Table of Content

15 February 2022, Volume 17 Issue 2 Previous Issue   

For Selected:

Download Citations EndNote Reference Manager ProCite BibTeX RefWorks

Toggle Thumbnails

Select

Deciphering the role of PGC-1α in neurological disorders: from mitochondrial dysfunction to synaptic failure Jessica D. Panes, Aline Wendt, Oscar Ramirez-Molina, Patricio A. Castro, Jorge Fuentealba 2022, 17 (2):  237-245.  doi: 10.4103/1673-5374.317957 Abstract ( 937 )   PDF (1395KB) ( 337 )   Save The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Additionally, it has been observed that PGC-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, PGC-1α downregulation in different brain areas (hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that PGC-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that PGC-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific PGC-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-to-date overview of the PGC-1α role in the physiopathology of neurodegenerative diseases, as well as establish the importance of PGC-1α function in synaptic transmission and neuronal survival.  Related Articles | Metrics

Select

Dying by fire: noncanonical functions of autophagy proteins in neuroinflammation and neurodegeneration Alexis D. Rickman, Addison Hilyard, Bradlee L. Heckmann 2022, 17 (2):  246-250.  doi: 10.4103/1673-5374.317958 Abstract ( 217 )   PDF (757KB) ( 118 )   Save Neuroinflammation and neurodegeneration are key components in the establishment and progression of neurodegenerative diseases including Alzheimer’s Disease (AD). Over the past decade increasing evidence is emerging for the use of components of the canonical autophagy machinery in pathways that are characterized by LC3 lipidation yet are distinct from traditional macro-autophagy. One such pathway that utilizes components of the autophagy machinery to target LC3 to endosomes, a process termed LC3-associated endocytosis (LANDO), has recently been identified and regulates neuroinflammation. Abrogation of LANDO in microglia cells results in a propensity for elevated neuroinflammatory cytokine production. Using the well-established 5xFAD model of AD to interrogate neuroinflammatory regulation, impairment of LANDO through deletion of a key upstream regulator Rubicon or other downstream autophagy components, exacerbated disease onset and severity, while deletion of microglial autophagy alone had no measurable effect. Mice presented with robust deposition of the neurotoxic AD protein β-amyloid (Aβ), microglial activation and inflammatory cytokine production, tau phosphorylation, and aggressive neurodegeneration culminating in severe memory impairment. LANDO-deficiency impaired recycling of receptors that recognize Aβ, including TLR4 and TREM2. LANDO-deficiency alone through deletion of the WD-domain of the autophagy protein ATG16L, revealed a role for LANDO in the spontaneous establishment of age-associated AD. LANDO-deficient mice aged to 2 years presented with advanced AD-like disease and pathology correlative to that observed in human AD patients. Together, these studies illustrate an important role for microglial LANDO in regulating CNS immune activation and protection against neurodegeneration. New evidence is emerging that demonstrates a putative linkage between pathways such as LANDO and cell death regulation via apoptosis and possibly necroptosis. Herein, we provide a review of the use of the autophagy machinery in non-canonical mechanisms that alter immune regulation and could have significant impact in furthering our understanding of not only CNS diseases like AD, but likely beyond.   Related Articles | Metrics

Select

Transcranial magnetic stimulation in animal models of neurodegeneration Mohammad Uzair, Turki Abualait, Muhammad Arshad, Woo-Kyoung Yoo, Ali Mir, Reem Fahd Bunyan, Shahid Bashir 2022, 17 (2):  251-265.  doi: 10.4103/1673-5374.317962 Abstract ( 273 )   PDF (11234KB) ( 67 )   Save Brain stimulation techniques offer powerful means of modulating the physiology of specific neural structures. In recent years, non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, have emerged as therapeutic tools for neurology and neuroscience. However, the possible repercussions of these techniques remain unclear, and there are few reports on the incisive recovery mechanisms through brain stimulation. Although several studies have recommended the use of non-invasive brain stimulation in clinical neuroscience, with a special emphasis on TMS, the suggested mechanisms of action have not been confirmed directly at the neural level. Insights into the neural mechanisms of non-invasive brain stimulation would unveil the strategies necessary to enhance the safety and efficacy of this progressive approach. Therefore, animal studies investigating the mechanisms of TMS-induced recovery at the neural level are crucial for the elaboration of non-invasive brain stimulation. Translational research done using animal models has several advantages and is able to investigate knowledge gaps by directly targeting neuronal levels. In this review, we have discussed the role of TMS in different animal models, the impact of animal studies on various disease states, and the findings regarding brain function of animal models after TMS in pharmacology research. Related Articles | Metrics

Select

SYNGR4 and PLEKHB1 deregulation in motor neurons of amyotrophic lateral sclerosis models: potential contributions to pathobiology Rita F. Marques, Kent E. Duncan 2022, 17 (2):  266-270.  doi: 10.4103/1673-5374.317960 Abstract ( 153 )   PDF (480KB) ( 131 )   Save Amyotrophic lateral sclerosis is the most common adult-onset neurodegenerative disease affecting motor neurons. Its defining feature is progressive loss of motor neuron function in the cortex, brainstem, and spinal cord, leading to paralysis and death. Despite major advances in identifying genes that can cause disease when mutated and model the disease in animals and cellular models, it still remains unclear why motor symptoms suddenly appear after a long pre-symptomatic phase of apparently normal function. One hypothesis is that age-related deregulation of specific proteins within key cell types, especially motor neurons themselves, initiates disease symptom appearance and may also drive progressive degeneration. Genome-wide in vivo cell-type-specific screening tools are enabling identification of candidates for such proteins. In this minireview, we first briefly discuss the methodology used in a recent study that applied a motor neuron-specific RNA-Seq screening approach to a standard model of TAR DNA-binding protein-43 (TDP-43)-driven amyotrophic lateral sclerosis. A key finding of this study is that synaptogyrin-4 and pleckstrin homology domain-containing family B member 1 are also deregulated at the protein level within motor neurons of two unrelated mouse models of mutant TDP-43 driven amyotrophic lateral sclerosis. Guided by what is known about molecular and cellular functions of these proteins and their orthologs, we outline here specific hypotheses for how changes in their levels might potentially alter cellular physiology of motor neurons and detrimentally affect motor neuron function. Where possible, we also discuss how this information could potentially be used in a translational context to develop new therapeutic strategies for this currently incurable, devastating disease.   Related Articles | Metrics

Select

Cholesterol synthesis inhibition or depletion in axon regeneration Bor Luen Tang 2022, 17 (2):  271-276.  doi: 10.4103/1673-5374.317956 Abstract ( 187 )   PDF (1065KB) ( 182 )   Save Cholesterol is biosynthesized by all animal cells. Beyond its metabolic role in steroidogenesis, it is enriched in the plasma membrane where it has key structural and regulatory functions. Cholesterol is thus presumably important for post-injury axon regrowth, and this notion is supported by studies showing that impairment of local cholesterol reutilization impeded regeneration. However, several studies have also shown that statins, inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, are enhancers of axon regeneration, presumably acting through an attenuation of the mevalonate isoprenoid pathway and consequent reduction in protein prenylation. Several recent reports have now shown that cholesterol depletion, as well as inhibition of cholesterol synthesis per se, enhances axon regeneration. Here, I discussed these findings and propose some possible underlying mechanisms. The latter would include possible disruptions to axon growth inhibitor signaling by lipid raft-localized receptors, as well as other yet unclear neuronal survival signaling process enhanced by cholesterol lowering or depletion. Related Articles | Metrics

Select

Challenges in developing therapeutic strategies for mild neonatal encephalopathy Alice McDouall, Guido Wassink, Laura Bennet, Alistair J. Gunn, Joanne O. Davidson 2022, 17 (2):  277-282.  doi: 10.4103/1673-5374.317963 Abstract ( 127 )   PDF (510KB) ( 90 )   Save There is increasing evidence that infants with mild neonatal encephalopathy (NE) have significant risks of mortality, brain injury and adverse neurodevelopmental outcomes. In the era of therapeutic hypothermia, infants need to be diagnosed within 6 hours of birth, corresponding with the window of opportunity for treatment of moderate to severe NE, compared to the retrospective grading over 2 to 3 days, typically with imaging and formal electroencephalographic assessment in the pre-hypothermia era. This shift in diagnosis may have increased the apparent prevalence of brain damage and poor neurological outcomes seen in infants with mild NE in the era of hypothermia. Abnormal short term outcomes observed in infants with mild NE include seizures, abnormal neurologic examination at discharge, abnormal brain magnetic resonance imaging and difficulty feeding. At 2 to 3 years of age, mild NE has been associated with an increased risk of autism, language and cognitive deficits. There are no approved treatment strategies for these infants as they were not included in the initial randomized controlled trials for therapeutic hypothermia. However, there is already therapeutic creep, with many centers treating infants with mild NE despite the limited evidence for its safety and efficacy. The optimal duration of treatment and therapeutic window of opportunity for effective treatment need to be specifically established for mild NE as the evolution of injury is likely to be slower, based on preclinical data. Randomized controlled trials of therapeutic hypothermia for infants with mild NE are urgently required to establish the safety and efficacy of treatment. This review will examine the evidence for adverse outcomes after mild NE and dissect some of the challenges in developing therapeutic strategies for mild NE, before analyzing the evidence for therapeutic hypothermia and other strategies for treatment of these infants. Related Articles | Metrics

Select

Delving into the recent advancements of spinal cord injury treatment: a review of recent progress Joseph A. Flack, Krishna Deo Sharma, Jennifer Yanhua Xie 2022, 17 (2):  283-291.  doi: 10.4103/1673-5374.317961 Abstract ( 531 )   PDF (721KB) ( 286 )   Save Spinal cord injury (SCI) research is a very complex field lending to why reviews of SCI literatures can be beneficial to current and future researchers. This review focuses on recent articles regarding potential modalities for the treatment and management of SCI. The modalities were broken down into four categories: neuroprotection-pharmacologic, neuroprotection-non-pharmacologic, neuroregeneration-pharmacologic, neuroregeneration-non-pharmacologic. Peer-reviewed articles were found using PubMed with search terms: “spinal cord injury”, “spinal cord injury neuroregeneration”, “olfactory ensheathing cells spinal cord injury”, “rho-rock inhibitors spinal cord injury”, “neural stem cell”, “scaffold”, “neural stem cell transplantation”, “exosomes and SCI”, “epidural stimulation SCI”, “brain-computer interfaces and SCI”. Most recent articles spanning two years were chosen for their relevance to the categories of SCI management and treatment. There has been a plethora of pre-clinical studies completed with their results being difficult to replicate in clinical studies. Therefore, scientists should focus on understanding and applying the results of previous research to develop more efficacious preclinical studies and clinical trials.  Related Articles | Metrics

Select

Hyperglycemia in acute ischemic stroke: physiopathological and therapeutic complexity Federica Ferrari, Antonio Moretti, Roberto Federico Villa 2022, 17 (2):  292-299.  doi: 10.4103/1673-5374.317959 Abstract ( 158 )   PDF (406KB) ( 178 )   Save Diabetes mellitus and associated chronic hyperglycemia enhance the risk of acute ischemic stroke and lead to worsened clinical outcome and increased mortality. However, post-stroke hyperglycemia is also present in a number of non-diabetic patients after acute ischemic stroke, presumably as a stress response. The aim of this review is to summarize the main effects of hyperglycemia when associated to ischemic injury in acute stroke patients, highlighting the clinical and neurological outcomes in these conditions and after the administration of the currently approved pharmacological treatment, i.e. insulin. The disappointing results of the clinical trials on insulin (including the hypoglycemic events) demand a change of strategy based on more focused therapies. Starting from the comprehensive evaluation of the physiopathological alterations occurring in the ischemic brain during hyperglycemic conditions, the effects of various classes of glucose-lowering drugs are reviewed, such as glucose-like peptide-1 receptor agonists, DPP-4 inhibitors and sodium glucose cotransporter 2 inhibitors, in the perspective of overcoming the up-to-date limitations and of evaluating the effectiveness of new potential therapeutic strategies. Related Articles | Metrics

Select

Inserting new synaptic connections into damaged neural circuits: towards synapse therapy? Ithai Rabinowitch 2022, 17 (2):  300-301.  doi: 10.4103/1673-5374.317964 Abstract ( 167 )   PDF (281KB) ( 93 )   Save Recovery from neural damage often requires reorganization of remaining neural tissue, including the formation of new synaptic connections between surviving neurons. Such rewiring may restore disrupted information flow caused by neuronal loss, and help adjust altered neural circuitry to reestablish diminished functionality. On occasion, proper rewiring may occur spontaneously, leading to successful recovery (Joy and Carmichael, 2021). However, in many cases natural rewiring is insufficient, and may even cause maladaptive deterioration due to miswiring (Nava and Röder, 2011). To overcome this, several interventional strategies have been developed to assist in the recovery process, by guiding synaptic rewiring in desirable directions (Su and Xu, 2020). For example, enhanced usage of the affected limbs or the impaired mental capacities can stimulate proper activity-dependent rewiring (Ganguly and Poo, 2013). Pharmaceutical targeting of specific molecular pathways (Joy and Carmichael, 2021) can bolster desirable plasticity processes and suppress unwanted ones. Cell-based therapy (Wechsler et al., 2018) can increase neurogenesis, replacing missing neurons and giving rise to new network connections. Brain-Machine Interfaces can serve as artificial communication pathways within the nervous system or between neurons and artificial effectors in order to bypass broken links in disrupted networks and establish new prosthetic neuronal connections (Wolpaw et al., 2020). Related Articles | Metrics

Select

Celeboxib-mediated neuroprotection in focal cerebral ischemia: an interplay between unfolded protein response and inflammation María Santos-Galdiano, Diego Pérez-Rodríguez, Arsenio Fernández-López 2022, 17 (2):  302-303.  doi: 10.4103/1673-5374.317970 Abstract ( 117 )   PDF (245KB) ( 111 )   Save Ischemic stroke results from the temporary or permanent lack of blood supply in the brain due to the occlusion of a brain blood vessel. Around 85% of patients with cerebrovascular accidents suffer from ischemic strokes. Although cerebrovascular accidents represent the major cause of death and permanent disability worldwide, thus far, only processes addressed at eliminating the vessel obstruction (chemical or mechanical) have been successfully developed. Many neuroprotective strategies have been tested in preclinical studies, but clinical trials have, so far, failed to result in beneficial effects. These issues may be due to the very complex pathophysiology of ischemic stroke, which involves the integration of multiple signaling pathways ultimately resulting in neuronal loss. Related Articles | Metrics

Select

Stressed axons craving for glial sugar: links to regeneration? Elisabetta Babetto, Bogdan Beirowski 2022, 17 (2):  304-306.  doi: 10.4103/1673-5374.317965 Abstract ( 119 )   PDF (18631KB) ( 25 )   Save The contrary but interrelated processes of axon degeneration and regeneration are the yin and yang of many neurodegenerative conditions. Here we discuss recent evidence for metabolic cross-talk between glia and injured axons regulating these processes. We especially focus on potential bioenergetic mechanisms as to how axon-flanking glia may promote regeneration. Related Articles | Metrics

Select

Contribution of adult-born neurons to memory consolidation during rapid eye movement sleep Akinobu Ohba, Masanori Sakaguchi 2022, 17 (2):  307-308.  doi: 10.4103/1673-5374.317966 Abstract ( 189 )   PDF (503KB) ( 152 )   Save Introduction: Memory consolidation stabilizes newly acquired memories by integrating them into pre-existing memory networks, which is thought to occur via changes in synaptic strength. Sleep may influence memory consolidation by modifying synaptic strength through local neuronal oscillatory activity. Recently, we found that the activity of hippocampal adult-born neurons (ABNs) is critical for memory consolidation during sleep (Kumar et al., 2020). Here, we propose a hypothesis for how changes in ABN synaptic plasticity synchronized with neural oscillations may contribute to memory consolidation during sleep.  Related Articles | Metrics

Select

A neuron’s ambrosia: non-autonomous unfolded protein response of the endoplasmic reticulum promotes lifespan Stefan Homentcovschi, Ryo Higuchi-Sanabria 2022, 17 (2):  309-310.  doi: 10.4103/1673-5374.317967 Abstract ( 186 )   PDF (1593KB) ( 124 )   Save The ability to protect cellular components in the face of deleterious conditions, such as exposure to chemical poisons, damaging radiation, or excessive heat, is crucial to organismal viability. Several compartmentalized stress response pathways have evolved to mitigate damage and increase cellular fitness in such environments, including the unfolded protein response of the endoplasmic reticulum (UPRER). The UPRER serves a critical protective role by promoting proteome integrity and lipid homeostasis while preventing the accumulation of damaged proteins and protein aggregates. The ability to mount an effective UPRER is a key determinant of organismal lifespan and stress resistance, however, as with other stress responses, it has been shown to decline markedly during the aging process. This leaves the proteomes of aged animals susceptible to dysregulation and dysfunction, which in turn further contributes to an accelerated aging process, development of age-associated pathology, and proteotoxicity (Higuchi-Sanabria et al., 2018). Related Articles | Metrics

Select

Effects of selenium-containing compounds on Cu2+/Zn2+-induced neuronal cell death and potential application as therapeutic agents for neurological diseases Ken-ichiro Tanaka, Mikako Shimoda, Masahiro Kawahara 2022, 17 (2):  311-312.  doi: 10.4103/1673-5374.317968 Abstract ( 161 )   PDF (912KB) ( 68 )   Save In many tissues, trace metals such as iron (Fe), zinc (Zn), and copper (Cu) are important for various physiological functions such as immune function, cell division, and enzyme function. However, it has been shown in humans and experimental animal models that excessive amounts of these trace metals in the body can induce various diseases in the central nervous system, liver, and respiratory tract. Although the role of zinc in the central nervous system is controversial, with some reports suggesting a protective role, we are interested in the negative effects of excessive amounts of zinc on the central nervous system. Previous studies suggest that zinc, which is released in excessive amounts after ischemic injury, is a major modulator of neuronal death, and that Zn2+-induced neuronal death is an important cause of dementia after ischemic injury (Koh et al., 1996). In addition, other trace metals are present in the brain and/or cerebrospinal fluid, and during neuronal excitation, Cu2+ accumulated in synaptic vesicles is released into the synaptic cleft (Opazo et al., 2014). As the concentrations of these trace metals have been noted to increase, especially under pathological conditions, our research group speculated that these metal-metal interactions may induce neuronal cell death and influence the onset and exacerbation of neurological diseases. Related Articles | Metrics

Select

Improving cell transplantation by understanding and manipulating the phagocytic activity of peripheral glia Lynn Nazareth, James St John, Jenny Ekberg 2022, 17 (2):  313-314.  doi: 10.4103/1673-5374.317969 Abstract ( 153 )   PDF (363KB) ( 100 )   Save One of the key challenges in neuroscience is that the central nervous system (CNS; the brain and spinal cord), is largely unable to regenerate after injury. One factor contributing to this lack of repair is the accumulation of cellular and myelin debris at the site of injury. The debris is not efficiently phagocytosed and can persist for years after the initial injury, resulting in an inflammatory environment which inhibits axonal regrowth (Lutz and Barres, 2014). The main cells responsible for phagocytosis in the CNS are microglia and astrocytes. While both these cells are competent phagocytes, their ability to clear cellular and myelin debris is diminished in CNS pathologies (Lutz and Barres, 2014). In contrast to the CNS, the peripheral nervous system can regenerate unless the injury is complex or large. This is partly due to the ability of peripheral glia to rapidly phagocytose debris after an injury, followed by modulation of inflammation and secretion of growth factors that support axonal growth (Barton et al., 2017). The ability to promote regeneration has led to the use of peripheral glia in transplantation therapies to treat CNS injuries, particularly spinal cord injury. These peripheral glia are (1) Schwann cells, which surround most peripheral nerves and (2) olfactory ensheathing cells (OECs), which are the glia of the olfactory nerve. While these glia share many similarities, there have distinct differences. For example, a comparison of the Schwann cell and OEC transcriptomes showed that OECs express higher levels of factors relating to tissue repair than Schwann cells, including those involved in phagocytosis and degradation (Franssen et al., 2008). Understanding these differences may guide and improve transplantation therapies to repair the CNS. Related Articles | Metrics

Select

Exosome treatment for stroke with diabetic comorbidity Poornima Venkat, Michael Chopp 2022, 17 (2):  315-317.  doi: 10.4103/1673-5374.319190 Abstract ( 139 )   PDF (975KB) ( 99 )   Save Ischemic stroke is a cerebrovascular disease with a high risk of mortality and long-lasting neurological disabilities. Medical advances have resulted in a declining trend in stroke incidence and deaths in the United States. However, increasing age and risk factors such as diabetes have contributed to an increased lifetime risk of stroke. Particularly, there is a dramatic worldwide increase in the incidence of type 2 diabetes mellitus (T2DM) and sustained increase in T2DM prevalence is projected over the next decade. T2DM is a chronic disease which increases the risk of stroke incidence, stroke recurrence and hospital readmission, and stroke related mortality and morbidity. Ischemic stroke patients with diabetes exhibit worse stroke outcome largely derived from metabolic abnormalities, extensive injury to the cerebral vasculature, white matter injury and an amplified inflammatory milieu that hinders recovery. Thus, there is a compelling need for clinical and research effort to mitigate the burden of diabetic-stroke related complications and improve stroke outcome in the diabetic population. Related Articles | Metrics

Select

Neuron-specific enolase in cerebrospinal fluid as a biomarker of brain damage in infants with hypoxic-ischemic encephalopathy  Alfredo Garcia-Alix, Juan Arnaez 2022, 17 (2):  318-319.  doi: 10.4103/1673-5374.317972 Abstract ( 148 )   PDF (587KB) ( 87 )   Save Neonatal encephalopathy resulting from an asphyxial episode occurring perinatally is a major cause of death and of permanent neurological disabilities worldwide. Therapeutic hypothermia (TH) started within 6 hours of life and maintained for 72 hours is now well established as standard treatment for infants with moderate-to-severe hypoxic-ischemic encephalopathy (HIE). Those infants have altered consciousness and other signs of neurological dysfunction. However, nearly half of infants with moderate-to-severe HIE treated with TH still die or survive with disability despite treatment. In addition, the globalization of TH is still pending, especially in low-to-middle income countries where prevalence rates of HIE are particularly high. Related Articles | Metrics

Select

Boosting proteolytic pathways as a treatment against glycation-derived damage in the brain? Allen Taylor, Eloy Bejarano 2022, 17 (2):  320-322.  doi: 10.4103/1673-5374.317971 Abstract ( 139 )   PDF (2339KB) ( 105 )   Save The worldwide adaptation of a Western lifestyle is associated with the increased consumption of high glycemia diets and an increased prevalence of obesity, metabolic syndrome, and diabetes. These diets increase the risk for a plethora of age-related diseases including cerebrovascular, cardiovascular, and eye-related disorders, which all share a common pathogenic factor: the accumulation of advanced glycation end-products (AGEs) (Semba et al., 2010; Aragno and Mastrocola, 2017). AGEs are a diverse group of pathogenic compounds formed via a non-enzymatic process called glycation in which dietary sugars, or reactive dicarbonyls formed during carbohydrate metabolism, are covalently attached to different biomolecules, inactivating them (Rabbani and Thornalley, 2015). A growing literature indicates that AGEs impact brain function and contribute to initiate and accelerate neurodegeneration and also interfere with the process of neuroregeneration (Li et al., 2012; Vicente Miranda et al., 2017; Fleitas et al., 2018; Bao et al., 2020). In order to avoid AGEs-derived toxicity, our cells have different anti-AGEs defense mechanisms including the clearance of these detrimental compounds through different proteolytic pathways. To date, the lysosomal system (autophagy) and the ubiquitin-proteasome system (UPS) have been identified as proteolytic routes able to degrade AGEs. Unfortunately, the proteolytic capacity declines with age, making tissues more vulnerable to AGEs-derived damage (Uchiki et al., 2012; Rowan et al., 2017; Aragonès et al., 2020). AGEs-modification also compromises the proteolytic machinery, leading to double jeopardy due to the higher glycemia diets or diabetes. Boosting proteolytic pathways might represent a therapeutic strategy to counteract the deposition of toxic, glycated, proteinaceous aggregates in the brain and other tissues with limited regeneration capacity, those most vulnerable to glycation-derived damage. Related Articles | Metrics

Select

Emerging roles of NRBF2/PI3KC3 axis in maintaining homeostasis of brain and guts Ming-Yue Wu, Cui-Zan Cai, Chuanbin Yang, Zhenyu Yue, Ye Chen, ZhaoXiang Bian, Min Li, Jia-Hong Lu 2022, 17 (2):  323-324.  doi: 10.4103/1673-5374.317973 Abstract ( 222 )   PDF (354KB) ( 119 )   Save NRBF2 has been identified as the fifth component of PI3KC3 complex and is required for maintaining the kinase activity to promote autophagy. However, the physiological and pathological roles of NRBF2 are largely unknown. In our recent studies, we have revealed that NRBF2 plays an important role in preventing the Alzheimer’s disease (AD) and inflammatory bowel disease (IBD) development, via the mechanisms involving regulating autophagosome maturation and phagosome maturation. The findings expand our understanding towards the physiological role of PI3KC3 complex and provide a potential strategy for AD and IBD treatment by regulating PI3KC3 complex activity.  Related Articles | Metrics

Select

Exploring the Alzheimer’s disease neuroepigenome: recent advances and future trends Haolin Zhang, Felice Elefant 2022, 17 (2):  325-327.  doi: 10.4103/1673-5374.317978 Abstract ( 165 )   PDF (1475KB) ( 144 )   Save Exploring the Alzheimer’s disease neuroepigenome: recent advances and future trends: Alzheimer’s disease (AD) is a chronic neurodegenerative disease and the most common cause of dementia. After decades of ongoing efforts by scientists, many hallmarks of AD, such as amyloid-β (Aβ) and tau pathologies, have finally been understood. But these milestone discoveries still failed to help us find a cure. In recent years, based on advances in genomics, researchers have discovered more than 20 AD-associated alleles. Three of these alleles can cause autosomal dominant AD: amyloid precursor protein and presenilin 1/2 genes. The rest of these alleles can increase the risk to AD, such as the apolipoprotein E gene. These risk loci implicate Aβ, tau, immunity, and lipid processing, which have helped us accurately understand the complex changes in AD patients’ molecular networks. Related Articles | Metrics

Select

Extracellular vesicles drive tau spreading in Alzheimer’s disease Zhi Ruan 2022, 17 (2):  328-329.  doi: 10.4103/1673-5374.317975 Abstract ( 210 )   PDF (394KB) ( 160 )   Save Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder that is characterized by memory loss and a decline in activities of daily life. More than 50 million people worldwide are affected by AD, and this number will continue to rise over 100 million within next three decades. Its major pathological features are the extracellular plaque deposits of the β-amyloid peptide and the intracellular flame-shaped neurofibrillary tangle-aggregation of hyperphosphorylated tau-proteins (pTau). A number of descriptive hypotheses including amyloid hypothesis and tau propagation hypothesis have been proposed to understand the causes of AD (Liu et al., 2019). According to the tau propagation hypothesis, the balance of kinase and phosphatase activity is changed in AD, generating various hyperphosphorylated species of tau. These pTau can bind with each other to produce oligomers, then contributing to the formation of paired helical filaments, the primary content of neurofibrillary tangle (Gendron and Petrucelli, 2009). Based on postmortem findings in AD patients, tau pathobiology was propagated to distinct brain regions in a stereotypical manner, starting from the entorhinal cortex then distributing to the hippocampus and neocortex. However, the mechanisms underlying this spread of pathological tau are still poorly understood.  Related Articles | Metrics

Select

Stem cell-based 3D brain organoids for mimicking, investigating, and challenging Alzheimer’s diseases Federica Cordella, Carlo Brighi, Alessandro Soloperto, Silvia Di Angelantonio 2022, 17 (2):  330-332.  doi: 10.4103/1673-5374.317976 Abstract ( 268 )   PDF (5457KB) ( 202 )   Save Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder that causes a decline of cognitive functions and a deterioration of behavioral and social performances. According to current estimations, AD is considered the prevalent cause of dementia, accounting for 60% and 80% of cases every year. The etiology of the disease is related to both genetic and environmental factors, making AD a cultifactorial disorder, with a major classification as late-onset AD and early-onset AD.  Related Articles | Metrics

Select

Brain insulin resistance: an early risk factor for Alzheimer’s disease development in Down syndrome Eugenio Barone 2022, 17 (2):  333-335.  doi: 10.4103/1673-5374.317979 Abstract ( 211 )   PDF (532KB) ( 83 )   Save Down syndrome (DS) is the most frequent chromosomal abnormality that causes intellectual disability, resulting from the presence of an extra complete or segment of chromosome 21 (HSA21) (Tramutola et al., 2020; Lanzillotta et al., 2021). Every year, approximately 6000 children are born with DS and most of them do not have an autonomous life. Thanks to the advancement in medical care, DS individuals live long and often outlive their parents (Lott and Head, 2019). As a consequence, individuals with DS are now experiencing a high incidence of age-associated health problems, especially Alzheimer’s disease (AD) dementia (Lott and Head, 2019). In particular, by the age of 40 years, virtually all individuals with DS show AD neuropathology (Lott and Head, 2019). The link between AD and DS is thought to be mainly related to the triplication of the amyloid precursor gene (APP), which is encoded on HSA21. However, trisomy of HSA21 results in increased gene dosage for other genes in addition to APP, which may also be involved in AD development. These include superoxide dismutase 1, which is involved in redox metabolism; adenosine triphosphate (ATP)-binding cassette sub-family G member 1, which is involved in cholesterol metabolism; cystatin B, beta-secretase 2, and synaptojanin 1 involved in beta-amyloid (Aβ) processing and clearance; the dual-specificity tyrosine phosphorylation-regulated kinase-1A, which is involved in Tau phosphorylation; regulator of calcineurin, which is involved in mitochondrial dysfunction; S100B involved in inflammatory responses (Lott and Head, 2019).  Related Articles | Metrics

Select

Emerging small-molecule therapeutic approaches for Alzheimer’s disease and Parkinson’s disease based on targeting microRNAs Somaya A. Abdelrahman, Moustafa T. Gabr 2022, 17 (2):  336-337.  doi: 10.4103/1673-5374.317977 Abstract ( 239 )   PDF (401KB) ( 118 )   Save The role of microRNAs in the progression of neurodegenerative diseases: MicroRNAs (miRNAs) are endogenous, non-coding and short RNA nucleotides that regulate gene expression through base pairing with the targeted messenger RNA (mRNA) at the 3′untranslated region (3′ UTR). Thus, miRNAs play fundamental role in the inhibition or degradation of messenger RNAs (Gebert and MacRae, 2019). Two ribonuclease (RNase) III enzymes control the biogenesis of miRNAs; Drosha and Dicer. The first step in the biogenesis includes the cleavage of primary miRNAs (pri-miRNAs) in cell nucleus by Drosha, which leads to the formation of short stem-loop pre-miRNAs. Subsequently, these pre-miRNAs are transported to the cytoplasm and further processed by Dicer resulting in mature miRNAs (O’Brien et al., 2018).   Related Articles | Metrics

Select

Transneuronal delivery of designer cytokines: perspectives for spinal cord injury Daniel Terheyden-Keighley, Marco Leibinger, Dietmar Fischer 2022, 17 (2):  338-340.  doi: 10.4103/1673-5374.317974 Abstract ( 138 )   PDF (668KB) ( 77 )   Save We recently achieved significant functional recovery after a complete spinal cord injury, allowing previously paralyzed mice to walk again. This was accomplished by a single, unilateral application of an adeno-associated virus (AAV) carrying the cDNA for the designer cytokine hyper-interleukin-6 (hIL-6) into the sensorimotor cortex after spinal cord injury. This treatment resulted in the transneuronal delivery of the designer cytokine to neurons in  subcortical locomotor centers, axon regeneration of cortical- and serotonergic neurons across the lesion site, and functional recovery of hindlimb stepping. Here we briefly cover the historical context, current implications, and future perspectives surrounding this new achievement.  Related Articles | Metrics

Select

A Drosophila perspective on retina functions and dysfunctions Elisabetta Catalani, Federica Silvestri, Davide Cervia 2022, 17 (2):  341-343.  doi: 10.4103/1673-5374.317980 Abstract ( 338 )   PDF (1531KB) ( 146 )   Save Due to the high degree of conservation of genes and mechanisms, the fruit fly Drosophila melanogaster is a powerful experimental in vivo tool to investigate complex diseases, thus complementing traditional vertebrate systems. Drosophila is also an advantageous system regarding the animal husbandry and the short generation time and lifespan. The growing interest in flies includes the establishment of easily manageable models to study visual degeneration which occur in humans (Gaspar et al., 2019). Related Articles | Metrics

Select

Association between inflammatory bowel diseases and Parkinson’s disease: systematic review and meta-analysis#br# Yu Zhu, Min Yuan, Yue Liu, Fang Yang, Wen-Zhi Chen, Zhen-Zhen Xu, Zheng-Bing Xiang, Ren-Shi Xu 2022, 17 (2):  344-353.  doi: 10.4103/1673-5374.317981 Abstract ( 306 )   PDF (932KB) ( 220 )   Save Growing evidence suggests that there are similar pathological mechanisms and closely related pathogenic risk factors for inflammatory bowel disease (IBD) and Parkinson’s disease (PD). However, the epidemiological features of these two diseases are different. This review systematically evaluated the relationship between inflammatory bowel diseases and Parkinson’s disease risk. We searched PubMed, Embase, and Cochrane databases to retrieve observational studies of IBD and PD published from inception to October 2019. Nine observational studies, involving 12,177,520 patients, were included in the final analysis. None of the studies had Newcastle–Ottawa Scale scores that suggested a high risk of bias. After adjusting for confounders and excluding heterogeneous studies, the overall risk of PD was significantly higher in IBD patients than in the general population (adjusted risk ratio [RR] = 1.24, 95% confidence interval [CI]: 1.15–1.34, P < 0.001). A meta-analysis of the temporal relationship revealed that the incidence of IBD was significantly increased before (adjusted hazard ratio [HR] = 1.26, 95% CI: 1.18–1.35, P < 0.001) and after (adjusted RR = 1.40, 95% CI: 1.20–1.80, P < 0.001) PD diagnosis. After excluding a heterogeneous study, the pooled risk of PD development in patients with ulcerative colitis (adjusted HR = 1.25, 95% CI: 1.13–1.38, P < 0.001) or Crohn’s disease (adjusted HR = 1.33, 95% CI: 1.21–1.45, P < 0.01) was significantly increased. Subgroup analysis revealed no significant differences in risk between men (adjusted HR = 1.23, 95% CI: 1.10–1.39) and women (adjusted HR = 1.26, 95% CI: 1.10–1.43); however, older (> 65 years old) IBD patients (adjusted HR = 1.32, 95% CI: 1.17–1.48) may have a higher risk than younger (≤ 65 years old) patients (adjusted HR = 1.24, 95% CI: 1.08–1.42). Patients with IBD who were not treated with anti-tumor necrosis factor-α or azathioprine had significantly higher PD risk (adjusted HR = 1.6, 95% CI: 1.2–2.2). Thus, our meta-analysis indicates a certain correlation between IBD and PD, and suggests that IBD may moderately increase PD risk regardless of sex, especially in patients over 65 years of age. Moreover, early anti-inflammatory therapies for IBD might reduce the risk of developing PD. Our findings suggest an urgent need for an individualized screening strategy for patients with IBD. However, most studies included in this paper were observational, and more randomized controlled trials are needed to confirm the precise association between IBD and PD. Related Articles | Metrics

Select

Pre-clinical study of human umbilical cord mesenchymal stem cell transplantation for the treatment of traumatic brain injury: safety evaluation from immunogenic and oncogenic perspectives Gang Wang, Hua-Ling Wu, Yue-Ping Liu, De-Qi Yan, Zi-Lin Yuan, Li Chen, Qian Yang, Yu-Song Gao, Bo Diao 2022, 17 (2):  354-361.  doi: 10.4103/1673-5374.317985 Abstract ( 187 )   PDF (11186KB) ( 81 )   Save Stem cell therapy is a promising strategy for the treatment of traumatic brain injury (TBI). However, animal experiments are needed to evaluate safety; in particular, to examine the immunogenicity and tumorigenicity of human umbilical cord mesenchymal stem cells (huMSCs) before clinical application. In this study, huMSCs were harvested from human amniotic membrane and umbilical cord vascular tissue. A rat model of TBI was established using the controlled cortical impact method. Starting from the third day after injury, the rats were injected with 10 μL of 5 × 106/mL huMSCs by cerebral stereotaxis or with 500 μL of 1 × 106/mL huMSCs via the tail vein for 3 successive days. huMSC transplantation decreased the serum levels of proinflammatory cytokines in rats with TBI and increased the serum levels of anti-inflammatory cytokines, thereby exhibiting good immunoregulatory function. The transplanted huMSCs were distributed in the liver, lung and brain injury sites. No abnormal proliferation or tumorigenesis was found in these organs up to 12 months after transplantation. The transplanted huMSCs negligibly proliferated in vivo, and apoptosis was gradually observed at later stages. These findings suggest that huMSC transplantation for the treatment of traumatic brain injury displays good safety. In addition, huMSCs exhibit good immunoregulatory function, which can help prevent and reduce secondary brain injury caused by the rapid release of inflammatory factors after TBI. This study was approved by the Ethics Committee of Wuhan General Hospital of PLA (approval No. 20160054) on November 1, 2016. Related Articles | Metrics

Select

Downregulation of EphB2 by RNA interference attenuates glial/fibrotic scar formation and promotes axon growth Jian Wu, Zhen-Yu Zhu, Zhi-Wei Fan, Ying Chen, Ri-Yun Yang, Yi Li 2022, 17 (2):  362-369.  doi: 10.4103/1673-5374.317988 Abstract ( 166 )   PDF (10254KB) ( 65 )   Save The rapid formation of a glial/fibrotic scar is one of the main factors hampering axon growth after spinal cord injury. The bidirectional EphB2/ephrin-B2 signaling of the fibroblast-astrocyte contact-dependent interaction is a trigger for glial/fibrotic scar formation. In the present study, a new in vitro model was produced by coculture of fibroblasts and astrocytes wounded by scratching to mimic glial/fibrotic scar-like structures using an improved slide system. After treatment with RNAi to downregulate EphB2, changes in glial/fibrotic scar formation and the growth of VSC4.1 motoneuron axons were examined. Following RNAi treatment, fibroblasts and astrocytes dispersed without forming a glial/fibrotic scar-like structure. Furthermore, the expression levels of neurocan, NG2 and collagen I in the coculture were reduced, and the growth of VSC4.1 motoneuron axons was enhanced. These findings suggest that suppression of EphB2 expression by RNAi attenuates the formation of a glial/fibrotic scar and promotes axon growth. This study was approved by the Laboratory Animal Ethics Committee of Jiangsu Province, China (approval No. 2019-0506-002) on May 6, 2019. Related Articles | Metrics

Select

High-frequency spinal cord stimulation produces long-lasting analgesic effects by restoring lysosomal function and autophagic flux in the spinal dorsal horn Zhi-Bin Wang, Yong-Da Liu, Shuo Wang, Ping Zhao 2022, 17 (2):  370-377.  doi: 10.4103/1673-5374.317989 Abstract ( 160 )   PDF (3579KB) ( 99 )   Save High-frequency spinal cord stimulation (HF-SCS) has been established as an effective therapy for neuropathic pain. However, the analgesic mechanisms involved in HF-SCS remain to be clarified. In our study, adult rat neuropathic pain was induced by spinal nerve ligation. Two days after modeling, the rats were subjected to 4 hours of HF-SCS (motor threshold 50%, frequency 10,000 Hz, and pulse width 0.024 ms) in the dorsal horn of the spinal cord. The results revealed that the tactile allodynia of spinal nerve-injured rats was markedly alleviated by HF-SCS, and the effects were sustained for 3 hours after the stimulation had ceased. HF-SCS restored lysosomal function, increased the levels of lysosome-associated membrane protein 2 (LAMP2) and the mature form of cathepsin D (matu-CTSD), and alleviated the abnormally elevated levels of microtubule-associated protein 1A/B-light chain 3 (LC3)-II and sequestosome 1 (P62) in spinal nerve-injured rats. HF-SCS also mostly restored the immunoreactivity of LAMP2, which was localized in neurons in the superficial layers of the spinal dorsal horn in spinal nerve-injured rats. In addition, intraperitoneal administration of 15 mg/kg chloroquine for 60 minutes reversed the expression of the aforementioned proteins and shortened the timing of the analgesic effects of HF-SCS. These findings suggest that HF-SCS may exhibit long-lasting analgesic effects on neuropathic pain in rats through improving lysosomal dysfunction and alleviating autophagic flux. This study was approved by the Laboratory Animal Ethics Committee of China Medical University, Shenyang, China (approval No. 2017PS196K) on March 1, 2017. Related Articles | Metrics

Select

Rapid GFAP and Iba1 expression changes in the female rat brain following spinal cord injury Mawj Mandwie, Jordan A. Piper, Catherine A. Gorrie, Kevin A. Keay, Giuseppe Musumeci, Ghaith Al-Badri, Alessandro Castorina 2022, 17 (2):  378-385.  doi: 10.4103/1673-5374.317982 Abstract ( 258 )   PDF (1490KB) ( 137 )   Save Evidence suggests that rapid changes to supporting glia may predispose individuals with spinal cord injury (SCI) to such comorbidities. Here, we interrogated the expression of astrocyte- and microglial-specific markers glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) in the rat brain in the first 24 hours following SCI. Female Sprague-Dawley rats underwent thoracic laminectomy; half of the rats received a mild contusion injury at the level of the T10 vertebral body (SCI group), the other half did not (Sham group). Twenty-four hours post-surgery the amygdala, periaqueductal grey, prefrontal cortex, hypothalamus, lateral thalamus, hippocampus (dorsal and ventral) in rats were collected. GFAP and Iba1 mRNA and protein levels were measured by real-time quantitative polymerase chain reaction and Western blot. In SCI rats, GFAP mRNA and protein expression increased in the amygdala and hypothalamus. In contrast, gene and protein expression decreased in the thalamus and dorsal hippocampus. Interestingly, Iba1 transcripts and proteins were significantly diminished only in the dorsal and ventral hippocampus, where gene expression diminished. These findings demonstrate that as early as 24 hours post-SCI there are region-specific disruptions of GFAP and Iba1 transcript and protein levels in higher brain regions. All procedures were approved by the University of Technology Sydney Institutional Animal Care and Ethics Committee (UTS ACEC13-0069). Related Articles | Metrics

Select

Genome-wide interrogation of transfer RNA-derived small RNAs in a mouse model of traumatic brain injury Xiao-Jian Xu, Meng-Shi Yang, Bin Zhang, Qian-Qian Ge, Fei Niu, Jin-Qian Dong, Yuan Zhuang, Bai-Yun Liu 2022, 17 (2):  386-394.  doi: 10.4103/1673-5374.314315 Abstract ( 182 )   PDF (2654KB) ( 190 )   Save Transfer RNA (tRNA)-derived small RNAs (tsRNAs) are a recently established family of regulatory small non-coding RNAs that modulate diverse biological processes. Growing evidence indicates that tsRNAs are involved in neurological disorders and play a role in the pathogenesis of neurodegenerative disease. However, whether tsRNAs are involved in traumatic brain injury-induced secondary injury remains poorly understood. In this study, a mouse controlled cortical impact model of traumatic brain injury was established, and integrated tsRNA and messenger RNA (mRNA) transcriptome sequencing were used. The results revealed that 103 tsRNAs were differentially expressed in the mouse model of traumatic brain injury at 72 hours, of which 56 tsRNAs were upregulated and 47 tsRNAs were downregulated. Based on microRNA-like seed matching and Pearson correlation analysis, 57 differentially expressed tsRNA-mRNA interaction pairs were identified, including 29 tsRNAs and 26 mRNAs. Moreover, Gene Ontology annotation of target genes revealed that the significantly enriched terms were primarily associated with inflammation and synaptic function. Collectively, our findings suggest that tsRNAs may be associated with traumatic brain injury-induced secondary brain injury, and are thus a potential therapeutic target for traumatic brain injury. The study was approved by the Beijing Neurosurgical Institute Animal Care and Use Committee (approval No. 20190411) on April 11, 2019. Related Articles | Metrics

Select

Hypoxic preconditioning reduces NLRP3 inflammasome expression and protects against cerebral ischemia/reperfusion injury Yi-Qiang Pang, Jing Yang, Chun-Mei Jia, Rui Zhang, Qi Pang 2022, 17 (2):  395-400.  doi: 10.4103/1673-5374.314317 Abstract ( 166 )   PDF (2467KB) ( 161 )   Save Hypoxic preconditioning can protect against cerebral ischemia/reperfusion injury. However, the underlying mechanisms that mediate this effect are not completely clear. In this study, mice were pretreated with continuous, intermittent hypoxic preconditioning; 1 hour later, cerebral ischemia/reperfusion models were generated by middle cerebral artery occlusion and reperfusion. Compared with control mice, mice with cerebral ischemia/reperfusion injury showed increased Bederson neurological function scores, significantly increased cerebral infarction volume, obvious pathological damage to the hippocampus, significantly increased apoptosis; upregulated interleukin-1β, interleukin-6, and interleukin-8 levels in brain tissue; and increased expression levels of NOD-like receptor family pyrin domain containing 3 (NLRP3), NLRP inflammasome-related protein caspase-1, and gasdermin D. However, hypoxic preconditioning significantly inhibited the above phenomena. Taken together, these data suggest that hypoxic preconditioning mitigates cerebral ischemia/reperfusion injury in mice by reducing NLRP3 inflammasome expression. This study was approved by the Medical Ethics Committee of the Fourth Hospital of Baotou, China (approval No. DWLL2019001) in November 2019. Related Articles | Metrics

Select

miR-103-3p targets Ndel1 to regulate neural stem cell proliferation and differentiation Wen Li, Shan-Shan Wang, Bo-Quan Shan, Jian-Bing Qin, He-Yan Zhao, Mei-Ling Tian, Hui He, Xiang Cheng, Xin-Hua Zhang, Guo-Hua Jin 2022, 17 (2):  401-408.  doi: 10.4103/1673-5374.317987 Abstract ( 154 )   PDF (9622KB) ( 51 )   Save The regulation of adult neural stem cells (NSCs) is critical for lifelong neurogenesis. MicroRNAs (miRNAs) are a type of small, endogenous RNAs that regulate gene expression post-transcriptionally and influence signaling networks responsible for several cellular processes. In this study, miR-103-3p was transfected into neural stem cells derived from embryonic hippocampal neural stem cells. The results showed that miR-103-3p suppressed neural stem cell proliferation and differentiation, and promoted apoptosis. In addition, miR-103-3p negatively regulated NudE neurodevelopment protein 1-like 1 (Ndel1) expression by binding to the 3′ untranslated region of Ndel1. Transduction of neural stem cells with a lentiviral vector overexpressing Ndel1 significantly increased cell proliferation and differentiation, decreased neural stem cell apoptosis, and decreased protein expression levels of Wnt3a, β-catenin, phosphor-GSK-3β, LEF1, c-myc, c-Jun, and cyclin D1, all members of the Wnt/β-catenin signaling pathway. These findings suggest that Ndel1 is a novel miR-103-3p target and that miR-103-3p acts by suppressing neural stem cell proliferation and promoting apoptosis and differentiation. This study was approved by the Animal Ethics Committee of Nantong University, China (approval No. 20200826-003) on August 26, 2020. Related Articles | Metrics

Select

Hydrogen-rich water ameliorates neuropathological impairments in a mouse model of Alzheimer’s disease through reducing neuroinflammation and modulating intestinal microbiota Yi-Tong Lin, Qing-Qing Shi, Lei Zhang, Cai-Ping Yue, Zhi-Jun He, Xue-Xia Li, Qian-Jun He, Qiong Liu, Xiu-Bo Du 2022, 17 (2):  409-417.  doi: 10.4103/1673-5374.317992 Abstract ( 210 )   PDF (1455KB) ( 186 )   Save Hydrogen exhibits the potential to treat Alzheimer’s disease. Stereotactic injection has been previously used as an invasive method of administering active hydrogen, but this method has limitations in clinical practice. In this study, triple transgenic (3×Tg) Alzheimer’s disease mice were treated with hydrogen-rich water for 7 months. The results showed that hydrogen-rich water prevented synaptic loss and neuronal death, inhibited senile plaques, and reduced hyperphosphorylated tau and neurofibrillary tangles in 3×Tg Alzheimer’s disease mice. In addition, hydrogen-rich water improved brain energy metabolism disorders and intestinal flora imbalances and reduced inflammatory reactions. These findings suggest that hydrogen-rich water is an effective hydrogen donor that can treat Alzheimer’s disease. This study was approved by the Animal Ethics and Welfare Committee of Shenzhen University, China (approval No. AEWC-20140615-002) on June 15, 2014. Related Articles | Metrics

Select

Brain functional remodeling caused by sciatic nerve transposition repair in rats identified by multiple-model resting-state blood oxygenation level-dependent functional magnetic resonance imaging analysis Yu-Song Yuan, Hai-Lin Xu, Zhong-Di Liu, Yu-Hui Kou, Bo Jin, Pei-Xun Zhang 2022, 17 (2):  418-426.  doi: 10.4103/1673-5374.317991 Abstract ( 130 )   PDF (5887KB) ( 128 )   Save Lower extremity nerve transposition repair has become an important treatment strategy for peripheral nerve injury; however, brain changes caused by this surgical procedure remain unclear. In this study, the distal stump of the right sciatic nerve in a rat model of sciatic nerve injury was connected to the proximal end of the left sciatic nerve using a chitin conduit. Neuroelectrophysiological test showed that the right lower limb displayed nerve conduction, and the structure of myelinated nerve fibers recovered greatly. Muscle wet weight of the anterior tibialis and gastrocnemius recovered as well. Multiple-model resting-state blood oxygenation level-dependent functional magnetic resonance imaging analysis revealed functional remodeling in multiple brain regions and the re-establishment of motor and sensory functions through a new reflex arc. These findings suggest that sciatic nerve transposition repair induces brain functional remodeling. The study was approved by the Ethics Committee of Peking University People’s Hospital on December 9, 2015 (approval No. 2015-50). Related Articles | Metrics

Select

Neurorehabilitation using a voluntary driven exoskeletal robot improves trunk function in patients with chronic spinal cord injury: a single-arm study Hiroki Okawara, Syoichi Tashiro, Tomonori Sawada, Keiko Sugai, Kohei Matsubayashi, Michiyuki Kawakami, Satoshi Nori, Osahiko Tsuji, Narihito Nagoshi, Morio Matsumoto, Masaya Nakamura 2022, 17 (2):  427-432.  doi: 10.4103/1673-5374.317983 Abstract ( 181 )   PDF (1019KB) ( 190 )   Save Body weight-supported treadmill training with the voluntary driven exoskeleton (VDE-BWSTT) has been shown to improve the gait function of patients with chronic spinal cord injury. However, little is known whether VDE-BWSTT can effectively improve the trunk function of patients with chronic spinal cord injury. In this open-label, single-arm study, nine patients with chronic spinal cord injury at the cervical or thoracic level (six males and three females, aged 37.8 ± 15.6 years, and time since injury 51.1 ± 31.8 months) who underwent outpatient VDE-BWSTT training program at Keio University Hospital, Japan from September 2017 to March 2019 were included. All patients underwent twenty 60-minute gait training sessions using VDE. Trunk muscular strength, i.e., the maximum force against which patient could maintain a sitting posture without any support, was evaluated in four directions: anterior, posterior, and lateral (right and left) after 10 and 20 training sessions. After intervention, lateral muscular strength significantly improved. In addition, a significant positive correlation was detected between the change in lateral trunk muscular strength after 20 training sessions relative to baseline and gait speed. The change in trunk muscular strength after 20 training sessions relative to baseline was greatly correlated with patient age. This suggests that older adult patients with chronic spinal cord injury achieved a greater improvement in trunk muscle strength following VDE-BWSTT. All these findings suggest that VDE-BWSTT can improve the trunk function of patients with chronic spinal cord injury and the effect might be greater in older adult patients. The study was approved by the Keio University of Medicine Ethics Committee (IRB No. 20150355-3) on September 26, 2017. Related Articles | Metrics

Select

Inhibition of microRNA-29b suppresses oxidative stress and reduces apoptosis in ischemic stroke Yao-Hua Ma, Wen-Jing Deng, Zhi-Yi Luo, Jing Jing, Peng-Wei Pan, Yao-Bing Yao, Yan-Bo Fang, Jun-Fang Teng 2022, 17 (2):  433-439.  doi: 10.4103/1673-5374.314319 Abstract ( 186 )   PDF (1651KB) ( 182 )   Save MicroRNAs (miRNAs) regulate protein expression by antagonizing the translation of mRNAs and are effective regulators of normal nervous system development, function, and disease. MicroRNA-29b (miR-29b) plays a broad and critical role in brain homeostasis. In this study, we tested the function of miR-29b in animal and cell models by inhibiting miR-29b expression. Mouse models of middle cerebral artery occlusion were established using the modified Zea-Longa suture method. Prior to modeling, 50 nmol/kg miR-29b antagomir was injected via the tail vein. MiR-29b expression was found to be abnormally increased in ischemic brain tissue. The inhibition of miR-29b expression decreased the neurological function score and reduced the cerebral infarction volume and cell apoptosis. In addition, the inhibition of miR-29b significantly decreased the malondialdehyde level, increased superoxide dismutase activity, and Bcl-2 expression, and inhibited Bax and Caspase3 expression. PC12 cells were treated with glutamate for 12 hours to establish in vitro cell models of ischemic stroke and then treated with the miR-29 antagomir for 48 hours. The results revealed that miR-29b inhibition in PC12 cells increased Bcl-2 expression and inhibited cell apoptosis and oxidative damage. These findings suggest that the inhibition of miR-29b inhibits oxidative stress and cell apoptosis in ischemic stroke, producing therapeutic effects in ischemic stroke. This study was approved by the Laboratory Animal Care and Use Committee of the First Affiliated Hospital of Zhengzhou University (approval No. 201709276S) on September 27, 2017. Related Articles | Metrics

Select

Gene and protein expression profiles of olfactory ensheathing cells from olfactory bulb versus olfactory mucosa  Yuan-Xiang Lan, Ping Yang, Zhong Zeng, Neeraj Yadav, Li-Jian Zhang, Li-Bin Wang, He-Chun Xia 2022, 17 (2):  440-449.  doi: 10.4103/1673-5374.317986 Abstract ( 131 )   PDF (4289KB) ( 164 )   Save Olfactory ensheathing cells (OECs) from the olfactory bulb (OB) and the olfactory mucosa (OM) have the capacity to repair nerve injury. However, the difference in the therapeutic effect between OB-derived OECs and OM-derived OECs remains unclear. In this study, we extracted OECs from OB and OM and compared the gene and protein expression profiles of the cells using transcriptomics and non-quantitative proteomics techniques. The results revealed that both OB-derived OECs and OM-derived OECs highly expressed genes and proteins that regulate cell growth, proliferation, apoptosis and vascular endothelial cell regeneration. The differentially expressed genes and proteins of OB-derived OECs play a key role in regulation of nerve regeneration and axon regeneration and extension, transmission of nerve impulses and response to axon injury. The differentially expressed genes and proteins of OM-derived OECs mainly participate in the positive regulation of inflammatory response, defense response, cytokine binding, cell migration and wound healing. These findings suggest that differentially expressed genes and proteins may explain why OB-derived OECs and OM-derived OECs exhibit different therapeutic roles. This study was approved by the Animal Ethics Committee of the General Hospital of Ningxia Medical University (approval No. 2017-073) on February 13, 2017. Related Articles | Metrics

Select

Pramipexole, a dopamine D3/D2 receptor-preferring agonist, attenuates reserpine-induced fibromyalgia-like model in mice Carlos Pereira Martins, Rodrigo Sebben Paes, Gabriela Mantovani Baldasso, Eduarda Gomes Ferrarini, Rahisa Scussel, Rubya Pereira Zaccaron, Ricardo Andrez Machado-de-Ávila, Paulo Cesar Lock Silveira, Rafael Cypriano Dutra 2022, 17 (2):  450-458.  doi: 10.4103/1673-5374.317984 Abstract ( 248 )   PDF (1689KB) ( 532 )   Save Fibromyalgia (FM) is a complex pathology described as persistent hyperalgesia including somatic and mood dysfunctions, depression and anxiety. Although the etiology of FM is still unknown, a significant decrease in biogenic amines is a common characteristic in its pathogenesis. Here, our main objective was to investigate the role of dopamine D3/D2 receptor during the reserpine-induced pain in mice. Our results showed that pramipexole (PPX) – a dopaminergic D3/D2 receptor agonist – inhibited mechanical allodynia and thermal sensitivity induced by reserpine. Relevantly, PPX treatment decreased immobility time and increased the number of grooming in the forced swimming test and splash test, respectively. Animals that received PPX remained longer in the open arms than the reserpine group using elevated plus-maze apparatus. The repeated PPX administration, given daily for 4 days, significantly blocked the mechanical and thermal allodynia during FM model, similarly to pregabalin, although it failed to affect the reserpine-induced thermal nociception. Reserpine administration induced significant downregulation of dopamine concentration in the central nervous system, and repeated treatment with PPX restored dopamine levels in the frontal cortex and spinal cord tissues. Moreover, PPX treatment inhibited oxidants production such as DCFH (2′,7′-dichlorodihydrofluorescein) and nitrite, also decreased oxidative damage (carbonyl), and upregulated the activity of superoxide dismutase in the spinal cord. Together, our findings demonstrated the ability of dopamine D3/D2 receptor-preferring agonist in reducing pain and mood dysfunction allied to FM in mice. All experimental protocols were approved by the Universidade Federal de Santa Catarina (UFSC) Ethics Committee (approval No. 2572210218) on May 10, 2018. Related Articles | Metrics

Select

Effects of delayed repair of peripheral nerve injury on the spatial distribution of motor endplates in target muscle Dong-Dong Li, Jin Deng, Bo Jin, Shuai Han, Xin-Yi Gu, Xue-Feng Zhou, Xiao-Feng Yin 2022, 17 (2):  459-464.  doi: 10.4103/1673-5374.317990 Abstract ( 166 )   PDF (2007KB) ( 77 )   Save Motor endplates (MEPs) are important sites of information exchange between motor neurons and skeletal muscle, and are distributed in an organized pattern of lamellae in the muscle. Delayed repair of peripheral nerve injury typically results in unsatisfactory functional recovery because of MEP degeneration. In this study, the mouse tibial nerve was transected and repaired with a biodegradable chitin conduit, immediately following or 1 or 3 months after the injury. Fluorescent α-bungarotoxin was injected to label MEPs. Tissue optical clearing combined with light-sheet microscopy revealed that MEPs were distributed in an organized pattern of lamellae in skeletal muscle after delayed repair for 1 and 3 months. However, the total number of MEPs, the number of MEPs per lamellar cluster, and the maturation of single MEPs in gastrocnemius muscle gradually decreased with increasing denervation time. These findings suggest that delayed repair can restore the spatial distribution of MEPs, but it has an adverse effect on the homogeneity of MEPs in the lamellar clusters and the total number of MEPs in the target muscle. The study procedures were approved by the Animal Ethics Committee of the Peking University People’s Hospital (approval No. 2019PHC015) on April 8, 2019. Related Articles | Metrics