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    15 May 2018, Volume 13 Issue 5 Previous Issue    Next Issue
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    The role of undifferentiated adipose-derived stem cells in peripheral nerve repair
    Rui Zhang, Joseph M. Rosen
    2018, 13 (5):  757-763.  doi: 10.4103/1673-5374.232457
    Abstract ( 120 )   PDF (427KB) ( 308 )   Save

    Peripheral nerve injuries impose significant health and economic consequences, yet no surgical repair can deliver a complete recovery of sensory or motor function. Traditional methods of repair are less than ideal: direct coaptation can only be performed when tension-free repair is possible, and transplantation of nerve autograft can cause donor-site morbidity and neuroma formation. Cell-based therapy delivered via nerve conduits has thus been explored as an alternative method of nerve repair in recent years. Stem cells are promising sources of the regenerative core material in a nerve conduit because stem cells are multipotent in function, abundant in supply, and more accessible than the myelinating Schwann cells. Among different types of stem cells, undifferentiated adipose-derived stem cell (uASC), which can be processed from adipose tissue in less than two hours, is a promising yet underexplored cell type. Studies of uASC have emerged in the past decade and have shown that autologous uASCs are non-immunogenic, easy to access, abundant in supply, and efficacious at promoting nerve regeneration. Two theories have been proposed as the primary regenerative mechanisms of uASC: in situ trans-differentiation towards Schwann cells, and secretion of trophic and anti-inflammatory factors. Future studies need to fully elucidate the mechanisms, side effects, and efficacy of uASC-based nerve regeneration so that uASCs can be utilized in clinical settings.

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    An update–tissue engineered nerve grafts for the repair of peripheral nerve injuries
    Nitesh P. Patel, Kristopher A. Lyon, Jason H. Huang
    2018, 13 (5):  764-774.  doi: 10.4103/1673-5374.232458
    Abstract ( 114 )   PDF (267KB) ( 262 )   Save

    Peripheral nerve injuries (PNI) are caused by a range of etiologies and result in a broad spectrum of disability. While nerve autografts are the current gold standard for the reconstruction of extensive nerve damage, the limited supply of autologous nerve and complications associated with harvesting nerve from a second surgical site has driven groups from multiple disciplines, including biomedical engineering, neurosurgery, plastic surgery, and orthopedic surgery, to develop a suitable or superior alternative to autografting. Over the last couple of decades, various types of scaffolds, such as acellular nerve grafts (ANGs), nerve guidance conduits, and non-nervous tissues, have been filled with Schwann cells, stem cells, and/or neurotrophic factors to develop tissue engineered nerve grafts (TENGs). Although these have shown promising effects on peripheral nerve regeneration in experimental models, the autograft has remained the gold standard for large nerve gaps. This review provides a discussion of recent advances in the development of TENGs and their efficacy in experimental models. Specifically, TENGs have been enhanced via incorporation of genetically engineered cells, methods to improve stem cell survival and differentiation, optimized delivery of neurotrophic factors via drug delivery systems (DDS), co-administration of platelet-rich plasma (PRP), and pretreatment with chondroitinase ABC (Ch-ABC). Other notable advancements include conduits that have been bioengineered to mimic native nerve structure via cell-derived extracellular matrix (ECM) deposition, and the development of transplantable living nervous tissue constructs from rat and human dorsal root ganglia (DRG) neurons. Grafts composed of non-nervous tissues, such as vein, artery, and muscle, will be briefly discussed.

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    Sigma-1 receptor: a new player in neuroprotection against chemotherapy-induced peripheral neuropathy
    Jordi Bruna, Roser Velasco
    2018, 13 (5):  775-778.  doi: 10.4103/1673-5374.232459
    Abstract ( 123 )   PDF (147KB) ( 287 )   Save

     

    Chemotherapy-induced peripheral neuropathy is a very frequent neurological complication in cancer. Oxaliplatin (OXA) is a platinum analogue used as a first-line agent in the treatment of colorectal cancer. OXA induced peripheral neuropathy (OIN) is the main toxicity both during and after the completion of chemotherapy that presents as two distinct syndromes: acute and chronic neuropathy. None of the neuroprotective agents previously tested had prevented or limited the acute and/or chronic OIN. MR309 (previously developed as E-52862) is a novel selective sigma-1 receptor (S1R) antagonist with preclinical analgesic activity in OXA-induced neuropathic pain in animal models. This review analyzes the results of the recently published phase II, randomized, double-blind, placebo-controlled clinical trial including 124 patients with colorectal cancer (CRC) treated with MR309. This study shows encouraging findings in the setting of neuroprotection against OIN with an acceptable safety profile. The study demonstrated MR309 usefulness in decreasing acute OIN, by reducing cold hypersensitivity experienced by patients, and pointed to the amelioration of chronic OIN by lowering the proportion of patients who developed severe chronic OIN. In addition, we provide a summary and discussion on the pathways that can be modulated by the S1R to explain the observed clinical benefits in the OIN.
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    Nerve conduction models in myelinated and unmyelinated nerves based on three-dimensional electrostatic interaction
    Tetsuya Akaishi
    2018, 13 (5):  779-785.  doi: 10.4103/1673-5374.232460
    Abstract ( 109 )   PDF (1319KB) ( 395 )   Save

    Until now, nerve conduction has been described on the basis of equivalent circuit model and cable theory, both of which supposed closed electric circuits spreading inside and outside the axoplasm. With these conventional models, we can simulate the propagating pattern of action potential along the axonal membrane based on Ohm’s law and Kirchhoff’s law. However, we could not fully explain the different conductive patterns in unmyelinated and myelinated nerves with these theories. Also, whether we can really suppose closed electrical circuits in the actual site of the nerves or not has not been fully discussed yet. In this report, a recently introduced new theoretical model of nerve conduction based on electrostatic molecular interactions within the axoplasm will be reviewed. With this new approach, we can explain the different conductive patterns in unmyelinated and myelinated nerves. This new mathematical conductive model based on electrostatic compressional wave in the intracellular fluid may also be able to explain the signal integration in the neuronal cell body and the back-propagation mechanism from the axons to the dendrites. With this new mathematical nerve conduction model based on electrostatic molecular interactions within the intracellular fluid, we may be able to achieve an integrated explanation for the physiological phenomena taking place in the nervous system.

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    Fatigability during volitional walking in incomplete spinal cord injury: cardiorespiratory and motor performance considerations
    Jared M. Gollie
    2018, 13 (5):  786-790.  doi: 10.4103/1673-5374.232461
    Abstract ( 128 )   PDF (365KB) ( 327 )   Save

    Fatigability describes the decline in force production (i.e., performance fatigability) and/or changes in sensations regulating performance (i.e., perceived fatigability) during whole-body activity and poses a major challenge to those living with spinal cord injuries (SCI). After SCI, the inability to overcome disruptions to metabolic homeostasis due to cardiorespiratory limitations and physical deconditioning may contribute to increase α fatigability severity. The increased susceptibility to fatigability may have implications for motor control strategies and motor learning. Locomotor training approaches designed to reduce fatigability and enhance aerobic capacity in combination with motor learning may be advantageous for promoting functional recovery after SCI. Future research is required to advance the understanding of the relationship between fatigability, cardiorespiratory function and motor performance following SCI.

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    Retinoid receptor-related orphan receptor alpha: a key gene setting brain circuits
    Tania Vitalis, Jean Mariani
    2018, 13 (5):  791-794.  doi: 10.4103/1673-5374.232462
    Abstract ( 129 )   PDF (773KB) ( 293 )   Save

     

    The retinoid receptor-related orphan receptor alpha (RORα) is thought to act as a constitutive activator of transcription by binding to the ROR response element (RORE) of target genes. Several mouse models in which RORα is defective have revealed the decisive roles of RORα on the development, maturation and neuroprotection of various cerebral regions including the cerebellar and somatosensory systems. We have recently shown that RORα is needed for accurate thalamic sensory system organization and somatosensory cortex development. The phenotype of various RORα deficient mice models (staggerer mutant or mouse lacking RORα in specific somatosensory regions) is, in part, reminiscent of what has been described in mice lacking thyroid hormone triiodothyronine (T3). As in in vitro studies or in other models, our studies strongly suggest that the T3/RORα-pathway, among others, is in part responsible for the staggerer phenotype. We have indeed identified some genes that were both regulated by T3 and RORα and that are known to be implicated in the cerebellar or somatosensory system development. Moreover, several groups have shown that RORα is at the crossroad of many biological processes and pathologies, including psychiatric and degenerative disorders. In particular, defective RORα-signalling has been demonstrated in humans to be associated with the emergence of autistic-like disorders. We believe that determining the appropriate amount of RORα activity could be crucial in detecting and preventing the emergence of specific brain diseases.
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     Semaphorin 3A: from growth cone repellent to promoter of neuronal regeneration
    Bor Luen Tang
    2018, 13 (5):  795-796.  doi: 10.4103/1673-5374.232463
    Abstract ( 156 )   PDF (234KB) ( 274 )   Save

    Semaphorin 3A is a classically known axonal guidance cue that mediates axonal growth cone repulsion and collapse. Recent works, however,suggest that it may have the apparently diametrically opposite activity of promoting neuronal regeneration.

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    Current opinion on a role of the astrocytes in neuroprotection
    Leon Teo, James A. Bourne
    2018, 13 (5):  797-798.  doi: 10.4103/1673-5374.232466
    Abstract ( 150 )   PDF (115KB) ( 312 )   Save

    Central nervous system (CNS) injuries remain a leading cause of functional disabilities worldwide, often resulting in permanent neurological impairments, due to the inability to repair and regenerate damaged connections. A major contributing factor to this loss of regenerative capacity is the formation of glial scar tissue (Cregg et al., 2014), traditionally regarded as a potent mechanical and molecular barrier to repair. The glial scar comprises primarily reactive astrocytes, a subset of NG2 glia, inflammatory cells and extracellular matrix (ECM) glycoproteins – mainly chondroitin sulfate proteoglycans (CSPG; Cregg et al., 2014). The transition of astrocytes into their reactive state, as a consequence of pathological insults to the CNS, including trauma, inflammation and strokes, is characterized by changes in their morphology, gene/protein expression and role.These features are regulated by a host of intrinsic and extrinsic factors that modulate astrocyte reactivity, behaviour, proliferation and ECM secretions, ultimately culminating in the formation of the glial scar (Sofroniew, 2009). While astrogliosis and glial scarring have been well studied, especially in the context of repair inhibition,new evidence has begun to shed light on the previously unspecified neuroprotective role of reactive astrocytes after injury. Therefore,this perspective will discuss the most recent and significant research that has had altered the once held view of the astrocyte being solely inhibitory to repair following CNS injury.

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    Novel function of the chemorepellent draxin as a regulator for hippocampal neurogenesis
    Hiroshi Tawarayama
    2018, 13 (5):  799-800.  doi: 10.4103/1673-5374.232465
    Abstract ( 146 )   PDF (665KB) ( 289 )   Save

    Hippocampal neurogenesis as a therapeutic target for neurological disorders: Mature granule cells are continuously differentiated from neural stem and progenitor cells and integrated into the preexisting neural system in the subgranular zone of the hippocampal dentate gyrus throughout life. Accumulating evidence indicates that these newborn granule cells are essential for the physiological functions of the hippocampus, such as memory formation, learning,regulation of emotions, and stress response. Alterations in hippocampal neurogenesis are observed in patients with cognitive and psychological diseases, such as epilepsy, ischemia, and traumatic brain injury (Yu et al., 2016). This suggests that hippocampal neurogenesis is a potential therapeutic target for the treatment of neurological disorders. To date, various secretory molecules have been identified as regulators of neurogenic processes, including neuronal proliferation, differentiation, and survival, such as morphogens,neurotrophic factors, neurotransmitters, transcription factors, and epigenetic modulators Canonical Wnts, which are a type of morphogen, are well-studied regulators of hippocampal neurogenesis. Canonical Wnt signals are transduced via the LRP  (low-density lipoprotein receptor-related protein) 5/6 and Frizzled receptor complex, followed by the intracellular mediator, β-catenin (MacDonald et al., 2009). Alterations in the Wnt/β-catenin signaling leads to impairments in hippocampal development, and the dysregulation of neuronal proliferation and differentiation of dentate granule cell precursors.

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    Forkhead box protein P1, a key player in neuronal development?
    Luca Braccioli, Cora H. Nijboer, Paul J. Coffer
    2018, 13 (5):  801-802.  doi: 10.4103/1673-5374.232467
    Abstract ( 180 )   PDF (328KB) ( 248 )   Save

    Forkhead box protein P1 (FOXP1) is a transcription factor belonging to the forkhead box (FOX) proteins, a family of transcriptional regulators sharing a highly conserved forkhead DNA-binding domain (Bacon and Rappold, 2012). Previous reports have proposed a role for FOXP1 in functionally regulating the central nervous system (CNS), while mutations in FOXP1 have been implicated in cognitive abnormalities (Bacon and Rappold, 2012). FOXP1 has been shown to promote differentiation of medium spiny neurons and to induce neuronal migration during embryonic neuronal development in the mouse cortex (Li et al., 2015; Precious et al., 2016). Mutations in FOXP1 have been linked to various neurodevelopmental diseases, including autism, intellectual disabilities and speech defects (Hamdan et al., 2010; Horn et al., 2010). Furthermore, Bacon and colleagues demonstrated that Cre-mediated Foxp1 deletion in Nestin-positive cells induces autism-like behavior in mice, and defects in morphology of the striatum upon postnatal development (Bacon et al., 2015). In line with these findings, heterozygous Foxp1+/– mice have been reported to show deficits in vocal communication as well as a deregulation of autism-associated genes in the hippocampus and striatum (Araujo et al.,2015). Taken together, this body of evidence indicates an important role of FOXP1 in regulating CNS development, however the molecular mechanisms underlying neuronal FOXP1 function have remained unclear.

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    When and how does brain-derived neurotrophic factor activate Nrf2 in astrocytes and neurons?
    Tetsuro Ishii, Giovanni E. Mann
    2018, 13 (5):  803-804.  doi: 10.4103/1673-5374.232468
    Abstract ( 144 )   PDF (176KB) ( 345 )   Save

    Circadian rhythm protects neurons: Although the master clock entrains the whole body rhythm, peripheral tissues also express core clock transcription factors Clock and Bmal1, which regulate expression of clock genes including Period (Per) and Cryptochrome (Cry) proteins. Complexes of Per and Cry proteins repress Bmal1- and Clock-mediated transcription forming a negative feedback loop, which regulates nearly a 24 hours self-sustained rhythm including energy metabolism. Circadian rhythm dysfunction is often observed in patients with Alzheimer’s, Parkinson’s and Huntington’s diseases. Clinical studies and experiments in animal models of neurodegenerative disorders have revealed the progressive nature of circadian dysfunction throughout the course of neurodegeneration. However, the importance of circadian rhythm in the protection of neurons remains to be elucidated.Recent studies suggest that disruption of the circadian rhythm can impair metabolic cooperation between neurons and astrocytes, and thereby enhance oxidative damages in the brain. Thus, understanding the molecular mechanisms by which endogenous antioxidant defense systems are controlled by the circadian rhythm may inform the design of novel therapeutic strategies to protect against neurodegenerative diseases. We recently proposed that neurotrophins activate the redox sensitive transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master regulator of cellular defense against oxidative stress, in a circadian rhythm dependent manner in astrocytes to support neurons in the brain

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    Visual prostheses, optogenetics, stem cell and gene therapies: splitting the cake
    Alejandro Barriga-Rivera, Gregg J. Suaning
    2018, 13 (5):  805-806.  doi: 10.4103/1673-5374.232469
    Abstract ( 142 )   PDF (292KB) ( 274 )   Save

    The size of the blind population in 2015 was estimated to be approximately 36 million (Bourne et al., 2017). According to the predictions by Bourne and co-workers, the number of the visually impaired is expected to reach nearly 100 million by 2050. Although some of these diseases can be treated, to date, some other eye conditions such as retinitis pigmentosa (RP), an inherited degenerative condition of the photoreceptors, have no treatment except electrical stimulation of the surviving neurons of the visual system. This therapy, delivered via a visual prosthesis, relies on an electrode array, implanted in close proximity to the target neurons, able to deliver a series of electrical impulses that activate these cells thus eliciting a visual sensation (Lewis et al., 2016). These electrodes can be implanted in the retina (three approaches exist: epiretinal, subretinal and suprachoroidal implants), the optic nerve, the lateral geniculate nucleus or the visual cortex. The medical device industry has spotted the opportunity and several companies have already obtained approval for commercialisation of their devices in the US and the European markets. However, the niche for these technologies may be soon occupied by new promising therapies based on a biological approach.

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    Magnesium acethyltaurate as a potential agent for retinal and optic nerve protection in glaucoma
    Igor Iezhitsa, Renu Agarwal
    2018, 13 (5):  807-808.  doi: 10.4103/1673-5374.232470
    Abstract ( 178 )   PDF (515KB) ( 278 )   Save

    Glaucoma is the second leading cause of irreversible vision impairment affecting more than 70 million people worldwide with approximately 10%suffering from glaucoma-related bilateral blind (Quigley and Broman,2006). It is a multi-factorial disease that is characterized by optic nerve damage and visual field loss. Progressive loss of retinal ganglion cells (RGCs) resulting in visual field deficits is the hallmark of glaucoma. Several etiological factors seem to be involved in its pathophysiology, however the precise mechanisms leading to its development remain unclear. Some of the widely described factors that contribute to RGC loss include axonal transport failure, neurotrophic factor depletion, excitotoxicity, mitochondrial dysfunction, activation of intrinsic and extrinsic apoptotic cascade and oxidative stress (Agarwal et al., 2009). The basic mechanisms that contribute to RGC degeneration in glaucoma are presented in Figure 1. Current treatment strategies for glaucoma are limited to the reduction of intraocular pressure (IOP); however, it is clear now that the disease progression may continue despite effective IOP lowering. Search for newer modalities has led to emergence of significant data from experimental research suggesting potentially new neuroprotective strategies that may add to the arsenal of existing antiglaucoma agents.

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    Silkworm silk biomaterials for spinal cord repair: promise for combinatorial therapies
    Anna Varone, Ann Marie Rajnicek, Wenlong Huang
    2018, 13 (5):  809-810.  doi: 10.4103/1673-5374.232471
    Abstract ( 137 )   PDF (578KB) ( 303 )   Save

    Traumatic injury to the adult mammalian spinal cord results in minimal axonal regrowth, cystic cavity formation at the injury site, poor functional recovery and there is no cure available.Due to the complex nature of spinal cord injury (SCI), a combination of therapeutic strategies may offer the most promise for successful regeneration (Ahuja et al., 2017). A key element considered for a combination strategy is a biomaterial scaffold to fill the cavity and to deliver growth promoting factors and transplanted cells. In the last few decades many synthetic and natural biomaterials have been explored for their suitability to repair damaged spinal cord,including hydrogels, guidance conduits and nanoparticles, but none has led to successful clinical translation (Siebert et al., 2015), likely due to failure in optimization of biomaterial characteristics required.The aim of this perspective is to first briefly outline the key characteristics of a biomaterial suited to spinal cord repair and then discuss the potential of using silkworm silk biomaterials such as degummed Antheraea pernyi filaments (DAPF) in a combinatorial context.

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    Functional changes after spinal lesions: implications for interventions
    David Parker
    2018, 13 (5):  811-812.  doi: 10.4103/1673-5374.232472
    Abstract ( 109 )   PDF (272KB) ( 222 )   Save

    We have known for many years that the spinal cord can generate some basic locomotor outputs under specific experimental conditions without any input from the brain or the periphery (Stuart and Hultborn,2008). However, when inputs from the brain are lost following spinal cord injury (SCI), the mammalian spinal cord is unable to generate normal, goal-directed locomotor outputs. In contrast, lower vertebrates spontaneously regenerate axons across lesion sites and recover locomotor function after complete spinal cord lesions (Cohen et al., 1988). The major focus of research into SCI in mammals has been to replicate this lower vertebrate capability by promoting the regeneration of lesioned axons or the sprouting of processes from spared axons, with the aim of reconnecting the spinal cord and thus repairing the damage caused by the injury (Steward et al., 2012). It is not that regeneration cannot occur in mammals, but it is instead actively inhibited. Why this inhibition has evolved in mammals is unknown. It would be useful to consider this question as it may help to explain why the various regeneration strategies that can successfully overcome this inhibition have so far failed to translate into an effective treatment for SCI (Steward et al., 2012). This article reviews work that we have done on the functional changes after recovery from SCI in the lamprey (Parker, 2017), and how these changes may relate to functional recovery in mammalian systems.

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    Autophagy inhibition: a new therapeutic target in spinal muscular atrophy
    Antonio Piras, Marina Boido
    2018, 13 (5):  813-814.  doi: 10.4103/1673-5374.232473
    Abstract ( 173 )   PDF (378KB) ( 318 )   Save

    Spinal muscular atrophy (SMA) is a hereditary pediatric motor neuron (MN) disease: survival motor neuron 1 (SMN1) gene mutation determines MN degeneration and, consequently, muscle atrophy, breathing and swallowing difficulties, and, in the most severe cases, premature death. A second unaffected gene (SMN2) is present, but it can only produce a limited amount of functional protein, modulating the disease severity and progression. SMN, ubiquitously expressed, is mainly involved in the assembly of small nuclear ribonucleoproteins and pre-mRNA splicing requirements (Lunn and Wang, 2008). Its reduction determines selective MN loss: the type of cell death leading to neurodegeneration remains debated, since evidence of both increased apoptosis and dysregulated autophagy have been reported in SMA.

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    The role of DJ-1 complexes and catecholamine metabolism: relevance for familial and idiopathic Parkinson’s disease
    Dominik Piston, Matthew E. Gegg
    2018, 13 (5):  815-816.  doi: 10.4103/1673-5374.2
    Abstract ( 152 )   PDF (228KB) ( 301 )   Save

    Autosomal recessive mutations in the PARK7 gene, which encodes for the protein DJ-1, result in a loss of function and are a cause of familial Parkinson’s disease (PD), while increased wild-type DJ-1 protein levels are associated with some forms of cancer. Several functions of DJ-1 have been described, with the greatest evidence indicating that DJ-1 is a redox-sensitive protein involved in the regulation of oxidative stress and cell survival. We have recently reported that the levels of DJ-1 oxidized at cysteine 106 (C106) was decreased in the cortex of idiopathic PD brains (Piston et al., 2017). Furthermore we found that DJ-1 forms high molecular weight complexes in human brain and the dopaminergic SH-SY5Y neuroblastoma cell line, and that these complexes could be oxidized at C106. Proteomics indicated that proteins involved in RNA transcription/translation were associated with these DJ-1 complexes, and the composition of complexes was affected by oxidation of DJ-1. RNA sequencing highlighted that transcripts associated with the catecholamine system, including dopamine (DA) metabolism, tended to be increased when complexes contained DJ-1 mimicking oxidation at C106. DJ-1 knock down (KD) cells also had increased intracellular DA and noradrenaline (NA) levels. In this perspective we will discuss the implications of DJ-1 acting as a redox sensor directly affecting RNA metabolism, and with respect to PD, how dysregulation of catecholamine metabolism in both familial and idiopathic PD, might contribute to some prodromal features of the disease and the increased susceptibility of specific neuronal populations to neurodegeneration.DJ-1 complexes associated with RNA metabolism

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    Hyperbaric oxygen therapy as a new treatment approach for Alzheimer’s disease
    Ronit Shapira, Shai Efrati, Uri Ashery
    2018, 13 (5):  817-818.  doi: 10.4103/1673-5374.232475
    Abstract ( 176 )   PDF (318KB) ( 1141 )   Save

    Hyperbaric oxygen therapy as a new treatment approach for Alzheimer’s disease (AD): Alongside the increase in life expectancy,the prevalence of age-related disorders, such as neurodegenerative diseases, is on the rise. For example, AD, the most common form of dementia in the elderly, accounts for 60–80% of all dementia cases.However, there is presently no cure for this disease and no effective treatment that would slow disease progression despite billions of dollars invested in drug development. As AD is a complex disease,the development of effective and specific drugs is difficult. Thus,examining alternative treatments that target several disease-related pathways in parallel is of the utmost importance. Hyperbaric oxygen treatment (HBOT) is the medical administration of 100% oxygen at environmental pressure greater than 1 atmosphere absolute (ATA). HBOT has been shown to improve neurological functions and life quality following neurological incidents such as stroke and traumatic brain injury, and to improve performance of healthy subjects in multitasking. The current perspective describes a recent study demonstrating that HBOT can ameliorate AD-related pathologies in an AD mouse model, and provides unique insights into HBOT’s mechanisms of action. Old triple-transgenic model (3xTg)-AD mice were exposed to 14 days of HBOT and showed reduced hypoxia and neuroinflammation, reduction in beta-amyloid (Aβ) plaques and phosphorylated tau, and improvement in behavioral tasks. This and additional studies have shown that cerebral ischemia is a common denominator in many of the pathological pathways and suggests that oxygen is an important tool in the arsenal for our fight against AD. Given that HBOT is used in the clinic to treat various neurological conditions, we suggest that this approach presents a new platform for the treatment of AD.

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    Dexmedetomidine attenuates traumatic brain injury: action pathway and mechanisms
    Dong Wang, Xin Xu, Yin-Gang Wu, Li Lyu, Zi-Wei Zhou, Jian-Ning Zhang
    2018, 13 (5):  819-826.  doi: 10.4103/1673-5374.232529
    Abstract ( 198 )   PDF (2468KB) ( 392 )   Save

    Traumatic brain injury induces potent inflammatory responses that can exacerbate secondary blood-brain barrier (BBB) disruption, neuronal injury, and neurological dysfunction. Dexmedetomidine is a novel α2-adrenergic receptor agonist that exert protective effects in various central nervous system diseases. The present study was designed to investigate the neuroprotective action of dexmedetomidine in a mouse traumatic brain injury model, and to explore the possible mechanisms. Adult male C57BL/6J mice were subjected to controlled cortical impact. After injury, animals received 3 days of consecutive dexmedetomidine therapy (25 μg/kg per day). The modified neurological severity score was used to assess neurological deficits. The rotarod test was used to evaluate accurate motor coordination and balance. Immunofluorescence was used to determine expression of ionized calcium binding adapter molecule-1, myeloperoxidase, and zonula occluden-1 at the injury site. An enzyme linked immunosorbent assay was used to measure the concentration of interleukin-1β (IL-1β), tumor necrosis factor α, and IL-6. The dry-wet weight method was used to measure brain water content. The Evans blue dye extravasation assay was used to measure BBB disruption. Western blot assay was used to measure protein expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1 p20, IL-1β, nuclear factor kappa B (NF-κB) p65, occluding, and zonula occluden-1.Flow cytometry was used to measure cellular apoptosis. Results showed that dexmedetomidine treatment attenuated early neurological dysfunction and brain edema. Further, dexmedetomidine attenuated post-traumatic inflammation, up-regulated tight junction protein expression,and reduced secondary BBB damage and apoptosis. These protective effects were accompanied by down-regulation of the NF-κB and NLRP3 inflammasome pathways. These findings suggest that dexmedetomidine exhibits neuroprotective effects against acute (3 days)post-traumatic inflammatory responses, potentially via suppression of NF-κB and NLRP3 inflammasome activation.

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    Inhibition of endoplasmic reticulum stress alleviates secondary injury after traumatic brain injury
    Hong-Ping Tan, Qiang Guo, Gang Hua, Jun-Xi Chen, Jun-Chao Liang
    2018, 13 (5):  827-836. 
    Abstract ( 187 )   PDF (1886KB) ( 322 )   Save

    Apoptosis after traumatic brain injury has been shown to be a major factor influencing prognosis and outcome. Endoplasmic reticulum stress may be involved in mitochondrial mediated neuronal apoptosis. Therefore, endoplasmic reticulum stress has become an important mechanism of secondary injury after traumatic brain injury. In this study, a rat model of traumatic brain injury was established by lateral fluid percussion injury. Fluorescence assays were used to measure reactive oxygen species content in the cerebral cortex. Western blot assays were used to determine expression of endoplasmic reticulum stress-related proteins. Hematoxylin-eosin staining was used to detect pathological changes in the cerebral cortex. Transmission electron microscopy was used to measure ultrastructural changes in the endoplasmic reticulum and mitochondria. Our results showed activation of the endoplasmic reticulum stress-related unfolded protein response. Meanwhile, both the endoplasmic reticulum stress response and mitochondrial apoptotic pathway were activated at different stages post-traumatic brain injury. Furthermore, pretreatment with the endoplasmic reticulum stress inhibitor, salubrinal (1 mg/kg), by intraperitoneal injection 30 minutes before injury significantly inhibited the endoplasmic reticulum stress response and reduced apoptosis. Moreover, salubrinal promoted recovery of mitochondrial function and inhibited activation of the mitochondrial apoptotic pathway post-traumatic brain injury. These results suggest that endoplasmic reticulum stress might be a key factor for secondary brain injury post-traumatic brain injury.

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    Chaihu-Shugan-San exerts an antidepressive effect by downregulating miR-124 and releasing inhibition of the MAPK14 and Gria3 signaling pathways
    Qiong Liu, Ning-Ning Sun, Zheng-Zhi Wu, Da-Hua Fan, Mei-Qun Cao
    2018, 13 (5):  837-845.  doi: 10.4103/1673-5374.232478
    Abstract ( 210 )   PDF (2056KB) ( 372 )   Save

    Dysregulation of miR-124 has been reported to be involved in the pathophysiology of depression. Chaihu-Shugan-San, a traditional Chinese medicine, has antidepressive activity; however, the underlying mechanisms remain unclear. In this study, to generate a rodent model of depression, rats were subjected to a combination of solitary confinement and chronic unpredictable mild stress for 28 days. Rats were intragastrically administered Chaihu-Shugan-San (2.835 mL/kg/d) for 4 weeks, once a day. Real-time reverse-transcription quantitative polymerase chain reaction, miRNA microarray, western blot assay and transmission electron microscopy demonstrated that Chaihu-Shugan-San downregulated miR-124 expression and upregulated the mRNA and protein levels of mitogen-activated protein kinase 14 (MAPK14) and glutamate receptor subunit 3 (Gria3). Chaihu-Shugan-San also promoted synapse formation in the hippocampus. The open field test, sucrose consumption test and forced swimming test were used to assess depression-like behavior. After intragastric administration of Chaihu-Shugan-San, sucrose consumption increased, while the depressive behaviors were substantially reduced. Together,these findings suggest that Chaihu-Shugan-San exerts an antidepressant-like effect by downregulating miR-124 expression and by releasing the inhibition of the MAPK14 and Gria3 signaling pathways

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     Baseline effects of lysophosphatidylcholine and nerve growth factor in a rat model of sciatic nerve regeneration after crush injury
    Ryan L. Wood, Keaton S. Karlinsey, Austin D. Thompson, Mark N. Rigby, Greggory D. Boatright, William G. Pitt, Beverly L. Roeder, Scott C. Steffensen, Alonzo D. Cook
    2018, 13 (5):  846-853.  doi: 10.4103/1673-5374.232479
    Abstract ( 156 )   PDF (880KB) ( 282 )   Save

    Schwann cells play a major role in helping heal injured nerves. They help clear debris, produce neurotrophins,upregulate neurotrophin receptors, and form bands of Büngner to guide the healing nerve. But nerves do not always produce enough neurotrophins and neurotrophin receptors to repair themselves. Nerve growth factor (NGF) is an important neurotrophin for promoting nerve healing and lysophosphatidylcholine (LPC) has been shown to stimulate NGF receptors (NGFR). This study tested the administration of a single intraneural injection of LPC (1 mg/mL for single LPC injection and 10 mg/mL for multiple LPC injections) at day 0 and one (day 7), two (days 5 and 7), or three (days 5, 7, and 9) injections of NGF (160 ng/mL for single injections and 80 ng/mL for multiple injections) to determine baseline effects on crush ed sciatic nerves in rats. The rats were randomly divided into four groups: control, crush, crush-NGF, and crush-LPC-NGF. The healing of the nerves was measured weekly by monitoring gait; electrophysiological parameters: compound muscle action potential (CMAP) amplitudes; and morphological parameters: total fascicle areas, myelinated fiber counts, fiber densities, fiber packing, and mean g-ratio values at weeks 3 and 6. The crush, crush-NGF, and crush-LPC-NGF groups statistically differed from the control group for all six weeks for the electrophysiological parameters but only differed from the control group at week 3 for the morphological parameters. The crush, crush-NGF, and crush-LPC-NGF groups did not differ from each other over the course of the study. Single injections of LPC and NGF one week apart or multiple treatments of NGF at 5, 7 and 9 days post-injury did not alter the healing rate of the sciatic nerves during weeks 1-6 of the study. These findings are important to define the baseline effects of NGF and LPC injections, as part of a larger effort to determine the minimal dose regimen of NGF to regenerate peripheral nerves.

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    Validation of a novel animal model for sciatic nerve repair with an adipose derived stem cell loaded fibrin conduit
    Maximilian M. Saller, Rosa-Eva Huettl, Julius M. Mayer, Annette Feuchtinger, Christian Krug, Thomas Holzbach, Elias Volkmer
    2018, 13 (5):  854-861.  doi: 10.4103/1673-5374.232481
    Abstract ( 168 )   PDF (7114KB) ( 169 )   Save

    Despite the regenerative capabilities of peripheral nerves, severe injuries or neuronal trauma of critical size impose immense hurdles for proper restoration of neuro-muscular circuitry. Autologous nerve grafts improve re-establishment of connectivity, but also comprise substantial donor site morbidity. We developed a rat model which allows the testing of different cell applications, i.e., mesenchymal stem cells, to improve nerve regeneration in vivo. To mimic inaccurate alignment of autologous nerve grafts with the injured nerve, a 20 mm portion of the sciatic nerve was excised, and sutured back in place in reversed direction.To validate the feasibility of our novel model, a fibrin gel conduit containing autologous undifferentiated adipose-derived stem cells was applied around the coaptation sites and compared to autologous nerve grafts. After evaluating sciatic nerve function for 16 weeks postoperatively, animals were sacrificed, and gastrocnemius muscle weight was determined along with morphological parameters (g-ratio, axon density & diameter) of regenerating axons. Interestingly, the addition of undifferentiated adipose-derived stem cells resulted in a significantly improved re-myelination, axon ingrowth and functional outcome, when compared to animals without a cell seeded conduit. The presented model thus displays several intriguing features: it imitates a certain mismatch in size, distribution and orientation of axons within the nerve coaptation site. The fibrin conduit itself allows for an easy application of cells and, as a true critical-size defect model, any observed improvement relates directly to the performed intervention. Since fibrin and adipose-derived stem cells have been approved for human applications, the technique can theoretically be performed on humans. Thus, we suggest that the model is a powerful tool to investigate cell mediated assistance of peripheral nerve regeneration.

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    Phrenic and intercostal nerves with rhythmic discharge can promote early nerve regeneration after brachial plexus repair in rats
    Jing Rui, Ya-Li Xu, Xin Zhao, Ji-Feng Li, Yu-Dong Gu, Jie Lao
    2018, 13 (5):  862-868.  doi: 10.4103/1673-5374.232482
    Abstract ( 166 )   PDF (2183KB) ( 596 )   Save

    Exogenous discharge can positively promote nerve repair. We, therefore, hypothesized that endogenous discharges may have similar effects. The phrenic nerve and intercostal nerve, controlled by the respiratory center, can emit regular nerve impulses; therefore these endogenous automatically discharging nerves might promote nerve regeneration. Action potential discharge patterns were examined in the diaphragm,external intercostal and latissimus dorsi muscles of rats. The phrenic and intercostal nerves showed rhythmic clusters of discharge, which were consistent with breathing frequency. From the first to the third intercostal nerves, spontaneous discharge amplitude was gradually increased. There was no obvious rhythmic discharge in the thoracodorsal nerve. Four animal groups were performed in rats as the musculocutaneous nerve cut and repaired was bland control. The other three groups were followed by a side-to-side anastomosis with the phrenic nerve, intercostal nerve and thoracodorsal nerve. Compound muscle action potentials in the biceps muscle innervated by the musculocutaneous nerve were recorded with electrodes. The tetanic forces of ipsilateral and contralateral biceps muscles were detected by a force displacement transducer. Wet muscle weight recovery rate was measured and pathological changes were observed using hematoxylin-eosin staining. The number of nerve fibers was observed using toluidine blue staining and changes in nerve ultrastructure were observed using transmission electron microscopy. The compound muscle action potential amplitude was significantly higher at 1 month after surgery in phrenic and intercostal nerve groups compared with the thoracodorsal nerve and blank control groups. The recovery rate of tetanic tension and wet weight of the right biceps were significantly lower at 2 months after surgery in the phrenic nerve, intercostal nerve, and thoracodorsal nerve groups compared with the negative control group. The number of myelinated axons distal to the coaptation site of the musculocutaneous nerve at 1 month after surgery was significantly higher in phrenic and intercostal nerve groups than in thoracodorsal nerve and negative control groups. These results indicate that endogenous autonomic discharge from phrenic and intercostal nerves can promote nerve regeneration in early stages after brachial plexus injury.

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     Early electrical field stimulation prevents the loss of spinal cord anterior horn motoneurons and muscle atrophy following spinal cord injury
    Cheng Zhang, Wei Rong, Guang-Hao Zhang, Ai-Hua Wang, Chang-Zhe Wu, Xiao-Lin Huo
    2018, 13 (5):  869-876.  doi: 10.4103/1673-5374.232483
    Abstract ( 149 )   PDF (2122KB) ( 257 )   Save

    Our previous study revealed that early application of electrical field stimulation (EFS) with the anode at the lesion and the cathode distal to the lesion reduced injury potential, inhibited secondary injury and was neuroprotective in the dorsal corticospinal tract after spinal cord injury (SCI). The objective of this study was to further evaluate the effect of EFS on protection of anterior horn motoneurons and their target musculature after SCI and its mechanism. Rats were randomized into three equal groups. The EFS group received EFS for 30 minutes immediately after injury at T10. SCI group rats were only subjected to SCI and sham group rats were only subjected to laminectomy. Luxol fast blue staining demonstrated that spinal cord tissue in the injury center was better protected; cross-sectional area and perimeter of injured tissue were significantly smaller in the EFS group than in the SCI group. Immunofluorescence and transmission electron microscopy showed that the number of spinal cord anterior horn motoneurons was greater and the number of abnormal neurons reduced in the EFS group compared with the SCI group. Wet weight and cross-sectional area of vastus lateralis muscles were smaller in the SCI group to in the sham group. However, EFS improved muscle atrophy and behavioral examination showed that EFS significantly increased the angle in the inclined plane test and Tarlov’s motor grading score. The above results confirm that early EFS can effectively impede spinal cord anterior horn motoneuron loss, promote motor function recovery and reduce muscle atrophy in rats after SCI.

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    Dynamic correlation of diffusion tensor imaging and neurological function scores in beagles with spinal cord injury
    Chang-Bin Liu, De-Gang Yang, Qian-Ru Meng, Da-Peng Li, Ming-Liang Yang, Wei Sun, Wen-Hao Zhang, Chang Cai, Liang-Jie Du, Jun Li, Feng Gao, Yan Yu, Xin Zhang, Zhen-Tao Zuo, Jian-Jun Li
    2018, 13 (5):  877-886.  doi: 10.4103/1673-5374.232485
    Abstract ( 169 )   PDF (1184KB) ( 317 )   Save

    Exploring the relationship between different structure of the spinal cord and functional assessment after spinal cord injury is important.Quantitative diffusion tensor imaging can provide information about the microstructure of nerve tissue and can quantify the pathological damage of spinal cord white matter and gray matter. In this study, a custom-designed spinal cord contusion-impactor was used to damage the T10 spinal cord of beagles. Diffusion tensor imaging was used to observe changes in the whole spinal cord, white matter, and gray matter, and the Texas Spinal Cord Injury Score was used to assess changes in neurological function at 3 hours, 24 hours, 6 weeks,and 12 weeks after injury. With time, fractional anisotropy values after spinal cord injury showed a downward trend, and the apparent diffusion coefficient, mean diffusivity, and radial diffusivity first decreased and then increased. The apparent diffusion-coefficient value was highly associated with the Texas Spinal Cord Injury Score for the whole spinal cord (R = 0.919, P = 0.027), white matter (R = 0.932, P = 0.021), and gray matter (R = 0.882, P = 0.048). Additionally, the other parameters had almost no correlation with the score (P > 0.05).In conclusion, the highest and most significant correlation between diffusion parameters and neurological function was the apparent diffusion-coefficient value for white matter, indicating that it could be used to predict the recovery of neurological function accurately after spinal cord injury.

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    Endothelial progenitor cell-conditioned medium promotes angiogenesis and is neuroprotective after spinal cord injury
    Tao Wang, Xiao Fang, Zong-Sheng Yin
    2018, 13 (5):  887-895.  doi: 10.4103/1673-5374.232484
    Abstract ( 134 )   PDF (2174KB) ( 516 )   Save

    Endothelial progenitor cells secrete a variety of growth factors that inhibit inflammation, promote angiogenesis and exert neuroprotective effects. Therefore, in this study, we investigated whether endothelial progenitor cell-conditioned medium might have therapeutic effectiveness for the treatment of spinal cord injury using both in vitro and in vivo experiments. After primary culture of bone marrow-derived macrophages, lipopolysaccharide stimulation was used to classically activate macrophages to their proinflammatory phenotype. These cells were then treated with endothelial progenitor cell-conditioned medium or control medium. Polymerase chain reaction was used to determine mRNA expression levels of related inflammatory factors. Afterwards, primary cultures of rat spinal cord neuronal cells were prepared and treated with H2O2 and either endothelial progenitor cell-conditioned medium or control medium. Hoechst 33258 and propidium iodide staining were used to calculate the proportion of neurons undergoing apoptosis. Aortic ring assay was performed to assess the effect of endothelial progenitor cell-conditioned medium on angiogenesis. Compared with control medium, endothelial progenitor cell-conditioned medium mitigated the macrophage inflammatory response at the spinal cord injury site, suppressed apoptosis, and promoted angiogenesis. Next, we used a rat model of spinal cord injury to examine the effects of the endothelial progenitor cell-conditioned medium in vivo. The rats were randomly administered intraperitoneal injection of PBS, control medium or endothelial progenitor cell-conditioned medium, once a day, for 6 consecutive weeks. Immunohistochemistry was used to observe neuronal morphology. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay was performed to detect the proportion of apoptotic neurons in the gray matter. The Basso, Beattie and Bresnahan Locomotor Rating Scale was used to evaluate the recovery of motor function of the bilateral hind limbs after spinal cord injury. Compared with the other two groups, the number of axons was increased, cavities in the spinal cord were decreased,the proportion of apoptotic neurons in the gray matter was reduced, and the Basso, Beattie and Bresnahan score was higher in the endothelial progenitor cell-conditioned medium group. Taken together, the in vivo and in vitro results suggest that endothelial progenitor cell-conditioned medium suppresses inflammation, promotes angiogenesis, provides neuroprotection, and promotes functional recovery after spinal cord injury.

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    Nogo receptor expression in microglia/macrophages during experimental autoimmune encephalomyelitis progression
    Amani A. Alrehaili, Jae Young Lee, Maha M. Bakhuraysah, Min Joung Kim, Pei-Mun Aui, Kylie A. Magee, Steven Petratos
    2018, 13 (5):  896-907.  doi: 10.4103/1673-5374.232488
    Abstract ( 148 )   PDF (2853KB) ( 254 )   Save

    Myelin-associated inhibitory factors within the central nervous system (CNS) are considered to be one of the main obstacles for axonal regeneration following disease or injury. The nogo receptor 1 (NgR1) has been well documented to play a key role in limiting axonal regrowth in the injured and diseased mammalian CNS. However, the role of nogo receptor in immune cell activation during CNS inflammation is yet to be mechanistically elucidated. Microglia/macrophages are immune cells that are regarded as pathogenic contributors to inflammatory demyelinating lesions in multiple sclerosis (MS). In this study, the animal model of MS, experimental autoimmune encephalomyelitis (EAE) was induced in ngr1+/+ and ngr1–/–female mice following injection with the myelin oligodendrocyte glycoprotein (MOG35–55) peptide. A fatemap analysis of microglia/macrophages was performed throughout spinal cord sections of EAE-induced mice at clinical scores of 0, 1, 2 and 3, respectively (increasing locomotor disability) from both genotypes,using the CD11b and Iba1 cell markers. Western immunoblotting using lysates from isolated spinal cord microglia/macrophages, along with immunohistochemistry and flow cytometric analysis, was performed to demonstrate the expression of nogo receptor and its two homologs during EAE progression. Myelin protein engulfment during EAE progression in ngr1+/+ and ngr1–/– mice was demonstrated by western immunblotting of lysates from isolated spinal cord microglia/macrophages, detecting levels of Nogo-A and MOG. The numbers of M1 and M2 microglia/macrophage phenotypes present in the spinal cords of EAE-induced ngr1+/+ and ngr1–/– mice, were assessed by flow cytometric analysis using CD38 and Erg-2 markers. A significant difference in microglia/macrophage numbers between ngr1+/+ and ngr1–/– mice was identified during the progression of the clinical symptoms of EAE, in the white versus gray matter regions of the spinal cord. This difference was unrelated to the expression of NgR on these macrophage/microglial cells. We have identified that as EAE progresses, the phagocytic activity of microglia/macrophages with myelin debris, in ngr1–/– mice, was enhanced. Moreover, we show a modulation from a predominant M1-pathogenic to the M2-neurotrophic cell phenotype in the ngr1–/– mice during EAE progression. These findings suggest that CNS-specific macrophages and microglia of ngr1–/– mice may exhibit an enhanced capacity to clear inhibitory molecules that are sequestered in inflammatory lesions.

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    Association between Alzheimer’s disease pathogenesis and early demyelination and oligodendrocyte dysfunction
    Yu-Xia Dong, Hui-Yu Zhang, Hui-Yuan Li, Pei-Hui Liu, Yi Sui, Xiao-Hong Sun
    2018, 13 (5):  908-914.  doi: 10.4103/1673-5374.232486
    Abstract ( 183 )   PDF (865KB) ( 280 )   Save

    The APPSwe/PSEN1dE9 (APP/PS1) transgenic mouse model is an Alzheimer’s disease mouse model exhibiting symptoms of dementia,and is commonly used to explore pathological changes in the development of Alzheimer’s disease. Previous clinical autopsy and imaging studies suggest that Alzheimer’s disease patients have white matter and oligodendrocyte damage, but the underlying mechanisms of these have not been revealed. Therefore, the present study used APP/PS1 mice to assess cognitive change, myelin loss, and corresponding changes in oligodendrocytes, and to explore the underlying mechanisms. Morris water maze tests were performed to evaluate cognitive change in APP/PS1 mice and normal C57BL/6 mice aged 3 and 6 months. Luxol fast blue staining of the corpus callosum and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for myelin basic protein (MBP) mRNA were carried out to quantify myelin damage. Immunohistochemistry staining for NG2 and qRT-PCR for monocarboxylic acid transporter 1 (MCT1) mRNA were conducted to assess corresponding changes in oligodendrocytes. Our results demonstrate that compared with C57BL/6 mice, there was a downregulation of MBP mRNA in APP/PS1 mice aged 3 months. This became more obvious in APP/PS1 mice aged 6 months accompanied by other abnormalities such as prolonged escape latency in the Morris water maze test, shrinkage of the corpus callosum, upregulation of NG2-immunoreactive cells, and downregulation of MCT1 mRNA. These findings indicate that the involvement of early demyelination at 3 months and the oligodendrocyte dysfunction at 6 months in APP/PS1 mice are in association with Alzheimer’s disease pathogenesis.

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    Trillium tschonoskii maxim extract attenuates abnormal Tau phosphorylation
    Hong-Bin Luo, Nan Shang, Wen-Zhi Xie, De-Jian Wen, Min Qu, Sheng Huang, Sha-Sha Fan, Wei Chen, Nan-Qiao Mou, Xiang-Yu Liu, Qin Chen, Feng-Feng Xie, Jun-Xu Li
    2018, 13 (5):  915-922.  doi: 10.4103/1673-5374.232487
    Abstract ( 223 )   PDF (3388KB) ( 311 )   Save

    Large-scale epidemiological studies have found that hyperhomocysteinemia is a powerful, independent risk factor for Alzheimer’s disease.Trillium tschonoskii maxim is a traditional Chinese medicine that is used to promote memory. However, scientific understanding of its mechanism of action is limited. This report studied the potential neuroprotective effects of Trillium tschonoskii maxim extract against homocysteine-induced cognitive deficits. Rats were intravenously injected with homocysteine (400 μg/kg) for 14 days to induce a model of Alzheimer’s disease. These rats were then intragastrically treated with Trillium tschonoskii maxim extract (0.125 or 0.25 g/kg) for 7 consecutive days. Open field test and Morris water maze test were conducted to measure spontaneous activity and learning and memory abilities.Western blot assay was used to detect the levels of Tau protein and other factors involved in Tau phosphorylation in the hippocampus.Immunohistochemical staining was used to examine Tau protein in the hippocampus. Golgi staining was applied to measure hippocampal dendritic spines. Our results demonstrated that homocysteine produced learning and memory deficits and increased levels of Tau phosphorylation,and diminished the activity of catalytic protein phosphatase 2A. The total number of hippocampal dendritic spines was also decreased. Trillium tschonoskii maxim extract treatment reversed the homocysteine-induced changes. The above results suggest that Trillium tschonoskii maxim extract can lessen homocysteine-induced abnormal Tau phosphorylation and improve cognitive deterioration such as that present in Alzheimer’s disease.

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    Inhibition of retinal ganglion cell apoptosis: regulation of mitochondrial function by PACAP
    Huan-Huan Cheng, Hui Ye, Rui-Ping Peng, Juan Deng, Yong Ding
    2018, 13 (5):  923-929.  doi: 10.4103/1673-5374.232489
    Abstract ( 168 )   PDF (557KB) ( 298 )   Save

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is an endogenous peptide with neuroprotective effects on retinal neurons, but the precise mechanism underlying these effects remains unknown. Considering the abundance of mitochondria in retinal ganglion cells (RGCs), we postulate that the protective effect of PACAP is associated with the regulation of mitochondrial function. RGC-5 cells were subjected to serum deprivation for 48 hours to induce apoptosis in the presence or absence of 100 nM PACAP. As revealed with the Cell Counting Kit-8 assay, PACAP at different concentrations significantly increased the viability of RGC-5 cells. PACAP also inhibited the excessive generation of reactive oxygen species in RGC-5 cells subjected to serum deprivation. We also showed by flow cytometry that PACAP inhibited serum deprivation-induced apoptosis in RGC-5 cells. The proportions of apoptotic cells and cells with mitochondria depolarization were significantly decreased with PACAP treatment. Western blot assays demonstrated that PACAP increased the levels of Bcl-2 and inhibited the compensatory increase of PAC1. Together, these data indicate protective effects of PACAP against serum deprivation-induced apoptosis in RGCs, and that the mechanism of this action is associated with maintaining mitochondrial function.

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    Exosomes: a novel therapeutic target for Alzheimer’s disease?
    Zhi-You Cai, Ming Xiao, Sohel H. Quazi, Zun-Yu Ke
    2018, 13 (5):  930-935.  doi: 10.4103/1673-5374.232490
    Abstract ( 389 )   PDF (308KB) ( 406 )   Save

    Extracellular exosomes are formed inside the cytoplasm of cells in compartments known as multivesicular bodies. Thus, exosomes contain cytoplasmic content. Multivesicular bodies fuse with the plasma membrane and release exosomes into the extracellular environment. Comprehensive research suggests that exosomes act as both inflammatory intermediaries and critical inducers of oxidative stress to drive progression of Alzheimer’s disease. An important role of exosomes in Alzheimer’s disease includes the formation of neurofibrillary tangles and beta-amyloid production, clearance, and accumulation. In addition, exosomes are involved in neuroinflammation and oxidative stress, which both act as triggers for beta-amyloid pathogenesis and tau hyperphosphorylation. Further, it has been shown that exosomes are strongly associated with beta-amyloid clearance. Thus, effective measures for regulating exosome metabolism may be novel drug targets for Alzheimer’s disease.

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    Weak phonation due to un­known injury of the corticobulbar tract in a patient with mild traumatic brain injury: a diffusion tensor tractography study
    Sung Ho Jang, Han Do Lee
    2018, 13 (5):  936-936.  doi: 10.4103/1673-5374.232491
    Abstract ( 139 )   PDF (301KB) ( 263 )   Save

    In this study, we report on a patient who showed weak phonation following mild traumatic brain injury (TBI), which was demonstrated by diffusion tensor tractography (DTT).

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