neuromuscular junction degeneration, and tended to improve motor neuron survival in the SOD1(G93A) mouse model. Suppression of miR-155 was also associated with increased lifespan, while lowering of miR-29a tended to improve lifespan in males and increase muscle strength in SOD1(G93A) mice. Overexpression of members of miR-17~92 cluster improved motor neuron survival in SOD1(G93A) mice. Treatment with an artificial miRNA designed to target hSOD1 increased lifespan and improved muscle strength in SOD1(G93A) animals. Further studies with animal models of amyotrophic lateral sclerosis are warranted to validate these findings and identify specific miRNAs whose suppression or directed against hSOD1 results in increased lifespan, improved muscle strength, reduced neuromuscular junction degeneration, and improved motor neuron survival in SOD1(G93A) animals. Related Articles | Metrics

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Significance of mitochondrial activity in neurogenesis and neurodegenerative diseases Serra Ozgen, Judith Krigman, Ruohan Zhang, Nuo Sun 2022, 17 (4):  741-747.  doi: 10.4103/1673-5374.322429 Abstract ( 507 )   PDF (543KB) ( 291 )   Save Mitochondria play a multidimensional role in the function and the vitality of the neurological system. From the generation of neural stem cells to the maintenance of neurons and their ultimate demise, mitochondria play a critical role in regulating our neural pathways’ homeostasis, a task that is critical to our cognitive health and neurological well-being. Mitochondria provide energy via oxidative phosphorylation for the neurotransmission and generation of an action potential along the neuron’s axon. This paper will first review and examine the molecular subtleties of the mitochondria’s role in neurogenesis and neuron vitality, as well as outlining the impact of defective mitochondria in neural aging. The authors will then summarize neurodegenerative diseases related to either neurogenesis or homeostatic dysfunction. Because of the significant detriment neurodegenerative diseases have on the quality of life, it is essential to understand their etiology and ongoing molecular mechanics. The mitochondrial role in neurogenesis and neuron vitality is essential. Dissecting and understanding this organelle’s role in the genesis and homeostasis of neurons should assist in finding pharmaceutical targets for neurodegenerative diseases. Related Articles | Metrics

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GDNF to the rescue: GDNF delivery effects on motor neurons and nerves, and muscle re-innervation after peripheral nerve injuries Alberto F. Cintrón-Colón, Gabriel Almeida-Alves, Juliana M. VanGyseghem, John M. Spitsbergen 2022, 17 (4):  748-753.  doi: 10.4103/1673-5374.322446 Abstract ( 446 )   PDF (12682KB) ( 86 )   Save Peripheral nerve injuries commonly occur due to trauma, like a traffic accident. Peripheral nerves get severed, causing motor neuron death and potential muscle atrophy. The current golden standard to treat peripheral nerve lesions, especially lesions with large (≥ 3 cm) nerve gaps, is the use of a nerve autograft or reimplantation in cases where nerve root avulsions occur. If not tended early, degeneration of motor neurons and loss of axon regeneration can occur, leading to loss of function. Although surgical procedures exist, patients often do not fully recover, and quality of life deteriorates. Peripheral nerves have limited regeneration, and it is usually mediated by Schwann cells and neurotrophic factors, like glial cell line-derived neurotrophic factor, as seen in Wallerian degeneration. Glial cell line-derived neurotrophic factor is a neurotrophic factor known to promote motor neuron survival and neurite outgrowth. Glial cell line-derived neurotrophic factor is upregulated in different forms of nerve injuries like axotomy, sciatic nerve crush, and compression, thus creating great interest to explore this protein as a potential treatment for peripheral nerve injuries. Exogenous glial cell line-derived neurotrophic factor has shown positive effects in regeneration and functional recovery when applied in experimental models of peripheral nerve injuries. In this review, we discuss the mechanism of repair provided by Schwann cells and upregulation of glial cell line-derived neurotrophic factor, the latest findings on the effects of glial cell line-derived neurotrophic factor in different types of peripheral nerve injuries, delivery systems, and complementary treatments (electrical muscle stimulation and exercise). Understanding and overcoming the challenges of proper timing and glial cell line-derived neurotrophic factor delivery is paramount to creating novel treatments to tend to peripheral nerve injuries to improve patients’ quality of life. Related Articles | Metrics

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Mitochondrial dysfunctions in neurodegenerative diseases: role in disease pathogenesis, strategies for analysis and therapeutic prospects Federica Rey, Sara Ottolenghi, Gian Vincenzo Zuccotti, Michele Samaja, Stephana Carelli 2022, 17 (4):  754-758.  doi: 10.4103/1673-5374.322430 Abstract ( 680 )   PDF (993KB) ( 263 )   Save Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes, the mitochondria are required for multiple pivotal processes that include the production of biological energy, the biosynthesis of reactive oxygen species, the control of calcium homeostasis, and the triggering of cell death. The disruption of anyone of these processes has been shown to impact strongly the function of all cells, but especially of neurons. In this review, we discuss the role of the mitochondria impairment in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis, Parkinson’s disease and Alzheimer’s disease. We highlight how mitochondria disruption revolves around the processes that underlie the mitochondria’s life cycle: fusion, fission, production of reactive oxygen species and energy failure. Both genetic and sporadic forms of neurodegenerative diseases are unavoidably accompanied with and often caused by the dysfunction in one or more of the key mitochondrial processes. Therefore, in order to get in depth insights into their health status in neurodegenerative diseases, we need to focus into innovative strategies aimed at characterizing the various mitochondrial processes. Current techniques include Mitostress, Mitotracker, transmission electron microscopy, oxidative stress assays along with expression measurement of the proteins that maintain the mitochondrial health. We will also discuss a panel of approaches aimed at mitigating the mitochondrial dysfunction. These include canonical drugs, natural compounds, supplements, lifestyle interventions and innovative approaches as mitochondria transplantation and gene therapy. In conclusion, because mitochondria are fundamental organelles necessary for virtually all the cell functions and are severely impaired in neurodegenerative diseases, it is critical to develop novel methods to measure the mitochondrial state, and novel therapeutic strategies aimed at improving their health. Related Articles | Metrics

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Three-dimensional in vitro models of neuromuscular tissue Paolo Raffa, Maria Easler, Anna Urciuolo 2022, 17 (4):  759-766.  doi: 10.4103/1673-5374.322447 Abstract ( 324 )   PDF (545KB) ( 166 )   Save Skeletal muscle is a dynamic tissue in which homeostasis and function are guaranteed by a very defined three-dimensional organization of myofibers in respect to other non-muscular components, including the extracellular matrix and the nervous network. In particular, communication between myofibers and the nervous system is essential for the overall correct development and function of the skeletal muscle. A wide range of chronic, acute and genetic-based human pathologies that lead to the alteration of muscle function are associated with modified preservation of the fine interaction between motor neurons and myofibers at the neuromuscular junction. Recent advancements in the development of in vitro models for human skeletal muscle have shown that three-dimensionality and integration of multiple cell types are both key parameters required to unveil pathophysiological relevant phenotypes. Here, we describe recent achievement reached in skeletal muscle modeling which used biomaterials for the generation of three-dimensional constructs of myotubes integrated with motor neurons.  Related Articles | Metrics

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Induced pluripotent stem cells for defining Parkinsonian patient subtypes: a further step toward precision medicine Federica Bono, Cristina Missale, Chiara Fiorentini 2022, 17 (4):  767-769.  doi: 10.4103/1673-5374.322448 Abstract ( 184 )   PDF (612KB) ( 90 )   Save Introduction: Parkinson’s disease (PD) is a common neurodegenerative disorder mainly characterized by the progressive decline of motor function with a prevalence that is greatly increasing since the pathology is principally driven by aging. The currently available treatments only mitigate motor symptoms; therefore, a great deal of studies are aimed at finding novel drugs that are able to arrest the evolution of the disease. Related Articles | Metrics

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A simple human cell model for TAU trafficking and tauopathy-related TAU pathology Michael Bell, Hans Zempel 2022, 17 (4):  770-772.  doi: 10.4103/1673-5374.322450 Abstract ( 218 )   PDF (6432KB) ( 136 )   Save The microtubule (MT)-associated protein TAU is highly abundant in the axon of human brain neurons, where it binds to and stabilizes MT filaments. Thereby, TAU regulates the dynamic (dis)assembly of MT strands and is involved in a wide range of neuronal functions. In Alzheimer’s disease (AD) and other tauopathies, TAU is missorted into the somatodendritic compartment. TAU missorting is accompanied by (or leads to) abnormal TAU phosphorylation, MT destabilization, and loss of dendritic spines and mitochondria, eventually resulting in TAU aggregation, neuronal dysfunction and cell death (Arendt et al., 2016). Strikingly, the mechanisms of TAU sorting, and the detrimental cascade upon its failure, are still not fully understood. Related Articles | Metrics

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Colony stimulating factor 1: friend or foe of neurons? Lorna Bo, Xuenong Bo 2022, 17 (4):  773-774.  doi: 10.4103/1673-5374.322451 Abstract ( 258 )   PDF (448KB) ( 102 )   Save Colony stimulating factor 1 receptor (CSF1R) is a tyrosine kinase receptor primarily expressed on microglia and a small subpopulation of neurons in the central nervous system (CNS), which directly controls the homeostasis, activation, and proliferation of microglia. Its ligands include CSF1 and interleukin-34 (IL-34), which bind to the same region of CSF1R. The two ligands have overlapping functions, however, they also have some differences in signal transduction and induce different transcription profiles. CSF1 and IL-34 are generally expressed by neurons in the CNS, but CSF1 is also expressed by astrocytes. The colony stimulating factors were first characterized by their ability to trigger the differentiation of bone marrow precursor cells into mature myeloid cells but were later found to also act on mature myeloid cells including microglia. In the homeostatic brain, a baseline level of CSF1 helps to maintain microglial roles of synaptic pruning, release of neurotrophic factors, and promotion of brain connectivity. However, over the past decade or so, chronic activation of microglia has been implicated in exacerbating neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) (Xu et al., 2021). Yet there have also been studies in contradiction, which showed that in other circumstances, activated microglia were therapeutic and might mitigate neurodegeneration. So, is CSF1 the friend or foe of neurons? Related Articles | Metrics

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Exploring the potential application of dental pulp stem cells in neuroregenerative medicine Nessma Sultan, Ben A. Scheven 2022, 17 (4):  775-776.  doi: 10.4103/1673-5374.322449 Abstract ( 250 )   PDF (435KB) ( 171 )   Save The trigeminal nerve and its peripheral branches are susceptible to injury in the dental practice due to surgical removal of impacted third molars and placement of dental implants. Although peripheral trigeminal nerve injuries can undergo spontaneous regeneration, some injuries may be permanent with varying degrees of continued sensory impairment and neuropathic pain ranging from mild numbness to complete anaesthesia (Tay and Zuniga, 2007). Adult neurons require continued neurotrophic support from surrounding cells to sustain neural viability, inhibit death-inducing pathways activating a variety of cell survival pathways (Zheng and Quirion, 2004).  Related Articles | Metrics

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APOE4 expression is associated with impaired autophagy and mitophagy in astrocytes Schmukler Eran, Pinkas-Kramarski Ronit 2022, 17 (4):  777-778.  doi: 10.4103/1673-5374.322452 Abstract ( 380 )   PDF (510KB) ( 150 )   Save Among the risk factors for late onset sporadic Alzheimer’s disease (AD) is the expression of ε4 allele of apolipoprotein E (APOE4) gene (Mahley et al., 2006). Elevated amyloid processing and reduced degradation of Aβ, which lead to Aβ plaque deposition, are evident in APOE4-positive AD patients and mice (Mahley et al., 2006). These features correlate with neuronal cell loss. Impaired mitochondrial activity and increased oxidative stress have long been recognized as additional hallmarks of AD pathology (Mahley et al., 2006). The effect of APOE4 expression on autophagy and mitochondrial dynamics and activity in astrocytes is discussed in this perspective and is summarized in Figure 1.  Related Articles | Metrics

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Clinical potential of tension-lengthening strategies during nerve repair Stanley Bazarek, Justin M. Brown, Sameer B. Shah 2022, 17 (4):  779-780.  doi: 10.4103/1673-5374.322461 Abstract ( 134 )   PDF (1261KB) ( 89 )   Save A (very) brief history of tension in nerve repair: Successful nerve repair is achieved by conveying as many axons successfully to their targets as possible. Typically, this is best achieved through a direct end-to-end repair under minimal tension (Millesi, 1986). However, this is not feasible in most cases of trauma, where a segment of tissue damage must be excised and overcome. This has most commonly been addressed with the use of nerve grafts to bridge the gap. Autologous nerve grafts are considered the gold standard, with allograft or synthetic substitutes demonstrating some success over shorter distances. Despite their utility, autologous grafts pose challenges of their own. These include functional deficit in the donor distribution (typically sensory), extended operative duration, additional scarring, and a lack of intrinsic blood supply. They are also a poor anatomical match for the stumps being bridged, both internally (disparate neuronal size and composition) as well as externally (often requiring cabled bundles to approximate the caliber of the nerve being repaired). Finally, unlike end-to-end repairs, autologous grafts also require axons to traverse a second repair interface, where a large proportion of axons are lost across the anatomical discontinuity. Related Articles | Metrics

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Accelerating peripheral nerve regeneration using electrical stimulation of selected power spectral densities Wei-Ming Yu, Madelyn A. McCullen, Vincent C.-F. Chen 2022, 17 (4):  781-782.  doi: 10.4103/1673-5374.322458 Abstract ( 201 )   PDF (862KB) ( 139 )   Save Peripheral nerve injuries are common consequences of extremity trauma or chronic compression with a prevalence of 43.8 per 1 million people (on average) reported in the United States annually, accompanied by a yearly increase in cost of care. Patients suffering from these injuries require surgical procedures and rehabilitative strategies to reinforce their extensive recovery. Several studies have found that the application of electrical stimulation can accelerate peripheral nerve regeneration, thus shortening the time of peripheral nerve growth and reducing the cost of care (Willand et al., 2016). The electrical stimulation paradigms that effectively enhanced functional recovery in most studies employed signals of sinusoidal waves delivered at higher frequencies (50–100 Hz) or pulsed waves delivered at lower frequencies (< 20 Hz). As it would be impractical to try to pinpoint the exact stimulation parameter (i.e., frequency or waveform) that will enhance the healing procedure, our task at hand is to conduct a series of experiments with the objective of identifying an optimal arrangement of stimulation parameters for clinical applications. Indeed, the goal of our research is to identify an improved stimulation strategy by precisely determining the contribution of different stimulation parameters and factoring in the possible contribution of these parameters to the response of peripheral glial cells.  Related Articles | Metrics

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Involvement of glucose transporter overexpression in the protection or damage after ischemic stroke Iván Alquisiras-Burgos, Penélope Aguilera 2022, 17 (4):  783-784.  doi: 10.4103/1673-5374.322456 Abstract ( 207 )   PDF (1083KB) ( 145 )   Save Cerebral ischemia and resultant energy collapse: The ischemic stroke is a complex neurological condition that can be devastating for patients and their families. This disease is the second leading cause of death worldwide and is characterized by a sudden decrease in cerebral blood flow due to major blood vessel blockage. Ischemic stroke generates two damaged zones with distinctive metabolic characteristics. The first is the ischemic core, the region directly irrigated by the occluded artery. A reduction to less than 20% of the baseline blood flow levels defines the area; therefore, depletion of glucose and adenosine triphosphate (ATP) cause an irreversible failure in the energy metabolism that leads to loss of ionic homeostasis, acidosis, and necrosis. The second is the region surrounding the ischemic core, called the penumbra, characterized by significantly depressed tissue perfusion that is barely sufficient to support basal oxygen, glucose, and ATP levels. The penumbra represents a region at risk that is functionally impaired but potentially recoverable and suitable for neuroregeneration. Therefore, physiological conditions must be reestablished rapidly after ischemia to avoid a permanent metabolic failure in the penumbra. Related Articles | Metrics

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Non-invasive gene delivery across the blood-brain barrier: present and future perspectives Seigo Kimura, Hideyoshi Harashima 2022, 17 (4):  785-787.  doi: 10.4103/1673-5374.320981 Abstract ( 182 )   PDF (446KB) ( 135 )   Save The aging of society has arrived, and is accompanied by an increase in the absolute numbers of patients with neurological disorders, such as Alzheimer’s and Parkinson’s diseases (Feigin et al., 2020). Such diseases, particularly Alzheimer’s disease and other forms of dementia, affect not only the patients themselves, but also the people around them, including family members and care givers. As a result, such neurological disorders are thought to carry a larger social burden compared to other diseases. The most critical point in the current situation is that there is no effective treatment despite the fact that the number of patients increase with the aging of the population. Gene therapy has great promise for the treatment of neurological disorders (Sun and Roy, 2021), but delivering therapeutic genes is a major impediment for the success of gene therapy. Nanotechnologies such as viral and non-viral vectors now permit the creation of efficient brain-targeted gene delivery systems. In 2019, the Food and Drug Administration approved Zolgensma, a gene therapy for the treatment of spinal muscular atrophy. The advent of Zolgensma confirmed that in vivo targeted gene therapy is a real possibility and is expected to further accelerate the development of drug delivery system technology in anticipation of gene therapy. Zolgensma involves the use of an adeno-associated virus (AAV) vector, one of the leading approaches to gene therapy, due to its high transfection efficiency; however there are issues associated with viral vectors including the production of neutralizing antibodies to the vectors and issues associated with high dose/large scale production. Regarding those points, non-viral vectors offer some distinct advantages. Non-viral delivery technologies have evolved dramatically over the past decade, especially in the use of nanoparticles in drug delivery as exemplified by lipid nanoparticles, liposomes, and micelles. The goal of this perspective is to provide a prospective look into this emerging field. To accomplish this, we mainly address three aspects of this situation: (1) brain-targeted AAV vectors; (2) non-viral delivery via non-invasive methods; (3) mechanistic studies concerning crossing the blood-brain barrier (BBB) and methodology for vector screening. Related Articles | Metrics

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Potential use of lactate for the treatment of neonatal hypoxic-ischemic encephalopathy Isadora D’Ávila Tassinari, Luciano Stürmer de Fraga 2022, 17 (4):  788-790.  doi: 10.4103/1673-5374.322459 Abstract ( 206 )   PDF (1192KB) ( 108 )   Save Function of lactate: Lactate is a three-carbon molecule produced by glycolytic metabolism that is a metabolic waste product with no known use in clinical therapy. Conversely, it is a metabolite that the body should quickly guarantee the clearance. However, lactate is now recognized as a potential energy substrate, as well as an anti-inflammatory signaling molecule. These actions were first reported in adult animal models with a brain injury, including a traumatic brain injury and cerebral ischemia, and have also been observed in human patients (Magistretti and Allaman, 2018). Recently, however, two studies by independent research groups described promising neuroprotective results from the use of lactate in animal models with neonatal hypoxia-ischemia (Roumes et al., 2021; Tassinari et al., 2020). Both studies suggested that lactate administered intraperitoneally was able to reach the brain and contribute to the reduction of brain injury, as well as improve behavioral parameters. Despite that the pre-clinical studies were performed using neonatal rats, they suggest the potential use of lactate as clinical therapy for the treatment of hypoxic-ischemic encephalopathy (HIE), a disorder still affecting a high number of newborns. Related Articles | Metrics

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Brain ischemia as a bridge to Alzheimer’s disease Ryszard Pluta 2022, 17 (4):  791-792.  doi: 10.4103/1673-5374.322453 Abstract ( 142 )   PDF (332KB) ( 94 )   Save An update of the etiology of Alzheimer’s disease (AD): The current theory of the etiology of AD and the guidelines for most of the wide-ranging treatments activities are built around amyloid and tau protein as causative agents of the disease (Atlante et al., 2020). At present, based on a comprehensive evaluation of existing and contemporary studies, important questions arise regarding the causal role of amyloid and tau protein in the pathogenesis of AD (Morris et al., 2018). Analyzes of the available evidence does not allow obvious conclusion that amyloid, and especially tau protein, plays a key role in the etiology of AD (Morris et al., 2018). Evaluation of new data shows that accumulation of amyloid and altered tau protein is not the main cause of AD and more research is needed (Morris et al., 2018). As for the two substances planted to contribute to the development of AD, recent data indicate that the changes of amyloid and tau protein level and structure is triggered by some as yet unspecified factors, and then the triggered amyloid and tau protein interact with each other, exerting synergistic toxic effects on neurons and damaged neurons initiate the development of AD (Morris et al., 2018). It is certain that the pathology of amyloid and tau protein is currently ruled out as the sole cause of the development of dementia, as it cannot explain why about half of the world’s population have accumulation of different kinds of amyloid plaques and neurofibrillary tangles in the absence of dementia (Atlante et al., 2020). In these people, it was observed that the accumulation of neurofibrillary tangles increased exponentially with age (Atlante et al., 2020). In addition, it was noted that the appearance of hippocampus atrophy in elderly people with normal cognitive performance was not dependent on the presence of level and structure of amyloid (Atlante et al., 2020). Moreover, a multicenter study found that in patients diagnosed with AD, about one-third of the cases had no brain amyloid (Atlante et al., 2020). Related Articles | Metrics

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Therapeutic potential of translocator protein ligands for age-related macular degeneration Xing Li, Zhiming He, Xinhua Shu 2022, 17 (4):  793-794.  doi: 10.4103/1673-5374.322460 Abstract ( 141 )   PDF (429KB) ( 100 )   Save Age-related macular degeneration: Age-related macular degeneration (AMD) is a retinal degenerative disorder, characterized by the irreversible loss of the central vision during ageing. This chronic, progressive disease has been estimated to currently affect around 196 million people worldwide and will increase to 288 million in 2040 (Wong, et al., 2014). Early AMD is defined by the presence of drusen underneath the retinal pigment epithelial (RPE) layer. Late AMD can be divided into two groups, “wet AMD” and “dry AMD”, depending on the underlying clinical features. Wet AMD demonstrates a clinic feature of choroidal neovascularization (CNV) in which new blood vessels protrude from the choroid through the Bruch’s membrane and interfere with the morphological architecture of RPE and the superficial retina. Wet AMD accounts for approximately 10% of AMD patients, but for around 90% of resultant blind registration. Targeting vascular endothelial growth factor treatment greatly suppresses CNV progression in most wet AMD patients. Dry AMD is characterized by geographic atrophy and no effective therapy is available for dry AMD patients (Pikuleva and Curcio, 2014; Wong et al., 2014). Related Articles | Metrics

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Diabetic retinopathy: neurovascular disease requiring neuroprotective and regenerative therapies Toshiyuki Oshitari 2022, 17 (4):  795-796.  doi: 10.4103/1673-5374.322457 Abstract ( 226 )   PDF (495KB) ( 784 )   Save It is well known that diabetic retinopathy is a neurovascular disease that is accompanied by dysfunction of neurovascular units composed of neurons, glial cells, and vascular cells (Antonetti et al., 2012; Figure 1). Many studies have reported that the neuronal abnormalities, such as neuronal cell death, frequently precedes vascular abnormalities including neovascularization (Sohn et al., 2016). Neuronal cell death and axonal degeneration are irreversible changes under normal physiological conditions, and they are directly linked to the vision decrease. In fact, there is a reduction of the thickness of retinal nerve fiber layer in patients without diabetic retinopathy (Sohn et al., 2016). The reduction in the thickness of the ganglion cell complex, which is made up of the retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer, is 0.54 μm/year which is similar to the reduction observed in advanced glaucoma (Sohn et al., 2016). These clinical findings strongly indicated that the axonal degeneration is associated with the pathogenesis of neuronal abnormalities in diabetic retinas. Thus, not only neuroprotection but also regenerative therapies are required for the protection and maintenance of visual function of eyes with diabetic retinopathy. Related Articles | Metrics

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Retinal microglial activation in glaucoma: evolution over time in a unilateral ocular hypertension model José A. Fernández-Albarral, Ana I. Ramírez, Rosa de Hoz, Juan J. Salazar 2022, 17 (4):  797-799.  doi: 10.4103/1673-5374.322454 Abstract ( 197 )   PDF (309KB) ( 60 )   Save Glaucoma is a neurodegenerative chronic pathology, characterized by the loss of retinal ganglion cells (RGC), which leads to an irreversible vision field loss. The increased intraocular pressure (IOP) constitutes its main risk factor. Nowadays, the main treatments for glaucoma are focused on decreasing IOP; nevertheless, the progression of the disease continues, despite IOP control. This fact shows the existence of other factors that could contribute to the advance of glaucomatous neurodegeneration. The early diagnostics, the use of neuroprotective therapies, and knowledge of the pathological processes are the major challenges associated with the management of this disease. Different pathogenic mechanisms have been proposed to be responsible for RGC death, including oxidative stress, mitochondrial dysfunction, glutamate excitotoxicity, and neuroinflammation (Casson et al., 2012) Related Articles | Metrics

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Visual system repair: what’s next? Noemie Vilallongue, Homaira Nawabi 2022, 17 (4):  800-802.  doi: 10.4103/1673-5374.323076 Abstract ( 199 )   PDF (829KB) ( 658 )   Save One of the hallmarks of the mature neurons from the central nervous system (CNS) is their inability to grow their axons after an insult. In turn, whenever a neuronal circuit is damaged, either by a neurodegenerative disease or a traumatic injury, the motor and/or cognitive functions associated with it are lost permanently. Therefore, understanding the molecular and cellular barriers to CNS repair is a major challenge not only for Neurosciences but also for public health. Related Articles | Metrics

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PCDH19 interplay with GABA(A) receptors: a window to DEE9 pathogenetic mechanisms Sara Mazzoleni, Silvia Bassani 2022, 17 (4):  803-805.  doi: 10.4103/1673-5374.322455 Abstract ( 165 )   PDF (2074KB) ( 99 )   Save Developmental and epileptic encephalopathy 9 (DEE9): The gene PCDH19 (Xq22.1), which encodes the calcium-dependent cell adhesion protein protocadherin-19 (PCDH19), is nowadays considered as one of the most important genes in monogenic epilepsy (Depienne and LeGuern, 2012). Mutations in PCDH19 are responsible for DEE9 (OMIM #300088), a severe neurodevelopmental disorder characterized by early-onset clustering epilepsy, various degrees of cognitive impairment and neuropsychiatric comorbidities, like autism spectrum disorder (ASD) and behavioural problems. DEE9 patients start suffering from seizures around the age of 10 months until adolescence, when seizures tend to reduce or even disappear, while the psychiatric symptoms persist (Depienne and LeGuern, 2012; Kolc et al., 2018).  Related Articles | Metrics

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Surface-based map plasticity of brain regions related to sensory motor and pain information processing after osteonecrosis of the femoral head Jie Ma, Xu-Yun Hua, Mou-Xiong Zheng, Jia-Jia Wu, Bei-Bei Huo, Xiang-Xin Xing, Sheng-Yi Feng, Bo Li, Jian-Guang Xu 2022, 17 (4):  806-811.  doi: 10.4103/1673-5374.322471 Abstract ( 163 )   PDF (678KB) ( 87 )   Save Pain is one of the manifestations of hip disorder and has been proven to lead to the remodeling of somatotopic map plasticity in the cortex. However, most studies are volume-based which may lead to inaccurate anatomical positioning of functional data. The methods that work on the cortical surface may be more sensitive than those using the full brain volume and thus be more suitable for map plasticity study. In this prospective cross-sectional study performed in Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, China, 20 patients with osteonecrosis of the femoral head (12 males and 8 females, aged 56.80 ± 13.60 years) and 20 healthy controls (9 males and 11 females, aged 54.56 ± 10.23 years) were included in this study. Data of resting-state functional magnetic resonance imaging were collected. The results revealed that compared with healthy controls, compared with the healthy controls, patients with osteonecrosis of the femoral head (ONFH) showed significantly increased surface-based regional homogeneity (ReHo) in areas distributed mainly in the left dorsolateral prefrontal cortex, frontal eye field, right frontal eye field, and the premotor cortex and decreased surface-based ReHo in the right primary motor cortex and primary sensory cortex. Regions showing significant differences in surface-based ReHo values between the healthy controls and patients with ONFH were defined as the regions of interests. Seed-based functional connectivity was performed to investigate interregional functional synchronization. When the areas with decreased surface-based ReHo in the frontal eye field and right premotor cortex were used as the regions of interest, compared with the healthy controls, the patients with ONFH displayed increased functional connectivity in the right middle frontal cortex and right inferior parietal cortex and decreased functional connectivity in the right precentral cortex and right middle occipital cortex. Compared with healthy controls, patients with ONFH showed significantly decreased cortical thickness in the para-insular area, posterior insular area, anterior superior temporal area, frontal eye field and supplementary motor cortex and reduced volume of subcortical gray matter nuclei in the right nucleus accumbens. These findings suggest that hip disorder patients showed cortical plasticity changes, mainly in sensorimotor- and pain-related regions. This study was approved by the Medical Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine (approval No. 2018-041) on August 1, 2018.  Related Articles | Metrics

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CircLphn3 protects the blood-brain barrier in traumatic brain injury Yu-Qi Cheng, Chen-Rui Wu, Meng-Ran Du, Qiang Zhou, Bi-Ying Wu, Jia-Yuan-Yuan Fu, Ehab Balawi, Wei-Lin Tan, Zheng-Bu Liao 2022, 17 (4):  812-818.  doi: 10.4103/1673-5374.322467 Abstract ( 177 )   PDF (6784KB) ( 145 )   Save Circular RNAs (circRNAs) are a new and large group of non-coding RNA molecules that are abundantly expressed in the central nervous system. However, very little is known about their roles in traumatic brain injury. In this study, we firstly screened differentially expressed circRNAs in normal and injured brain tissues of mice after traumatic brain injury. We found that the expression of circLphn3 was substantially decreased in mouse models of traumatic brain injury and in hemin-treated bEnd.3 (mouse brain cell line) cells. After overexpressing circLphn3 in bEnd.3 cells, the expression of the tight junction proteins, ZO-1, ZO-2, and occludin, was upregulated, and the expression of miR-185-5p was decreased. In bEnd.3 cells transfected with miR-185-5p mimics, the expression of ZO-1 was decreased. Dual-luciferase reporter assays showed that circLphn3 bound to miR-185-5p, and that miR-185-5p bound to ZO-1. Additionally, circLphn3 overexpression attenuated the hemin-induced high permeability of the in vitro bEnd.3 cell model of the blood-brain barrier, while miR-185-5p transfection increased the permeability. These findings suggest that circLphn3, as a molecular sponge of miR-185-5p, regulates tight junction proteins’ expression after traumatic brain injury, and it thereby improves the permeability of the blood-brain barrier. This study was approved by the Animal Care and Use Committee of Chongqing Medical University of China (approval No. 2021-177) on March 22, 2021.  Related Articles | Metrics

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Leukoaraiosis is associated with clinical symptom severity, poor neurological function prognosis and stroke recurrence in mild intracerebral hemorrhage: a prospective multi-center cohort study Tian-Qi Xu, Wei-Zhi Lin, Yu-Lan Feng, Fan-Xia Shen, Jie Chen, Wei-Wen Wu, Xiao-Dong Zhu, Lin Gu, Yi Fu 2022, 17 (4):  819-823.  doi: 10.4103/1673-5374.322469 Abstract ( 202 )   PDF (444KB) ( 122 )   Save Leukoaraiosis (LA) results from ischemic injury in small cerebral vessels, which may be attributable to decreased vascular density, reduced cerebrovascular angiogenesis, decreased cerebral blood flow, or microcirculatory dysfunction in the brain. In this study, we enrolled 357 patients with mild intracerebral hemorrhage (ICH) from five hospitals in China and analyzed the relationships between LA and clinical symptom severity at admission, neurological function prognosis at 3 months, and 1-year stroke recurrence. Patients were divided into groups based on Fazekas scale scores: no LA (n = 83), mild LA (n = 64), moderate LA (n = 98) and severe LA (n = 112). More severe LA, larger hematoma volume, and higher blood glucose level at admission were associated with more severe neurological deficit. More severe LA, older age and larger hematoma volume were associated with worse neurological function prognosis at 3 months. In addition, moderate-to-severe LA, admission glucose and symptom-free cerebral infarction were associated with 1-year stroke recurrence. These findings suggest that LA severity may be a potential marker of individual ICH vulnerability, which can be characterized by poor tolerance to intracerebral attack or poor recovery ability after ICH. Evaluating LA severity in patients with mild ICH may help neurologists to optimize treatment protocols. This study was approved by the Ethics Committee of Ruijin Hospital Affiliated to Shanghai Jiao Tong University (approval No. 12) on March 10, 2011.  Related Articles | Metrics

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Long non-coding RNA MEG3 regulates autophagy after cerebral ischemia/reperfusion injury Tian-Hao Li, Hong-Wei Sun, Lai-Jun Song, Bo Yang, Peng Zhang, Dong-Ming Yan, Xian-Zhi Liu, Yu-Ru Luo 2022, 17 (4):  824-831.  doi: 10.4103/1673-5374.322466 Abstract ( 195 )   PDF (3791KB) ( 130 )   Save Severe cerebral ischemia/reperfusion injury has been shown to induce high-level autophagy and neuronal death. Therefore, it is extremely important to search for a target that inhibits autophagy activation. Long non-coding RNA MEG3 participates in autophagy. However, it remains unclear whether it can be targeted to regulate cerebral ischemia/reperfusion injury. Our results revealed that in oxygen and glucose deprivation/reoxygenation-treated HT22 cells, MEG3 expression was obviously upregulated, and autophagy was increased, while knockdown of MEG3 expression greatly reduced autophagy. Furthermore, MEG3 bound miR-181c-5p and inhibited its expression, while miR-181c-5p bound to autophagy-related gene ATG7 and inhibited its expression. Further experiments revealed that mir-181c-5p overexpression reversed the effect of MEG3 on autophagy and ATG7 expression in HT22 cells subjected to oxygen and glucose deprivation/reoxygenation. In vivo experiments revealed that MEG3 knockdown suppressed autophagy, infarct volume and behavioral deficits in cerebral ischemia/reperfusion mice. These findings suggest that MEG3 knockdown inhibited autophagy and alleviated cerebral ischemia/reperfusion injury through the miR-181c-5p/ATG7 signaling pathway. Therefore, MEG3 can be considered as an intervention target for the treatment of cerebral ischemia/reperfusion injury. This study was approved by the Animal Ethics Committee of the First Affiliated Hospital of Zhengzhou University, China (approval No. XF20190538) on January 4, 2019. Related Articles | Metrics

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Histochemistry of microinfarcts in the mouse brain after injection of fluorescent microspheres into the common carotid artery Yi Shen, Ming-Jiang Yao, Yu-Xin Su, Dong-Sheng Xu, Jia Wang, Guang-Rui Wang, Jing-Jing Cui, Jian-Liang Zhang, Wan-Zhu Bai 2022, 17 (4):  832-837.  doi: 10.4103/1673-5374.322470 Abstract ( 235 )   PDF (4676KB) ( 125 )   Save The mouse model of multiple cerebral infarctions, established by injecting fluorescent microspheres into the common carotid artery, is a recent development in animal models of cerebral ischemia. To investigate its effectiveness, mouse models of cerebral infarction were created by injecting fluorescent microspheres, 45–53 µm in diameter, into the common carotid artery. Six hours after modeling, fluorescent microspheres were observed directly through a fluorescence stereomicroscope, both on the brain surface and in brain sections. Changes in blood vessels, neurons and glial cells associated with microinfarcts were examined using fluorescence histochemistry and immunohistochemistry. The microspheres were distributed mainly in the cerebral cortex, striatum and hippocampus ipsilateral to the side of injection. Microinfarcts were found in the brain regions where the fluorescent microspheres were present. Here the lodged microspheres induced vascular and neuronal injury and the activation of astroglia and microglia. These histopathological changes indicate that this animal model of multiple cerebral infarctions effectively simulates the changes of various cell types observed in multifocal microinfarcts. This model is an effective, additional tool to study the pathogenesis of ischemic stroke and could be used to evaluate therapeutic interventions. This study was approved by the Animal Ethics Committee of the Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences (approval No. D2021-03-16-1) on March 16, 2021. Related Articles | Metrics

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Diffusion tensor imaging of the hippocampus reflects the severity of hippocampal injury induced by global cerebral ischemia/reperfusion injury Wen-Zhu Wang, Xu Liu, Zheng-Yi Yang, Yi-Zheng Wang, Hai-Tao Lu 2022, 17 (4):  838-844.  doi: 10.4103/1673-5374.322468 Abstract ( 168 )   PDF (2018KB) ( 76 )   Save At present, predicting the severity of brain injury caused by global cerebral ischemia/reperfusion injury (GCI/RI) is a clinical problem. After such an injury, clinical indicators that can directly reflect neurological dysfunction are lacking. The change in hippocampal microstructure is the key to memory formation and consolidation. Diffusion tensor imaging is a highly sensitive tool for visualizing injury to hippocampal microstructure. Although hippocampal microstructure, brain-derived neurotrophic factor (BDNF), and tropomyosin-related kinase B (TrkB) levels are closely related to nerve injury and the repair process after GCI/RI, whether these indicators can reflect the severity of such hippocampal injury remains unknown. To address this issue, we established rat models of GCI/RI using the four-vessel occlusion method. Diffusion tensor imaging parameters, BDNF, and TrkB levels were correlated with modified neurological severity scores. The results revealed that after GCI/RI, while neurological function was not related to BDNF and TrkB levels, it was related to hippocampal fractional anisotropy. These findings suggest that hippocampal fractional anisotropy can reflect the severity of hippocampal injury after global GCI/RI. The study was approved by the Institutional Animal Care and Use Committee of Capital Medical University, China (approval No. AEEI-2015-139) on November 9, 2015. Related Articles | Metrics

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Baculoviral inhibitor of apoptosis protein repeat-containing protein 3 delays early Wallerian degeneration after sciatic nerve injury Min Cai, Jian Shao, Bryant Yung, Yi Wang, Nan-Nan Gao, Xi Xu, Huan-Huan Zhang, Yu-Mei Feng, Deng-Bing Yao 2022, 17 (4):  845-853.  doi: 10.4103/1673-5374.322474 Abstract ( 156 )   PDF (4790KB) ( 168 )   Save Wallerian degeneration is a complex biological process that occurs after nerve injury, and involves nerve degeneration and regeneration. Schwann cells play a crucial role in the cellular and molecular events of Wallerian degeneration of the peripheral nervous system. However, Wallerian degeneration regulating nerve injury and repair remains largely unknown, especially the early response. We have previously reported some key regulators of Wallerian degeneration after sciatic nerve injury. Baculoviral inhibitor of apoptosis protein repeat-containing protein 3 (BIRC3) is an important factor that regulates apoptosis-inhibiting protein. In this study, we established rat models of right sciatic nerve injury. In vitro Schwann cell models were also established and subjected to gene transfection to inhibit and overexpress BIRC3. The data indicated that BIRC3 expression was significantly up-regulated after sciatic nerve injury. Both BIRC3 upregulation and downregulation affected the migration, proliferation and apoptosis of Schwan cells and affected the expression of related factors through activating c-fos and ERK signal pathway. Inhibition of BIRC3 delayed early Wallerian degeneration through inhibiting the apoptosis of Schwann cells after sciatic nerve injury. These findings suggest that BIRC3 plays an important role in peripheral nerve injury repair and regeneration. The study was approved by the Institutional Animal Care and Use Committee of Nantong University, China (approval No. 2019-nsfc004) on March 1, 2019.  Related Articles | Metrics

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Cerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration Manuel A. Fernandez-Parrilla, David Reyes-Corona, Yazmin M. Flores-Martinez, Rasajna Nadella, Michael J. Bannon, Lourdes Escobedo, Minerva Maldonado-Berny, Jaime Santoyo-Salazar, Luis O. Soto-Rojas, Claudia Luna-Herrera, Jose Ayala-Davila, Juan A. Gonzalez-Barrios, Gonzalo Flores, Maria E. Gutierrez-Castillo, Armando J. Espadas-Alvarez, Irma A. Martínez-Dávila, Porfirio Nava, Daniel Martinez-Fong 2022, 17 (4):  854-866.  doi: 10.4103/1673-5374.321001 Abstract ( 178 )   PDF (19771KB) ( 41 )   Save Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system, a hallmark in Parkinson’s disease. The human cerebral dopamine neurotrophic factor (hCDNF) has recently emerged as a strong candidate for Parkinson’s disease therapy. This study shows that hCDNF expression in dopamine neurons using the neurotensin-polyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological, biochemical, and behavioral alterations. Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the hCDNF gene, ranging in size from 20 to 150 nm, enabled the expression of a secretable hCDNF in vitro. Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable hCDNF in dopamine neurons, whose levels remained constant throughout the study in the substantia nigra compacta and striatum. Compared with the lesioned group, tyrosine hydroxylase-positive (TH+) nigral cell population and TH+ fiber density rose in the substantia nigra compacta and striatum after hCDNF transfection. An increase in βIII-tubulin and growth-associated protein 43 phospho-S41 (GAP43p) followed TH+ cell recovery, as well as dopamine and its catabolite levels. Partial reversal (80%) of drug-activated circling behavior and full recovery of spontaneous motor and non-motor behavior were achieved. Brain-derived neurotrophic factor recovery in dopamine neurons that also occurred suggests its participation in the neurotrophic effects. These findings support the potential of nanoparticle-mediated hCDNF gene delivery to develop a disease-modifying treatment against Parkinson’s disease. The Institutional Animal Care and Use Committee of Centro de Investigación y de Estudios Avanzados approved our experimental procedures for animal use (authorization No. 162-15) on June 9, 2019. Related Articles | Metrics

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Striatal oxidative damages and neuroinflammation correlate with progression and survival of Lewy body and Alzheimer diseases Huifangjie Li, William C. Knight, Jinbin Xu 2022, 17 (4):  867-874.  doi: 10.4103/1673-5374.322463 Abstract ( 195 )   PDF (1861KB) ( 154 )   Save Neurodegenerative diseases are a class of chronic and complex disorders featuring progressive loss of neurons in distinct brain areas. The mechanisms responsible for the disease progression in neurodegeneration are not fully illustrated. In this observational study, we have examined diverse biochemical parameters in the caudate and putamen of patients with Lewy body diseases (LBDs) and Alzheimer disease (AD), shedding some light on the involvement of oxidative damage and neuroinflammation in advanced neurodegeneration. We performed Spearman and Mantel-Cox analyses to investigate how oxidative stress and neuroinflammation exert comprehensive effects on disease progression and survival. Disease progression in LBDs correlated positively with poly (ADP-Ribose) and triggering receptors expressed on myeloid cell 2 levels in the striatum of LBD cohorts, indicating that potential parthanatos was a dominant feature of worsening disease progression and might contribute to switching microglial inflammatory phenotypes. Disease progression in AD corresponds negatively with 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG) and myeloperoxidase concentrations in the striatum, suggesting that possible mitochondria dysfunction may be involved in the progression of AD via a mechanism of β-amyloid entering the mitochondria and subsequent free radicals generation. Patients with lower striatal 8-oxo-dG and myeloperoxidase levels had a survival advantage in AD. The age of onset also affected disease progression. Tissue requests for the postmortem biochemistry, genetics, and autoradiography studies were approved by the Washington University Alzheimer’s Disease Research Center (ADRC) Biospecimens Committee (ethics approval reference number: T1705, approval date: August 6, 2019). Recombinant DNA and Hazardous Research Materials were approved by the Washington University Environmental Health & Safety Biological Safety Committee (approval code: 3739, approval date: February 25, 2020). Radioactive Material Authorization was approved by the Washington University Environmental Health & Safety Radiation Safety Committee (approval code: 1056, approval date:  September 18, 2019).  Related Articles | Metrics

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Neutrophil-to-lymphocyte ratio in sporadic amyotrophic lateral sclerosis Qian-Qian Wei, Yan-Bing Hou, Ling-Yu Zhang, Ru-Wei Ou, Bei Cao, Yong-Ping Chen, Hui-Fang Shang 2022, 17 (4):  875-880.  doi: 10.4103/1673-5374.322476 Abstract ( 148 )   PDF (840KB) ( 144 )   Save The neutrophil-to-lymphocyte ratio (NLR) is considered a robust prognostic biomarker for predicting patient survival outcomes in many diseases. However, it remains unclear whether it can be used as a biomarker for amyotrophic lateral sclerosis (ALS). To correlate NLR with disease progression and survival in sporadic ALS, 1030 patients with ALS between January 2012 and December 2018 were included in this study. These patients were assigned into three groups according to their NLR values: Group 1 (NLR < 2, n = 544 [52.8%]), Group 2 (NLR = 2–3, n = 314 [30.5%]), and Group 3 (NLR > 3, n = 172 [16.7%]). All patients were followed up until April 2020. Patients in Group 3 had a significantly older onset age, a lower score on the Revised ALS Functional Rating Scale, and rapidly progressing disease conditions. Furthermore, faster disease progression rates were associated with higher NLR values (odds ratio = 1.211, 95% confidence interval [CI]: 1.090–1.346, P < 0.001) after adjusting for other risk factors. Compared with Groups 1 and 2, the survival time in Group 3 was significantly shorter (log-rank P = 0.002). The NLR value was considered an independent parameter for the prediction of survival in ALS patients after normalizing for all other potential parameters (hazard ratio [HR] = 1.079, 95% CI: 1.016–1.146, P = 0.014). The effects on ALS survival remained significant when adjusted for treatment (HR = 1.074, 95% CI: 1.012–1.141, Ptrend = 0.019) or when considering the stratified NLR value (HR = 1.115, 95% CI: 1.009–1.232, Ptrend = 0.033). Thus, the NLR may help to predict the rate of disease progression and survival in patients with sporadic ALS. The study was approved by the Institutional Ethics Committee of West China Hospital of Sichuan University, China (approval No. 2015 (236)) on December 23, 2015. Related Articles | Metrics

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Involvement of A5/A7 noradrenergic neurons and B2 serotonergic neurons in nociceptive processing: a fiber photometry study Shunpei Moriya, Akira Yamashita, Daiki Masukawa, Junichi Sakaguchi, Yoko Ikoma, Yoshimune Sameshima, Yuki Kambe, Akihiro Yamanaka, Tomoyuki Kuwaki 2022, 17 (4):  881-886.  doi: 10.4103/1673-5374.322465 Abstract ( 134 )   PDF (4060KB) ( 97 )   Save In the central nervous system, the A6 noradrenaline (NA) and the B3 serotonin (5-HT) cell groups are well-recognized players in the descending antinociceptive system, while other NA/5-HT cell groups are not well characterized. A5/A7 NA and B2 5-HT cells project to the spinal horn and form descending pathways. We recorded G-CaMP6 green fluorescence signal intensities in the A5/A7 NA and the B2 5-HT cell groups of awake mice in response to acute tail pinch stimuli, acute heat stimuli, and in the context of a non-noxious control test, using fiber photometry with a calcium imaging system. We first introduced G-CaMP6 in the A5/A7 NA or B2 5-HT neuronal soma, using transgenic mice carrying the tetracycline-controlled transactivator transgene under the control of either a dopamine β-hydroxylase or a tryptophan hydroxylase-2 promoters and by the site-specific injection of adeno-associated virus (AAV-TetO(3G)-G-CaMP6). After confirming the specific expression patterns of G-CaMP6, we recorded G-CaMP6 green fluorescence signals in these sites in awake mice in response to acute nociceptive stimuli. G-CaMP6 fluorescence intensity in the A5, A7, and B2 cell groups was rapidly increased in response to acute nociceptive stimuli and soon after, it returned to baseline fluorescence intensity. This was not observed in the non-noxious control test. The results indicate that acute nociceptive stimuli rapidly increase the activities of A5/A7 NA or B2 5-HT neurons but the non-noxious stimuli do not. The present study suggests that A5/A7 NA or B2 5-HT neurons play important roles in nociceptive processing in the central nervous system. We suggest that A5/A7/B2 neurons may be new therapeutic targets. All performed procedures were approved by the Institutional Animal Use Committee of Kagoshima University (MD17105) on February 22, 2018. Related Articles | Metrics

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HOTTIP downregulation reduces neuronal damage and microglial activation in Parkinson’s disease cell and mouse models Peng Lun, Tao Ji, De-Hong Wan, Xia Liu, Xiao-Dong Chen, Shuai Yu, Peng Sun 2022, 17 (4):  887-897.  doi: 10.4103/1673-5374.322475 Abstract ( 192 )   PDF (4173KB) ( 114 )   Save HOXA transcript at the distal tip (HOTTIP), a newly identified long noncoding RNA, has been shown to exhibit anti-inflammatory effects and inhibit oxygen-glucose deprivation-induced neuronal apoptosis. However, its role in Parkinson’s disease (PD) remains unclear. 1-Methyl-4-phenylpyridium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were used to establish PD models in SH-SY5Y and BV2 cells and in C57BL/6 male mice, respectively. In vitro, after HOTTIP knockdown by sh-HOTTIP transfection, HOTTIP and FOXO1 overexpression promoted SH-SY5Y apoptosis, BV2 microglial activation, proinflammatory cytokine expression, and nuclear factor kappa-B and NACHT, LRR and PYD domains-containing protein 3 inflammasome activation. Overexpression of miR-615-3p inhibited MPP+-induced neuronal apoptosis and microglial inflammation and ameliorated HOTTIP- and FOXO1-mediated nerve injury and inflammation. In vivo, HOTTIP knockdown alleviated motor dysfunction in PD mice and reduced neuronal apoptosis and microglial activation in the substantia nigra. These findings suggest that inhibition of HOTTIP mitigates neuronal apoptosis and microglial activation in PD models by modulating miR-615-3p/FOXO1. This study was approved by the Ethics Review Committee of the Affiliated Hospital of Qingdao University, China (approval No. UDX-2018-042) in June 2018.  Related Articles | Metrics

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The mechanism behind activation of the Nod-like receptor family protein 3 inflammasome in Parkinson’s disease Jing Wang, Xiao-Na Zhang, Jin-Ni Fang, Fei-Fei Hua, Jing-Yang Han, Zeng-Qiang Yuan, An-Mu Xie 2022, 17 (4):  898-904.  doi: 10.4103/1673-5374.323077 Abstract ( 290 )   PDF (1996KB) ( 146 )   Save Previous studies have shown that the ATP-P2X4 receptor signaling pathway mediates the activation of the Nod-like receptor family protein 3 (NLRP3) inflammasome. The NLRP3 inflammasome may promote renal interstitial inflammation in diabetic nephropathy. As inflammation also plays an important role in the pathogenesis of Parkinson’s disease, we hypothesized that the ATP-P2X4 receptor signaling pathway may activate the NLRP3 inflammasome in Parkinson’s disease. A male rat model of Parkinson’s disease was induced by stereotactic injection of 6-hydroxydopamine into the pars compacta of the substantia nigra. The P2X4 receptor and the NLRP3 inflammasome (interleukin-1β and interleukin-18) were activated. Intracerebroventricular injection of the selective P2X4 receptor antagonist 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one (5-BDBD) or knockdown of P2X4 receptor expression by siRNA inhibited the activation of the NLRP3 inflammasome and alleviated dopaminergic neurodegeneration and neuroinflammation. Our results suggest that the ATP-P2X4 receptor signaling pathway mediates NLRP3 inflammasome activation, dopaminergic neurodegeneration, and dopamine levels. These findings reveal a novel role of the ATP-P2X4 axis in the molecular mechanisms underlying Parkinson’s disease, thus providing a new target for treatment. This study was approved by the Animal Ethics Committee of Qingdao University, China, on March 5, 2015 (approval No. QYFYWZLL 26119). Related Articles | Metrics

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Effects of electroacupuncture on pain sensation in a rat model of hyperalgesia with nicotine dependence Shu-Ju Wang, Yan-Ping Zhang, Keith A. Candiotti 2022, 17 (4):  905-910.  doi: 10.4103/1673-5374.322477 Abstract ( 217 )   PDF (602KB) ( 109 )   Save Tobacco smoking is considered to be one of the main risk factors in the development of chronic pain. Long-term chronic exposure to nicotine and other forms of tobacco have been shown to be associated with an increased incidence of pain. Studies have shown that acupuncture can help smokers to reduce their desire to smoke, reduce their withdrawal symptoms, and avoid a relapse after treatment. However, little has been reported about the effects of acupuncture on pain sensitivity caused by long-term smoking. Models of hyperalgesia were established in rats exposed to nicotine for 6 weeks. After 6 weeks of continuous nicotine exposure, electroacupuncture at bilateral acupoints Zusanli (ST36) and Taichong (LR3) was performed 20 minutes per day for 6 days at a continuous wave with a frequency of 2 Hz and a stimulus intensity of 1 mA. The results revealed that electroacupuncture treatment increased the mechanical response threshold of hind paw of nicotine-dependent rats with hyperalgesia and up-regulated the protein expression of pain-related factors μ-opioid receptor, β-endorphin and glutamic acid decarboxylase 65 in the spinal cord and midbrain periaqueductal gray and the protein expression of glutamic acid decarboxylase 67 in the spinal cord. These findings suggest that electroacupuncture treatment has positive analgesic effects on pain sensitivity caused by long-term chronic nicotine exposure. One possible mechanism for the improved analgesia is that electroacupuncture increases the expression of pain-related factors in the spinal cord and midbrain periaqueductal gray. This study was approved by Institutional Animal Care and Use Committee (IACUC) of the University of Miami (#18-167) on December 12, 2018. Related Articles | Metrics

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Identification of key genes involved in axon regeneration and Wallerian degeneration by weighted gene co-expression network analysis Yan Lu, Qi Shan, Mei Ling, Xi-An Ni, Su-Su Mao, Bin Yu, Qian-Qian Cao 2022, 17 (4):  911-919.  doi: 10.4103/1673-5374.322473 Abstract ( 157 )   PDF (6270KB) ( 206 )   Save Peripheral nerve injury repair requires a certain degree of cooperation between axon regeneration and Wallerian degeneration. Therefore, investigating how axon regeneration and degeneration work together to repair peripheral nerve injury may uncover the molecular mechanisms and signal cascades underlying peripheral nerve repair and provide potential strategies for improving the low axon regeneration capacity of the central nervous system. In this study, we applied weighted gene co-expression network analysis to identify differentially expressed genes in proximal and distal sciatic nerve segments from rats with sciatic nerve injury. We identified 31 and 15 co-expression modules from the proximal and distal sciatic nerve segments, respectively. Functional enrichment analysis revealed that the differentially expressed genes in proximal modules promoted regeneration, while the differentially expressed genes in distal modules promoted neurodegeneration. Next, we constructed hub gene networks for selected modules and identified a key hub gene, Kif22, which was up-regulated in both nerve segments. In vitro experiments confirmed that Kif22 knockdown inhibited proliferation and migration of Schwann cells by modulating the activity of the extracellular signal-regulated kinase signaling pathway. Collectively, our findings provide a comparative framework of gene modules that are co-expressed in injured proximal and distal sciatic nerve segments, and identify Kif22 as a potential therapeutic target for promoting peripheral nerve injury repair via Schwann cell proliferation and migration. All animal experiments were approved by the Institutional Animal Ethics Committee of Nantong University, China (approval No. S20210322-008) on March 22, 2021. Related Articles | Metrics

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Social skills and psychopathology are associated with autonomic function in children: a cross-sectional observational study Elisa Cainelli, Luca Vedovelli, Daniele Bottigliengo, Dario Boschiero, Agnese Suppiej 2022, 17 (4):  920-928.  doi: 10.4103/1673-5374.322464 Abstract ( 188 )   PDF (3105KB) ( 179 )   Save In recent years, the increase of psychopathological disorders in the population has become a health emergency, leading to a great effort to understand psychological vulnerability mechanisms. In this scenario, the role of the autonomic nervous system (ANS) has become increasingly important. This study investigated the association between ANS, social skills, and psychopathological functioning in children. As an ANS status proxy, we measured heart rate variability (HRV). Infants admitted to the neonatal intensive care unit of the University Hospital of Padova because of preterm birth or neonatal hypoxic-ischemic encephalopathy were sequentially recruited from January 2011 to June 2013 and followed long-term up to school age in this cross-sectional observational study. We recorded 5 minutes of HRV immediately before measuring performance in social abilities tasks (affect recognition and theory of mind, NEPSY-II) in 50 children (mean age 7.4 ± 1.4 years) with and without risk factors for developing neuropsychiatric disorders due to pre-/perinatal insults without major sequelae. Children also completed extensive cognitive, neuropsychological, and psychosocial assessment. Parents were assessed with psychopathological interviews and a questionnaire (CBCL 6-18). Analysis in a robust Bayesian framework was used to unearth dependencies between HRV, social skills, and psychopathological functioning. Social task scores were associated with HRV components, with high frequency the most consistent. HRV bands were also associated with the psychopathological questionnaire. Only normalized HRV high frequency was able to distinguish impaired children in the affect recognition task. Our data suggest that ANS may be implicated in social cognition both in typical and atypical developmental conditions and that HRV has cross-disease sensitivity. We suggest that HRV parameters may reflect a neurobiological vulnerability to psychopathology. The study was approved by the Ethics Committee of the University Hospital of Padova (Comitato Etico per la Sperimentazione, Azienda Opedaliera di Padova, approval No. 1693P). Related Articles | Metrics