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Table of Content

    15 December 2024, Volume 19 Issue 12 Previous Issue   
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    Inhibition of tubulin detyrosination: a novel strategy to promote central nervous system regeneration
    Charlotte Zeitler, Marco Leibinger, Dietmar Fischer
    2024, 19 (12):  2557-2558.  doi: 10.4103/NRR.NRR-D-23-02015
    Abstract ( 114 )   PDF (791KB) ( 75 )   Save
    The adult mammalian central nervous system (CNS) coordinates essential functions such as sensation, movement, autonomic control, thought processes, and communication. Consequently, injuries or diseases of the CNS are often associated with devastating and permanent functional impairments because damaged axons normally fail to regenerate. An insufficient neuron-intrinsic growth capacity and an inhibitory environment at the injury site are the leading causes of this regenerative failure. Although numerous strategies addressing these issues have enabled considerable axon regeneration in various experimental injury models, clinically applicable treatment options or drugs promoting functional recovery are not yet available.
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    Contribution of astrocytes to the neurovascular elimination of tau
    Maxwell Eisenbaum, Corbin Bachmeier
    2024, 19 (12):  2559-2560.  doi: 10.4103/NRR.NRR-D-23-01705
    Abstract ( 91 )   PDF (799KB) ( 95 )   Save
    Tauopathies encompass a collection of chronic, progressive neurodegenerative diseases, including Alzheimer’s disease (AD), chronic traumatic encephalopathy, and corticobasal degeneration, characterized by the accumulation of pathogenic aggregates of the microtubule-associated protein tau in neurons and/or glia (Reid et al., 2020). For decades before the onset of disease symptoms, local pathogenic misfolded tau replication and subsequent trans-synaptic transmission, silently propagates along anatomically connected regions. A spectrum of clinical symptoms begins to emerge once the brain’s compensatory and resistance measures are exhausted, ranging from behavioral, cognitive, and/or motor dysfunction. Recent therapeutic attempts to target soluble pathogenic species of tau have largely proven to be clinically ineffective and may have the same fate as so many amyloid-lowering therapies. To avoid the pitfalls that have contributed to the ongoing multi-decade long failures of amyloid-targeting strategies, it is critical to address the fundamental knowledge gaps regarding tau dynamics and processing in the brain.
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    Structural changes in the obese brain
    Anna R.R. Da Conceicao, Marcelo N.N. Vieira, Fernanda G. De Felice
    2024, 19 (12):  2561-2562.  doi: 10.4103/NRR.NRR-D-23-01123
    Abstract ( 71 )   PDF (651KB) ( 58 )   Save
    Obesity represents a major global health concern, with widespread growing prevalence and severe consequences for the quality of life and life expectancy of affected individuals and for the economic burden of healthcare systems (Prospective Studies Collaboration, 2009). Obesity is a well-established risk factor for a variety of conditions including metabolic, vascular, and heart diseases, and several types of cancer (Prospective Studies Collaboration, 2009). In addition, in the past few decades, accumulating clinical and epidemiological evidence associates obesity with cognitive decline and a higher risk for developing neurodegenerative and neuropsychiatric disorders such as Alzheimer’s disease (AD), anxiety, and depression. A recent large-scale cross-sectional study concluded that midlife obesity is now the most prominent modifiable risk factor for developing AD and related dementia in the US (Nianogo et al., 2022). Further evidence from a prospective study with 1 million UK women (mean age of 56 years at baseline) shows that a body mass index (the anthropometric marker for obesity) > 30 kg/m2 at baseline was associated with a higher incidence of dementia 15 years later (Floud et al., 2018).
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    Apoer2/Lrp8: the undercover cop of synaptic homeostasis
    Gordon C. Werthmann, Joachim Herz
    2024, 19 (12):  2563-2564.  doi: 10.4103/NRR.NRR-D-23-02002
    Abstract ( 79 )   PDF (1753KB) ( 39 )   Save
    Apolipoprotein E receptor 2 (ApoER2) is a receptor for the protein ApoE, the most common genetic risk factor for late-onset Alzheimer’s disease (AD). It is also a key modulator of synaptic homeostasis, in part through its effect on the expression of neuronal genes including those implicated in AD and other neuropsychiatric disorders. In this perspective, we highlight several genes affected by ApoER2 and its alternatively spliced forms and how aberrant expression can be rescued by the reintroduction of the ApoER2 intracellular domain in the mouse hippocampus.
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    Self-assembly of tau fragments as a key pathologic event in tauopathies
    Ly Thi Huong Luu Le, Jung Hoon Lee, Min Jae Lee
    2024, 19 (12):  2565-2566.  doi: 10.4103/NRR.NRR-D-23-01720
    Abstract ( 96 )   PDF (2479KB) ( 32 )   Save
    Tau protein is encoded by the microtubule-associated protein tau (MAPT) gene and stabilizes microtubules in the neurons. Tau has unique biophysical properties that make it both highly water-soluble and positively charged. Although tau is an intrinsically disordered protein lacking defined secondary structures, it can acquire highly organized -sheet structures and stack into a filamentous inclusion such as a paired helical filament (PHF). This is a common feature of tauopathies including Alzheimer’s disease (AD). The progression of tauopathies, both biochemically and symptomatically, is directly correlated with the extent of tau fibrillization. Extensive research has been conducted to determine the mechanisms underlying this phenomenon. A growing body of research indicates that genetic mutations linked to autosomal dominant tauopathies may be insufficient to cause significant conformational changes in tau. Instead, several post-translational modifications, including phosphorylation, acetylation, ubiquitylation, and O-GlcNAcylation, as well as their complex interaction, appear to play a crucial role in inducing fibrillization (Park et al., 2018; Kim et al., 2021). Tau phosphorylation, which weakens the electrostatic interactions between tau and axonal microtubules, has been a primary pharmacological target for AD treatment (Basheer et al., 2023). It has, however, failed to provide significant benefits for patients.
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    Glial progenitor heterogeneity and plasticity in the adult spinal cord
    Haichao Wei, Jia Qian Wu
    2024, 19 (12):  2567-2568.  doi: 10.4103/NRR.NRR-D-23-01988
    Abstract ( 76 )   PDF (1307KB) ( 30 )   Save
    Glial progenitor cells were reported to have the capacity to generate various types of cells in both the central nervous system (CNS) and peripheral nervous system. Glial progenitor cells can respond to diverse environmental signals and transform into distinct populations, each serving specific functions. Notably, the adult spinal cord hosts various populations of glial progenitors, a region integral to the central nervous system. During development, glial progenitors express glial fibrillary acidic protein (GFAP; Dimou and Gotz, 2014). However, the specific identities of GFAP-expressing progenitors in the adult spinal cord were not thoroughly investigated. Glial progenitors in the adult spinal cord may hold more heterogeneity and plasticity than previously thought.
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    Sex differences in Alzheimer’s disease: an urgent research venue to follow
    Raquel Jiménez-Herrera, Ana Contreras, Juan D. Navarro-López, Lydia Jiménez-Díaz
    2024, 19 (12):  2569-2570.  doi: 10.4103/NRR.NRR-D-23-01971
    Abstract ( 159 )   PDF (1792KB) ( 80 )   Save
    Due to increasing life expectancy, the amount of people with dementia worldwide is expected to experience a substantial rise, with estimates indicating a growth from 55 million in 2019 to a staggering 139 million by the year 2050. Among the various forms of dementia, Alzheimer’s disease (AD) stands out as the predominant and most prevalent. According to the Alzheimer’s Association (No authors listed, 2023), nearly two thirds of AD patients in the US are women and similar numbers are found in Europe. Both the “pandemic” incidence and demographic disparity emphasize the importance of studying AD with a sex-inclusive approach. 
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    Oncostatin M: a love-hate relationship in neuroinflammation
    Doryssa Hermans, Niels Hellings, Bieke Broux
    2024, 19 (12):  2571-2572.  doi: 10.4103/NRR.NRR-D-23-02011
    Abstract ( 83 )   PDF (713KB) ( 46 )   Save
    Oncostatin M and multiple sclerosis: Every 5 minutes, someone in the world is diagnosed with multiple sclerosis (MS), a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS appears in unpredictable episodes of symptoms, which are highly patient-dependent, but often include visual impairment, muscle weakness/spasms, fatigue, cognitive difficulties, and bladder, bowel, or sexual dysfunction. In severe cases, MS patients become wheelchair-bound due to paralysis. These symptoms are the result of a dysfunctional signal transduction from one neuron to another after the immune system has attacked the neuron’s insulating myelin sheath. Therefore, hyperactivation of immune cells and the presence of demyelinating plaques in the CNS are the main pathological hallmarks of MS.
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    Microglial autophagy in neurogenesis: a new player in Alzheimer’s disease
    Xin Tang, Aarti Nagayach, Chenran Wang
    2024, 19 (12):  2573-2574.  doi: 10.4103/NRR.NRR-D-23-01962
    Abstract ( 89 )   PDF (1432KB) ( 24 )   Save
    While extensive studies have illuminated the impact of Alzheimer’s disease (AD) on neuronal survival, there is growing evidence that abnormal postnatal neurogenesis in early AD brains contributes to disease progression. Postnatal neurogenesis serves as a mechanism to replace dead or damaged neurons. New neurons generated from neural stem cells (NSCs) in the subgranular zone (SGZ) of the dentate gyrus integrate into the existing hippocampal circuit, which is essential for learning and memory and is one of the first regions affected in AD. Macroautophagy (referred to as autophagy) is a conserved self-degrading process for cytoplasm or organelles through the formation of autophagosomes and subsequent fusion with lysosomes. Autophagy is important to maintain protein homeostasis. Microglia are the brain-resident macrophages and their functions in the pathogenesis of AD are gaining attention. Since microglia are the first cell population responding to early changes in AD, it is pivotal to understand the interplay between microglia and other neural cells in AD.
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    A seed and soil model of loneliness in Alzheimer’s disease
    Hannah L. Apostolou, Ian M. McDonough
    2024, 19 (12):  2575-2576.  doi: 10.4103/NRR.NRR-D-23-01618
    Abstract ( 70 )   PDF (818KB) ( 31 )   Save
    Loneliness is classically defined as a result of perceiving a discrepancy between the desired quantity and quality of one’s social life and actual social relationships (Perlman and Peplau, 1984). Lifespan research has indicated older adults are among the highest risk for experiencing loneliness because their social network size decreases more frequently than that of younger adults. In part, this is due to the growing risk of losing one’s partner and peers through death, the loss of social roles, and limitations of mobility. Despite this risk, levels of loneliness are highly stable in old age and relatively low compared to other points in the lifespan, likely owing to the improved emotion regulation skills often found among healthy older adults (Mund et al., 2020). However, to the extent that increases in loneliness do occur among older adults, this subset of individuals might be at advanced risk for Alzheimer’s disease (AD) and related neurocognitive disorders (Lara et al., 2019). In the present perspective paper, we use the seed and soil model of neurocognitive disorders to better understand how loneliness impacts the brain to potentially increase one’s risk for AD prior to frank cognitive decline and an AD diagnosis (McDonough and Allen, 2019).
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    A novel approach to Parkinson’s disease treatment with a potentially dual-acting therapeutic agent that targets α-synuclein aggregation and neuron death
    Allison R. Balaj, Hiroaki Kaku
    2024, 19 (12):  2577-2578.  doi: 10.4103/NRR.NRR-D-23-01934
    Abstract ( 61 )   PDF (409KB) ( 40 )   Save
    Parkinson’s disease (PD), a prevalent neurodegenerative disorder, is characterized by the loss of dopaminergic neurons and the aggregation of α-synuclein protein into Lewy bodies. While the current standards of therapy have been successful in providing some symptom relief, they fail to address the underlying pathophysiology of PD and as a result, they have no effect on disease progression. They also carry the risk of unacceptable side effects that can impair quality of life. Fortunately, recent research has pointed towards Fas apoptosis inhibitory molecule (FAIM) as a less problematic and potentially disease modifying target for new therapies given the newfound evidence of a possible link between FAIM, PD pathogenesis, and α-synuclein aggregation. This perspective seeks to elucidate this relationship and its implications for future research and treatment modalities.
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    Molecular biomarkers for vascular cognitive impairment and dementia: the current status and directions for the future
    Satoshi Hosoki, Perminder S. Sachdev
    2024, 19 (12):  2579-2580.  doi: 10.4103/NRR.NRR-D-23-01938
    Abstract ( 223 )   PDF (569KB) ( 207 )   Save
    Dementia is a syndrome with various underlying pathologies acting independently or in concert to cause cognitive dysfunction. The development of disease-specific treatments and targeted prevention strategies requires precise clinical sub-typing via etiology and pathophysiological processes. Furthermore, recent research advances in biomarkers, especially for Alzheimer’s disease (AD) diagnosis, have improved diagnostic precision for dementia. This has led to the proposal of an AT(N) framework for AD diagnosis, with A, T, and N signifying the demonstrated presence of amyloid (A) and tau (T) pathologies as well as neurodegeneration (N) respectively. Many authors have proposed to add other pathophysiological mechanisms to the traditional AT(N) framework, such as neuroimmune dysregulation, synaptic dysfunction, and/or blood-brain barrier (BBB) alterations, to make the ATX(N) more accommodating of a range of pathologies important for dementia. This has included the special consideration of vascular pathogenesis being represented by a “V” (Sachdev, 2020). This indicates that cerebrovascular disease (CVD) is a common cause of dementia alone or in combination with AD, and the importance of developing biomarkers of vascular “V” brain pathology has been argued. Research progress in vascular cognitive impairment and dementia (VCID), the second most common cause of dementia, has however been slow, partly because of limited research in VCID relative to AD. The diagnosis of VCID presently relies mainly on clinical information and neuroimaging including magnetic resonance imaging and computed tomography. Consequently, there exists an imperative to develop molecular biomarkers for VCID with high sensitivity and accuracy.
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    Strain-dependent alpha-synuclein spreading in Parkinson’s disease and multiple system atrophy
    Shuyu Zhang, Paul Lingor
    2024, 19 (12):  2581-2582.  doi: 10.4103/NRR.NRR-D-23-01900
    Abstract ( 72 )   PDF (784KB) ( 44 )   Save
    Parkinson’s disease (PD) and atypical Parkinsonian syndromes, such as multiple system atrophy (MSA) and Dementia with Lewy bodies, are neurodegenerative movement disorders characterized by the accumulation of alpha-synuclein (α-syn) aggregates. These α-syn aggregates propagate throughout the brain in a prion-like manner, where pathological α-syn recruits endogenous α-syn to form insoluble aggregates. Oligomeric forms representing intermediates on the way to insoluble aggregates result in the most pronounced neurotoxic effects. α-Syn aggregates can further assemble into Lewy bodies (LB) in PD and glial cytoplasmatic inclusions (GCI) in MSA, leading to neuronal dysfunction and degeneration.
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    Are we close to using Alzheimer blood biomarkers in clinical practice?
    Bruno P. Imbimbo, Simone Lista, Camillo Imbimbo, Robert Nisticò
    2024, 19 (12):  2583-2585.  doi: 10.4103/NRR.NRR-D-23-01945
    Abstract ( 87 )   PDF (1533KB) ( 48 )   Save
    Alzheimer’s disease (AD) is a progressive neurodegenerative disease histologically characterized by the presence of extraneuronal plaques, mainly formed by the 42-aminoacid isoform of amyloid-β (Aβ1–42), and by intraneuronal neurofibrillary tangles, mainly formed by the tau protein and its hyperphosphorylated isoforms (p-tau). AD is the most common cause of dementia, with an estimated lifetime risk of about 1 in 10 for men and 1 in 5 for women. As of 2020, there were approximately 50 million people living with dementia worldwide, a number set to increase to 152 million by 2050 (Scheltens et al., 2021). Two forms of AD exist. The most common form is late-onset AD with onset at ≥ 65 years which in most cases is a sporadic disorder with a number of genetic risk factors (e.g., APOE, CLU, CR1, TREM2, and PICALM). Early-onset AD occurs at ≤ 65 years and accounts for 5% to 6% of total cases of which about 10% have an autosomal-dominant form associated with point mutations of genes codifying for amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2), which are involved in Aβ production. Clinical features of sporadic and autosomal-dominant AD are similar, with early and prominent episodic memory loss (Scheltens et al., 2021). The Aβ cascade hypothesis of AD postulates that the accumulation of Aβ in the brain is the initial causative event of the disease process, starting 15–20 years before the onset of clinical symptoms. The accumulation of Aβ in the brain would trigger the aggregation of tau protein in neurofibrillary tangles. These effects are interconnected with microglial activation and astrocyte reactivity leading to neuritic dystrophy and disease progression. Over the past 30 years, this hypothesis has inspired intense research efforts to develop and test compounds that counteract the accumulation of Aβ in the brain (Karran et al., 2022).
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    Bone marrow-derived microglia confer neuroprotection to a mouse model of amyotrophic lateral sclerosis
    Beka Solomon
    2024, 19 (12):  2586-2587.  doi: 10.4103/NRR.NRR-D-23-01763
    Abstract ( 67 )   PDF (634KB) ( 21 )   Save
    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes the progressive loss of both upper and lower motor neurons in the brain, brainstem, and spinal cord. The exact mechanisms of ALS are still unclear, but genetic and molecular studies have revealed some key factors that may contribute to motor neuron death. Besides motor neurons, other cell types in the nervous system, such as reactive astrocytes and activated microglia, also show pathological changes and secrete harmful substances and inflammatory cytokines (Appel et al., 2011).
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    A core scientific problem in the treatment of central nervous system diseases: newborn neurons
    Peng Hao, Zhaoyang Yang, Kwok-Fai So, Xiaoguang Li
    2024, 19 (12):  2588-2601.  doi: 10.4103/NRR.NRR-D-23-01775
    Abstract ( 347 )   PDF (10835KB) ( 140 )   Save
    It has long been asserted that failure to recover from central nervous system diseases is due to the system’s intricate structure and the regenerative incapacity of adult neurons. Yet over recent decades, numerous studies have established that endogenous neurogenesis occurs in the adult central nervous system, including humans’. This has challenged the long-held scientific consensus that the number of adult neurons remains constant, and that new central nervous system neurons cannot be created or renewed. Herein, we present a comprehensive overview of the alterations and regulatory mechanisms of endogenous neurogenesis following central nervous system injury, and describe novel treatment strategies that target endogenous neurogenesis and newborn neurons in the treatment of central nervous system injury. Central nervous system injury frequently results in alterations of endogenous neurogenesis, encompassing the activation, proliferation, ectopic migration, differentiation, and functional integration of endogenous neural stem cells. Because of the unfavorable local microenvironment, most activated neural stem cells differentiate into glial cells rather than neurons. Consequently, the injury-induced endogenous neurogenesis response is inadequate for repairing impaired neural function. Scientists have attempted to enhance endogenous neurogenesis using various strategies, including using neurotrophic factors, bioactive materials, and cell reprogramming techniques. Used alone or in combination, these therapeutic strategies can promote targeted migration of neural stem cells to an injured area, ensure their survival and differentiation into mature functional neurons, and facilitate their integration into the neural circuit. Thus can integration replenish lost neurons after central nervous system injury, by improving the local microenvironment. By regulating each phase of endogenous neurogenesis, endogenous neural stem cells can be harnessed to promote effective regeneration of newborn neurons. This offers a novel approach for treating central nervous system injury.
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    On the functions of astrocyte-mediated neuronal slow inward currents
    Balázs Pál
    2024, 19 (12):  2602-2612.  doi: 10.4103/NRR.NRR-D-23-01723
    Abstract ( 104 )   PDF (1482KB) ( 74 )   Save
    Slow inward currents are known as neuronal excitatory currents mediated by glutamate release and activation of neuronal extrasynaptic N-methyl-D-aspartate receptors with the contribution of astrocytes. These events are significantly slower than the excitatory postsynaptic currents. Parameters of slow inward currents are determined by several factors including the mechanisms of astrocytic activation and glutamate release, as well as the diffusion pathways from the release site towards the extrasynaptic receptors. Astrocytes are stimulated by neuronal network activity, which in turn excite neurons, forming an astrocyte-neuron feedback loop. Mostly as a consequence of brain edema, astrocytic swelling can also induce slow inward currents under pathological conditions. There is a growing body of evidence on the roles of slow inward currents on a single neuron or local network level. These events often occur in synchrony on neurons located in the same astrocytic domain. Besides synchronization of neuronal excitability, slow inward currents also set synaptic strength via eliciting timing-dependent synaptic plasticity. In addition, slow inward currents are also subject to non-synaptic plasticity triggered by long-lasting stimulation of the excitatory inputs. Of note, there might be important region-specific differences in the roles and actions triggering slow inward currents. In greater networks, the pathophysiological roles of slow inward currents can be better understood than physiological ones. Slow inward currents are identified in the pathophysiological background of autism, as slow inward currents drive early hypersynchrony of the neural networks. Slow inward currents are significant contributors to paroxysmal depolarizational shifts/interictal spikes. These events are related to epilepsy, but also found in Alzheimer’s disease, Parkinson’s disease, and stroke, leading to the decline of cognitive functions. Events with features overlapping with slow inward currents (excitatory, N-methyl-D-aspartate-receptor mediated currents with astrocytic contribution) as ischemic currents and spreading depolarization also have a well-known pathophysiological role in worsening consequences of stroke, traumatic brain injury, or epilepsy. One might assume that slow inward currents occurring with low frequency under physiological conditions might contribute to synaptic plasticity and memory formation. However, to state this, more experimental evidence from greater neuronal networks or the level of the individual is needed. In this review, I aimed to summarize findings on slow inward currents and to speculate on the potential functions of it.
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    A systematic review of salivary biomarkers in Parkinson’s disease
    Maria Ilenia De Bartolo, Daniele Belvisi, Romina Mancinelli, Matteo Costanzo, Claudia Caturano, Giorgio Leodori, Alfredo Berardelli, Giovanni Fabbrini, Giorgio Vivacqua
    2024, 19 (12):  2613-2625.  doi: 10.4103/NRR.NRR-D-23-01677
    Abstract ( 74 )   PDF (2439KB) ( 81 )   Save
    The search for reliable and easily accessible biomarkers in Parkinson’s disease is receiving a growing emphasis, to detect neurodegeneration from the prodromal phase and to enforce disease-modifying therapies. Despite the need for non-invasively accessible biomarkers, the majority of the studies have pointed to cerebrospinal fluid or peripheral biopsies biomarkers, which require invasive collection procedures. Saliva represents an easily accessible biofluid and an incredibly wide source of molecular biomarkers. In the present study, after presenting the morphological and biological bases for looking at saliva in the search of biomarkers for Parkinson’s disease, we systematically reviewed the results achieved so far in the saliva of different cohorts of Parkinson’s disease patients. A comprehensive literature search on PubMed and SCOPUS led to the discovery of 289 articles. After screening and exclusion, 34 relevant articles were derived for systematic review. Alpha-synuclein, the histopathological hallmark of Parkinson’s disease, has been the most investigated Parkinson’s disease biomarker in saliva, with oligomeric alpha-synuclein consistently found increased in Parkinson’s disease patients in comparison to healthy controls, while conflicting results have been reported regarding the levels of total alpha-synuclein and phosphorylated alpha-synuclein, and few studies described an increased oligomeric alpha-synuclein/total alpha-synuclein ratio in Parkinson’s disease. Beyond alpha-synuclein, other biomarkers targeting different molecular pathways have been explored in the saliva of Parkinson’s disease patients: total tau, phosphorylated tau, amyloid-β1–42 (pathological protein aggregation biomarkers); DJ-1, heme-oxygenase-1, metabolites (altered energy homeostasis biomarkers); MAPLC-3beta (aberrant proteostasis biomarker); cortisol, tumor necrosis factor-alpha (inflammation biomarkers); DNA methylation, miRNA (DNA/RNA defects biomarkers); acetylcholinesterase activity (synaptic and neuronal network dysfunction biomarkers); Raman spectra, proteome, and caffeine. Despite a few studies investigating biomarkers targeting molecular pathways different from alpha-synuclein in Parkinson’s disease, these results should be replicated and observed in studies on larger cohorts, considering the potential role of these biomarkers in determining the molecular variance among Parkinson’s disease subtypes. Although the need for standardization in sample collection and processing, salivary-based biomarkers studies have reported encouraging results, calling for large-scale longitudinal studies and multicentric assessments, given the great molecular potentials and the non-invasive accessibility of saliva.
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    Biomaterial engineering strategies for modeling the Bruch’s membrane in age-related macular degeneration
    Blanca Molins, Andrea Rodríguez, Víctor Llorenç, Alfredo Adán
    2024, 19 (12):  2626-2636.  doi: 10.4103/NRR.NRR-D-23-01789
    Abstract ( 74 )   PDF (2261KB) ( 57 )   Save
    Age-related macular degeneration, a multifactorial inflammatory degenerative retinal disease, ranks as the leading cause of blindness in the elderly. Strikingly, there is a scarcity of curative therapies, especially for the atrophic advanced form of age-related macular degeneration, likely due to the lack of models able to fully recapitulate the native structure of the outer blood retinal barrier, the prime target tissue of age-related macular degeneration. Standard in vitro systems rely on 2D monocultures unable to adequately reproduce the structure and function of the outer blood retinal barrier, integrated by the dynamic interaction of the retinal pigment epithelium, the Bruch’s membrane, and the underlying choriocapillaris. The Bruch’s membrane provides structural and mechanical support and regulates the molecular trafficking in the outer blood retinal barrier, and therefore adequate Bruch’s membrane-mimics are key for the development of physiologically relevant models of the outer blood retinal barrier. In the last years, advances in the field of biomaterial engineering have provided novel approaches to mimic the Bruch’s membrane from a variety of materials. This review provides a discussion of the integrated properties and function of outer blood retinal barrier components in healthy and age-related macular degeneration status to understand the requirements to adequately fabricate Bruch’s membrane biomimetic systems. Then, we discuss novel materials and techniques to fabricate Bruch’s membrane-like scaffolds for age-related macular degeneration in vitro modeling, discussing their advantages and challenges with a special focus on the potential of Bruch’s membrane-like mimics based on decellularized tissue.
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    Epileptic brain network mechanisms and neuroimaging techniques for the brain network
    Yi Guo, Zhonghua Lin, Zhen Fan, Xin Tian
    2024, 19 (12):  2637-2648.  doi: 10.4103/1673-5374.391307
    Abstract ( 255 )   PDF (1645KB) ( 103 )   Save
    Epilepsy can be defined as a dysfunction of the brain network, and each type of epilepsy involves different brain-network changes that are implicated differently in the control and propagation of interictal or ictal discharges. Gaining more detailed information on brain network alterations can help us to further understand the mechanisms of epilepsy and pave the way for brain network-based precise therapeutic approaches in clinical practice. An increasing number of advanced neuroimaging techniques and electrophysiological techniques such as diffusion tensor imaging-based fiber tractography, diffusion kurtosis imaging-based fiber tractography, fiber ball imaging-based tractography, electroencephalography, functional magnetic resonance imaging, magnetoencephalography, positron emission tomography, molecular imaging, and functional ultrasound imaging have been extensively used to delineate epileptic networks. In this review, we summarize the relevant neuroimaging and neuroelectrophysiological techniques for assessing structural and functional brain networks in patients with epilepsy, and extensively analyze the imaging mechanisms, advantages, limitations, and clinical application ranges of each technique. A greater focus on emerging advanced technologies, new data analysis software, a combination of multiple techniques, and the construction of personalized virtual epilepsy models can provide a theoretical basis to better understand the brain network mechanisms of epilepsy and make surgical decisions.
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    Dysfunction of synaptic endocytic trafficking in Parkinson’s disease
    Xin Yi Ng, Mian Cao
    2024, 19 (12):  2649-2660.  doi: 10.4103/NRR.NRR-D-23-01624
    Abstract ( 92 )   PDF (1761KB) ( 69 )   Save
    Parkinson’s disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum. The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive. Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson’s disease. Notably, several of these genes are linked to the synaptic vesicle recycling process, particularly the clathrin-mediated endocytosis pathway. This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson’s disease, followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a “dying back” mechanism. Recently, several new animal and cellular models with Parkinson’s disease-linked mutations affecting the endocytic pathway have been created and extensively characterized. These models faithfully recapitulate certain Parkinson’s disease-like features at the animal, circuit, and cellular levels, and exhibit defects in synaptic membrane trafficking, further supporting the findings from human genetics and clinical studies. In this review, we will first summarize the cellular and molecular findings from the models of two Parkinson’s disease-linked clathrin uncoating proteins: auxilin (DNAJC6/PARK19) and synaptojanin 1 (SYNJ1/PARK20). The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect. Subsequently, we will delve into the involvement of several clathrin-mediated endocytosis-related proteins (GAK, endophilin A1, SAC2/INPP5F, synaptotagmin-11), identified as Parkinson’s disease risk factors through genome-wide association studies, in Parkinson’s disease pathogenesis. We will also explore the direct or indirect roles of some common Parkinson’s disease-linked proteins (alpha-synuclein (PARK1/4), Parkin (PARK2), and LRRK2 (PARK8)) in synaptic endocytic trafficking. Additionally, we will discuss the emerging novel functions of these endocytic proteins in downstream membrane traffic pathways, particularly autophagy. Given that synaptic dysfunction is considered as an early event in Parkinson’s disease, a deeper understanding of the cellular mechanisms underlying synaptic vesicle endocytic trafficking may unveil novel targets for early diagnosis and the development of interventional therapies for Parkinson’s disease. Future research should aim to elucidate why generalized synaptic endocytic dysfunction leads to the selective degeneration of nigrostriatal dopamine neurons in Parkinson’s disease.
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    Glymphatic system: a gateway for neuroinflammation
    Kailu Zou, Qingwei Deng, Hong Zhang, Changsheng Huang
    2024, 19 (12):  2661-2672.  doi: 10.4103/1673-5374.391312
    Abstract ( 204 )   PDF (3070KB) ( 183 )   Save
    The glymphatic system is a relatively recently identified fluid exchange and transport system in the brain. Accumulating evidence indicates that glymphatic function is impaired not only in central nervous system disorders but also in systemic diseases. Systemic diseases can trigger the inflammatory responses in the central nervous system, occasionally leading to sustained inflammation and functional disturbance of the central nervous system. This review summarizes the current knowledge on the association between glymphatic dysfunction and central nervous system inflammation. In addition, we discuss the hypothesis that disease conditions initially associated with peripheral inflammation overwhelm the performance of the glymphatic system, thereby triggering central nervous system dysfunction, chronic neuroinflammation, and neurodegeneration. Future research investigating the role of the glymphatic system in neuroinflammation may offer innovative therapeutic approaches for central nervous system disorders.
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    Neurogenic potential of NG2 in neurotrauma: a systematic review#br#
    Yuri R. Rigo, Radharani Benvenutti, Luis V. Portela, Nathan R. Strogulski
    2024, 19 (12):  2673-2683.  doi: 10.4103/NRR.NRR-D-23-01031
    Abstract ( 83 )   PDF (1242KB) ( 30 )   Save
    Regenerative approaches towards neuronal loss following traumatic brain or spinal cord injury have long been considered a dogma in neuroscience and remain a cutting-edge area of research. This is reflected in a large disparity between the number of studies investigating primary and secondary injury as therapeutic targets in spinal cord and traumatic brain injuries. Significant advances in biotechnology may have the potential to reshape the current state-of-the-art and bring focus to primary injury neurotrauma research. Recent studies using neural-glial factor/antigen 2 (NG2) cells indicate that they may differentiate into neurons even in the developed brain. As these cells show great potential to play a regenerative role, studies have been conducted to test various manipulations in neurotrauma models aimed at eliciting a neurogenic response from them. In the present study, we systematically reviewed the experimental protocols and findings described in the scientific literature, which were peer-reviewed original research articles (1) describing preclinical experimental studies, (2) investigating NG2 cells, (3) associated with neurogenesis and neurotrauma, and (4) in vitro and/or in vivo, available in PubMed/MEDLINE, Web of Science or SCOPUS, from 1998 to 2022. Here, we have reviewed a total of 1504 papers, and summarized findings that ultimately suggest that NG2 cells possess an inducible neurogenic potential in animal models and in vitro. We also discriminate findings of NG2 neurogenesis promoted by different pharmacological and genetic approaches over functional and biochemical outcomes of traumatic brain injury and spinal cord injury models, and provide mounting evidence for the potential benefits of manipulated NG2 cell ex vivo transplantation in primary injury treatment. These findings indicate the feasibility of NG2 cell neurogenesis strategies and add new players in the development of therapeutic alternatives for neurotrauma.
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    Na+/K+-ATPase: ion pump, signal transducer, or cytoprotective protein, and novel biological functions
    Songqiang Huang, Wanting Dong, Xiaoqian Lin, Jinsong Bian
    2024, 19 (12):  2684-2697.  doi: 10.4103/NRR.NRR-D-23-01175
    Abstract ( 523 )   PDF (26069KB) ( 155 )   Save
    Na+/K+-ATPase is a transmembrane protein that has important roles in the maintenance of electrochemical gradients across cell membranes by transporting three Na+ out of and two K+ into cells. Additionally, Na+/K+-ATPase participates in Ca2+-signaling transduction and neurotransmitter release by coordinating the ion concentration gradient across the cell membrane. Na+/K+-ATPase works synergistically with multiple ion channels in the cell membrane to form a dynamic network of ion homeostatic regulation and affects cellular communication by regulating chemical signals and the ion balance among different types of cells. Therefore, it is not surprising that Na+/K+-ATPase dysfunction has emerged as a risk factor for a variety of neurological diseases. However, published studies have so far only elucidated the important roles of Na+/K+-ATPase dysfunction in disease development, and we are lacking detailed mechanisms to clarify how Na+/K+-ATPase affects cell function. Our recent studies revealed that membrane loss of Na+/K+-ATPase is a key mechanism in many neurological disorders, particularly stroke and Parkinson’s disease. Stabilization of plasma membrane Na+/K+-ATPase with an antibody is a novel strategy to treat these diseases. For this reason, Na+/K+-ATPase acts not only as a simple ion pump but also as a sensor/regulator or cytoprotective protein, participating in signal transduction such as neuronal autophagy and apoptosis, and glial cell migration. Thus, the present review attempts to summarize the novel biological functions of Na+/K+-ATPase and Na+/K+-ATPase-related pathogenesis. The potential for novel strategies to treat Na+/K+-ATPase-related brain diseases will also be discussed. 
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    MicroRNA-502-3p regulates GABAergic synapse function in hippocampal neurons
    Bhupender Sharma, Melissa M. Torres, Sheryl Rodriguez, Laxman Gangwani, Subodh Kumar
    2024, 19 (12):  2698-2707.  doi: 10.4103/NRR.NRR-D-23-01064
    Abstract ( 92 )   PDF (3712KB) ( 67 )   Save
    Gamma-aminobutyric acid (GABA)ergic neurons, the most abundant inhibitory neurons in the human brain, have been found to be reduced in many neurological disorders, including Alzheimer’s disease and Alzheimer’s disease-related dementia. Our previous study identified the upregulation of microRNA-502-3p (miR-502-3p) and downregulation of GABA type A receptor subunit α-1 in Alzheimer’s disease synapses. This study investigated a new molecular relationship between miR-502-3p and GABAergic synapse function. In vitro studies were performed using the mouse hippocampal neuronal cell line HT22 and miR-502-3p agomiRs and antagomiRs. In silico analysis identified multiple binding sites of miR-502-3p at GABA type A receptor subunit α-1 mRNA. Luciferase assay confirmed that miR-502-3p targets the GABA type A receptor subunit α-1 gene and suppresses the luciferase activity. Furthermore, quantitative reverse transcription-polymerase chain reaction, miRNA in situ hybridization, immunoblotting, and immunostaining analysis confirmed that overexpression of miR-502-3p reduced the GABA type A receptor subunit α-1 level, while suppression of miR-502-3p increased the level of GABA type A receptor subunit α-1 protein. Notably, as a result of the overexpression of miR-502-3p, cell viability was found to be reduced, and the population of necrotic cells was found to be increased. The whole cell patch-clamp analysis of human-GABA receptor A-α1/β3/γ2L human embryonic kidney (HEK) recombinant cell line also showed that overexpression of miR-502-3p reduced the GABA current and overall GABA function, suggesting a negative correlation between miR-502-3p levels and GABAergic synapse function. Additionally, the levels of proteins associated with Alzheimer’s disease were high with miR-502-3p overexpression and reduced with miR-502-3p suppression. The present study provides insight into the molecular mechanism of regulation of GABAergic synapses by miR-502-3p. We propose that micro-RNA, in particular miR-502-3p, could be a potential therapeutic target to modulate GABAergic synapse function in neurological disorders, including Alzheimer’s disease and Alzheimer’s disease-related dementia.
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    Repressing iron overload ameliorates central post-stroke pain via the Hdac2-Kv1.2 axis in a rat model of hemorrhagic stroke
    He Fang, Mengjie Li, Jingchen Yang, Shunping Ma, Li Zhang, Hongqi Yang, Qiongyan Tang, Jing Cao, Weimin Yang
    2024, 19 (12):  2708-2722.  doi: 10.4103/NRR.NRR-D-23-01498
    Abstract ( 157 )   PDF (6228KB) ( 120 )   Save
    Thalamic hemorrhage can lead to the development of central post-stroke pain. Changes in histone acetylation levels, which are regulated by histone deacetylases, affect the excitability of neurons surrounding the hemorrhagic area. However, the regulatory mechanism of histone deacetylases in central post-stroke pain remains unclear. Here, we show that iron overload leads to an increase in histone deacetylase 2 expression in damaged ventral posterolateral nucleus neurons. Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium (Kv) channel subunit gene in a rat model of central post-stroke pain, thereby increasing Kcna2 expression and relieving central pain. However, in the absence of nerve injury, increasing histone deacetylase 2 expression decreased Kcna2 expression, decreased Kv current, increased the excitability of neurons in the ventral posterolateral nucleus area, and led to neuropathic pain symptoms. Moreover, treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage, reversed histone deacetylase 2 upregulation and Kv1.2 downregulation, and alleviated mechanical hypersensitivity in central post-stroke pain rats. These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation, mediated by iron overload, are important factors in central post-stroke pain pathogenesis and could serve as new targets for central post-stroke pain treatment.
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    Screening biomarkers for spinal cord injury using weighted gene co-expression network analysis and machine learning 
    Xiaolu Li, Ye Yang, Senming Xu, Yuchang Gui, Jianmin Chen, Jianwen Xu
    2024, 19 (12):  2723-2734.  doi: 10.4103/1673-5374.391306
    Abstract ( 176 )   PDF (7562KB) ( 63 )   Save
    Immune changes and inflammatory responses have been identified as central events in the pathological process of spinal cord injury. They can greatly affect nerve regeneration and functional recovery. However, there is still limited understanding of the peripheral immune inflammatory response in spinal cord injury. In this study, we obtained microRNA expression profiles from the peripheral blood of patients with spinal cord injury using high-throughput sequencing. We also obtained the mRNA expression profile of spinal cord injury patients from the Gene Expression Omnibus (GEO) database (GSE151371). We identified 54 differentially expressed microRNAs and 1656 differentially expressed genes using bioinformatics approaches. Functional enrichment analysis revealed that various common immune and inflammation-related signaling pathways, such as neutrophil extracellular trap formation pathway, T cell receptor signaling pathway, and nuclear factor-κB signal pathway, were abnormally activated or inhibited in spinal cord injury patient samples. We applied an integrated strategy that combines weighted gene co-expression network analysis, LASSO logistic regression, and SVM-RFE algorithm and identified three biomarkers associated with spinal cord injury: ANO10, BST1, and ZFP36L2. We verified the expression levels and diagnostic performance of these three genes in the original training dataset and clinical samples through the receiver operating characteristic curve. Quantitative polymerase chain reaction results showed that ANO10 and BST1 mRNA levels were increased and ZFP36L2 mRNA was decreased in the peripheral blood of spinal cord injury patients. We also constructed a small RNA-mRNA interaction network using Cytoscape. Additionally, we evaluated the proportion of 22 types of immune cells in the peripheral blood of spinal cord injury patients using the CIBERSORT tool. The proportions of naïve B cells, plasma cells, monocytes, and neutrophils were increased while the proportions of memory B cells, CD8+ T cells, resting natural killer cells, resting dendritic cells, and eosinophils were markedly decreased in spinal cord injury patients increased compared with healthy subjects, and ANO10, BST1 and ZFP26L2 were closely related to the proportion of certain immune cell types. The findings from this study provide new directions for the development of treatment strategies related to immune inflammation in spinal cord injury and suggest that ANO10, BST1, and ZFP36L2 are potential biomarkers for spinal cord injury. The study was registered in the Chinese Clinical Trial Registry (registration No. ChiCTR2200066985, December 12, 2022).
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    Biomarkers for neuromyelitis optica: a visual analysis of emerging research trends
    Xiangjun Li, Jiandong Zhang, Siqi Zhang, Shengling Shi, Yi’an Lu, Ying Leng, Chunyan Li
    2024, 19 (12):  2735-2749.  doi: 10.4103/NRR.NRR-D-24-00109
    Abstract ( 212 )   PDF (1836KB) ( 116 )   Save
    Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system that differs from multiple sclerosis. Over the past 20 years, the search for biomarkers for neuromyelitis optica has been ongoing. Here, we used a bibliometric approach to analyze the main research focus in the field of biomarkers for neuromyelitis optica. Research in this area is consistently increasing, with China and the United States leading the way on the number of studies conducted. The Mayo Clinic is a highly reputable institution in the United States, and was identified as the most authoritative institution in this field. Furthermore, Professor Wingerchuk from the Mayo Clinic was the most authoritative expert in this field. Keyword analysis revealed that the terms “neuromyelitis optica” (261 times), “multiple sclerosis” (220 times), “neuromyelitis optica spectrum disorder” (132 times), “aquaporin 4” (99 times), and “optical neuritis” (87 times) were the most frequently used keywords in literature related to this field. Comprehensive analysis of the classical literature showed that the majority of publications provide conclusive research evidence supporting the use of aquaporin-4-IgG and neuromyelitis optica-IgG to effectively diagnose and differentiate neuromyelitis optica from multiple sclerosis. Furthermore, aquaporin-4-IgG has emerged as a highly specific diagnostic biomarker for neuromyelitis optica spectrum disorder. Myelin oligodendrocyte glycoprotein-IgG is a diagnostic biomarker for myelin oligodendrocyte glycoprotein antibody-associated disease. Recent biomarkers for neuromyelitis optica include cerebrospinal fluid immunological biomarkers such as glial fibrillary acidic protein, serum astrocyte damage biomarkers like FAM19A5, serum albumin, and gamma-aminobutyric acid. The latest prospective clinical trials are exploring the potential of these biomarkers. Preliminary results indicate that glial fibrillary acidic protein is emerging as a promising candidate biomarker for neuromyelitis optica spectrum disorder. The ultimate goal of future research is to identify non-invasive biomarkers with high sensitivity, specificity, and safety for the accurate diagnosis of neuromyelitis optica.
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    Vanillylacetone attenuates cadmium chloride-induced hippocampal damage and memory loss through up-regulation of nuclear factor erythroid 2-related factor 2 gene and protein expression
    Fahaid H. AL-Hashem, Salah O. Bashir, Amal F. Dawood, Moutasem S. Aboonq, Ismaeel Bin-Jaliah, Abdulaiziz M. Al-Garni, Mohamed D. Morsy
    2024, 19 (12):  2750-2759.  doi: 10.4103/1673-5374.391300
    Abstract ( 77 )   PDF (1715KB) ( 49 )   Save
    Memory loss and dementia are major public health concerns with a substantial economic burden. Oxidative stress has been shown to play a crucial role in the pathophysiology of hippocampal damage-induced memory impairment. To investigate whether the antioxidant and anti-inflammatory compound vanillylacetone (zingerone) can protect against hippocampal damage and memory loss induced by cadmium chloride (CdCl2) administration in rats, we explored the potential involvement of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, which is known to modulate oxidative stress and inflammation. Sixty healthy male Wistar rats were divided into five groups: vehicle-treated (control), vanillylacetone, CdCl2, vanillylacetone + CdCl2, vanillylacetone + CdCl2 + brusatol (a selective pharmacological Nrf2 inhibitor) groups. Vanillylacetone effectively attenuated CdCl2-induced damage in the dental gyrus of the hippocampus and improved the memory function assessed by the Morris Water Maze test. Additionally, vanillylacetone markedly decreased the hippocampal tissue levels of inflammatory biomarkers (interleukin-6, tumor necrosis factor-α, intracellular cell adhesive molecules) and apoptosis biomarkers (Bax and cleaved caspase-3). The control and CdCl2-treated groups treated with vanillylacetone showed reduced generation of reactive oxygen species, decreased malondialdehyde levels, and increased superoxide dismutase and glutathione activities, along with significant elevation of nuclear Nrf2 mRNA and protein expression in hippocampal tissue. All the protective effects of vanillylacetone were substantially blocked by the co-administration of brusatol (a selective Nrf2 inhibitor). Vanillylacetone mitigated hippocampal damage and memory loss induced by CdCl2, at least in part, by activating the nuclear transcription factor Nrf2. Additionally, vanillylacetone exerted its potent antioxidant and anti-inflammatory actions.
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    Nicotinamide adenine dinucleotide treatment confers resistance to neonatal ischemia and hypoxia: effects on neurobehavioral phenotypes
    Xiaowen Xu, Xinxin Wang, Li Zhang, Yiming Jin, Lili Li, Meifang Jin, Lianyong Li, Hong Ni
    2024, 19 (12):  2760-2772.  doi: 10.4103/NRR.NRR-D-23-01490
    Abstract ( 117 )   PDF (7203KB) ( 56 )   Save
    Neonatal hypoxic-ischemic brain injury is the main cause of hypoxic-ischemic encephalopathy and cerebral palsy. Currently, there are few effective clinical treatments for neonatal hypoxic-ischemic brain injury. Here, we investigated the neuroprotective and molecular mechanisms of exogenous nicotinamide adenine dinucleotide, which can protect against hypoxic injury in adulthood, in a mouse model of neonatal hypoxic-ischemic brain injury. In this study, nicotinamide adenine dinucleotide (5 mg/kg) was intraperitoneally administered 30 minutes before surgery and every 24 hours thereafter. The results showed that nicotinamide adenine dinucleotide treatment improved body weight, brain structure, adenosine triphosphate levels, oxidative damage, neurobehavioral test outcomes, and seizure threshold in experimental mice. Tandem mass tag proteomics revealed that numerous proteins were altered after nicotinamide adenine dinucleotide treatment in hypoxic-ischemic brain injury mice. Parallel reaction monitoring and western blotting confirmed changes in the expression levels of proteins including serine (or cysteine) peptidase inhibitor, clade A, member 3N, fibronectin 1, 5′-nucleotidase, cytosolic IA, microtubule associated protein 2, and complexin 2. Proteomics analyses showed that nicotinamide adenine dinucleotide ameliorated hypoxic-ischemic injury through inflammation-related signaling pathways (e.g., nuclear factor-kappa B, mitogen-activated protein kinase, and phosphatidylinositol 3 kinase/protein kinase B). These findings suggest that nicotinamide adenine dinucleotide treatment can improve neurobehavioral phenotypes in hypoxic-ischemic brain injury mice through inflammation-related pathways.
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    Surgical intervention combined with weight-bearing walking training promotes recovery in patients with chronic spinal cord injury: a randomized controlled study
    Hui Zhu, James D. Guest, Sarah Dunlop, Jia-Xin Xie, Sujuan Gao, Zhuojing Luo, Joe E. Springer, Wutian Wu, Wise Young, Wai Sang Poon, Song Liu, Hongkun Gao, Tao Yu, Dianchun Wang, Libing Zhou, Shengping Wu, Lei Zhong, Fang Niu, Xiaomei Wang, Yansheng Liu, Kwok-Fai So, Xiao-Ming Xu
    2024, 19 (12):  2773-2784.  doi: 10.4103/NRR.NRR-D-23-01198
    Abstract ( 115 )   PDF (1925KB) ( 43 )   Save
    For patients with chronic spinal cord injury, the conventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection, pressure sores, osteoporosis, and deep vein thrombosis. Surgery is rarely performed on spinal cord injury in the chronic phase, and few treatments have been proven effective in chronic spinal cord injury patients. Development of effective therapies for chronic spinal cord injury patients is needed. We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal cord injury to compare intensive rehabilitation (weight-bearing walking training) alone with surgical intervention plus intensive rehabilitation. This clinical trial was registered at ClinicalTrials.gov (NCT02663310). The goal of surgical intervention was spinal cord detethering, restoration of cerebrospinal fluid flow, and elimination of residual spinal cord compression. We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement, reduced spasticity, and more rapid bowel and bladder functional recovery than weight-bearing walking training alone. Overall, the surgical procedures and intensive rehabilitation were safe. American Spinal Injury Association Impairment Scale improvement was more common in T7–T11 injuries than in T2–T6 injuries. Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.
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