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15 March 2016, Volume 11 Issue 3 Previous Issue    Next Issue

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Matrix metalloproteinases in neural development: a phylogenetically diverse perspective Christopher D. Small, Bryan D. Crawford 2016, 11 (3):  357-362.  doi: 10.4103/1673-5374.179030 Abstract ( 191 )   PDF (220KB) ( 544 )   Save The matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases originally characterized as secreted proteases responsible for degrading extracellular matrix proteins. Their canonical role in matrix remodelling is of significant importance in neural development and regeneration, but emerging roles for MMPs, especially in signal transduction pathways, are also of obvious importance in a neural context. Misregulation of MMP activity is a hallmark of many neuropathologies, and members of every branch of the MMP family have been implicated in aspects of neural development and disease. However, while extraordinary research efforts have been made to elucidate the molecular mechanisms involving MMPs, methodological constraints and complexities of the research models have impeded progress. Here we discuss the current state of our understanding of the roles of MMPs in neural development using recent examples and advocate a phylogenetically diverse approach to MMP research as a means to both circumvent the challenges associated with specific model organisms, and to provide a broader evolutionary context from which to synthesize an understanding of the underlying biology. Related Articles | Metrics

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Deconstructing brain-derived neurotrophic factor actions in adult brain circuits to bridge an existing informational gap in neuro-cell biology Heather Bowling, Aditi Bhattacharya, Eric Klann, Moses V. Chao 2016, 11 (3):  363-367.  doi: 10.4103/1673-5374.179031 Abstract ( 205 )   PDF (281KB) ( 712 )   Save Brain-derived neurotrophic factor (BDNF) plays an important role in neurodevelopment, synaptic plasticity,learning and memory, and in preventing neurodegeneration. Despite decades of investigations into downstream signaling cascades and changes in cellular processes, the mechanisms of how BDNF reshapes circuits in vivo remain unclear. This informational gap partly arises from the fact that the bulk of studies into the molecular actions of BDNF have been performed in dissociated neuronal cultures, while the majority of studies on synaptic plasticity, learning and memory were performed in acute brain slices or in vivo. A recent study by Bowling-Bhattacharya et al., measured the proteomic changes in acute adult hippocampal slices following treatment and reported changes in proteins of neuronal and non-neuronal origin that may in concert modulate synaptic release and secretion in the slice. In this paper, we place these findings into the context of existing literature and discuss how they impact our understanding of how BDNF can reshape the brain Related Articles | Metrics

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Acute development of collateral circulation and therapeutic prospects in ischemic stroke Eri Iwasawa, Masahiko Ichijo, Satoru Ishibashi, Takanori Yokota 2016, 11 (3):  368-371.  doi: 10.4103/1673-5374.179033 Abstract ( 395 )   PDF (447KB) ( 847 )   Save In acute ischemic stroke, collateral circulation plays an important role in maintaining blood flow to the tissue that is at risk of progressing into ischemia, and in increasing the successful recanalization rate without hemorrhagic transformation. We have reported that well-developed collateral circulation is associated with smaller infarct volume and better long-term neurological outcome, and it disappears promptly once the effective recanalization is achieved. Contrary to the belief that collateral vessels develop over time in chronic stenotic condition, there exists a phenomenon that collateral circulation develops immediately in acute stenosis or occlusion of the arteries and it seems to be triggered by fluid shear stress, which occurs between the territories of stenotic/occluded arteries and those fed by surrounding intact arteries. We believe that this acute development of collateral circulation is a target of novel therapeutics in ischemic stroke and refer our recent attempt in enhancing collateral circulation by modulating sphingosine-1-phosphate receptor 1, which is a known shear-stress mechanosensing protein. Related Articles | Metrics

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Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR Kenneth Maiese 2016, 11 (3):  372-385.  doi: 10.4103/1673-5374.179032 Abstract ( 190 )   PDF (530KB) ( 638 )   Save Throughout the globe, diabetes mellitus (DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder. DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy. The mechanistic target of rapamycin (mTOR) is a promising agent for the development of novel regenerative strategies for the treatment of DM. mTOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis, insulin resistance, insulin secretion, stem cell proliferation and differentiation, pancreatic β-cell function, and programmed cell death with apoptosis and autophagy. mTOR is central element for the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1 (WISP1), and growth factors. As a result, mTOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease. Future studies directed to elucidate the delicate balance mTOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM. Related Articles | Metrics

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Microscale tissue-engineered models: overcoming barriers to adoption for neural regeneration research Michael J. Moore 2016, 11 (3):  386-387.  doi: 10.4103/1673-5374.179034 Abstract ( 218 )   PDF (283KB) ( 529 )   Save The last decade has seen a steady proliferation in the use of tissue-engineered cell culture systems, and these have been put to good use for studying neural axon growth and guidance. These systems have been designed to more closely mimic the natural microenvironment of the developing or repairing nervous system and to enable spatiotemporal control over certain aspects of the microenvironment. The 3D nature of these culture systems provides a more physiologically-relevant microenvironment, while spatiotemporal control addresses aspects of tissue architecture and molecular presentation for quantitative investigation into how specific physical or molecular variables might influence axon growth. These capabilities should be tremendously important to the study of neural regeneration, since it is well known that developing and regenerating axons of both the central and peripheral nervous systems respond to particular attractive or repulsive cues presented in their microenvironments that may be sensed by the growth cones of these extending axons. Tissue-engineered model systems are well suited to the investigation into precise mechanisms of action of these cues, the elucidation of novel mechanisms, and for testing potential therapeutic strategies. To date, biologists have yet to fully leverage the engineering developments of these model systems for neural regeneration research. This is important because molecular neuroscientists, who are trained for hypothesis-driven research, are arguably better suited to the utilization of these models than bioengineers (such as this author), who may be better suited to their design and validation. The main barriers to adoption of these tools are somewhat obvious: nonstandardized techniques and the need for specialized equipment, devices, and materials. But a more subtle barrier arises because engineers and molecular biologists approach problems differently, frequent different circles, and speak different scientific languages. These differences lead various fields of experts to ignore the advances or dismiss the methodologies of those in other fields, though they may be most relevant. Tissue-engineered culture models have come of age, and are poised to play an integral role in neural regeneration research. For this to occur, the technical and intellectual barriers to adoption of these models can and must be overcome. Related Articles | Metrics

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Can we protect the brain via preconditioning? Role of microRNAs in neuroprotection Sean Quinlan, Eva M. Jimenez-Mateos 2016, 11 (3):  388-389.  doi: 10.4103/1673-5374.179037 Abstract ( 275 )   PDF (136KB) ( 452 )   Save Preconditioning is an adaptive response, whereby a small dose of a harmful substance protects the brain from a subsequent damaging insult. Consequently, several preconditioning treatment paradigms are used in the clinic to protect patients against an ischemic insult in heart pathologies. This data shows the importance of understanding the underlying mechanism to preconditioning, and its translation in the clinic in brain disorders. In concordance, any injury to the brain applied below the threshold of cell damage, including seizures, will induce preconditioning and neuro-protection to the brain. Preconditioning can induce neuroprotection over two phases: Phase one, rapid tolerance, this occurs in a short period of time and is independent of protein production and associated with synapse remodelling. Phase two, delayed (classical) tolerance, this evolves over 1-3 days and requires de novo protein production with a peak at 3 days and diminishes over the course of 1 week. MicroRNAs are defined as small non-coding RNAs (~ 20-22 nucleotides) that regulate gene expression at a post-transcriptional level in a sequence-specific manner. MiRNAs are abundantly expressed in the central nervous system, being involved in diverse functions, including neuronal migration and differentiation, synaptic plasticity and maintenance of functions. The role of microRNAs in preconditioning in brain has been analysed in several experimental models, including ischemic and epileptic murine models. In these studies several microRNAs have been identified as mediators of the neuro-protected effect of the preconditioning stimulus. Both microRNAs regulated pathways are associated with de novo-protein synthesis regulation, supporting the original findings of the association of preconditioning with the de novo-protein synthesis and the efficiency of the preconditioning treatment in the brain. One major question is how faithful is the peripheral profile to the original biological situation in the CNS. However, the same microRNA will not be used as a biomarker and therapeutics target. But still, more deep studies should be necessary to evaluate the correlation between the circulating microRNAs and the neuro-physiological condition. Related Articles | Metrics

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76nt RNAs are transported axonally into regenerating axons and growth cones. What are they doing there? Nicholas A. Ingoglia, Binta Jalloh 2016, 11 (3):  390-391.  doi: 10.4103/1673-5374.179035 Abstract ( 283 )   PDF (273KB) ( 689 )   Save Successful nerve regeneration requires not only that neurons reconstruct new axons distal to the site of injury, but also that those growing axons must navigate through the neuropil to make appropriate synaptic connections with target cells. While this is an imposing task for the thousands of axons that may occupy a regenerating nerve or central nervous system tract, the billions of neurons in the developing brain must accomplish similar tasks making connections that number in the trillions. How do neurons do this? One of the ways researchers have studied these questions is to introduce radiolabeled amino acids into cell bodies of neurons in anaesthetized, experimental animals during embryonic development or nerve regeneration. This in vivo approach labels newly synthesized proteins in the neuron, some of which are transported into the elongating axon. A similar approach has been used to investigate the possibility that RNA is transported axonally, substituting radiolabeled RNA precursors for amino acids. The original goal of these experiments was to explore the possibility that protein synthesis could occur locally in axons, the logic being that if proteins were being synthesized in axons, then the major stable RNAs (ribosomal and transfer RNAs) should be produced in the neuronal cell body and transported into the axon. These studies resulted in the surprising finding that in vertebrate neurons only a single species of RNA, 4S RNA (that co-migrated on SDS PAGE with 76nt, tRNA markers), could be demonstrated to be transported axonally, and only during axon growth (in regenerating optic axons of goldfish and sciatic nerves of rats), and during elongation of optic axons in developing rat and chick brains. Thus, the axonal transport of 76nt RNAs, parallels that of GAP-43. Related Articles | Metrics

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Recent advances and future directions in preclinical research of arginine-vasopressin (AVP) receptor blocker conivaptan in the context of stroke Emil Zeynalov, Susan M. Jones 2016, 11 (3):  392-393.  doi: 10.4103/1673-5374.179038 Abstract ( 169 )   PDF (235KB) ( 468 )   Save Stroke is a major cause of mortality and permanent disability. The onset of stroke is followed by life-threatening pathophysiological responses including brain edema, elevation of intracranial pressure, disruption of blood-brain barrier (BBB), brain infarct and permanent tissue damage. Brain edema develops due to accumulation of water in intracellular and extracellular compartments of the brain, which causes an increase in brain volume and elevation of intracranial pressure. Compression of the brain tissue has an impact on cerebral blood flow which results in secondary brain injury. Often, clinical presentation of stroke is accompanied by hyponatremia caused either by the syndrome of inappropriate release of antidiuretic hormone (SIADH) or cerebral salt wasting (CSW). SIADH is the result of uncontrolled secretion of antidiuretic hormone (ADH) also called arginine-vasopressin (AVP). AVP acts on V1a and V2 receptors triggering vasoconstriction, platelet aggregation, and water retention followed by hypervolemic or normovolemic hyponatremia and low plasma osmolality. Current therapeutic applications against brain edema (such as decompression craniotomy or hypertonic saline) do not fully address complications caused by SIADH or CSW.  Therefore, new research approaches are required to identify and target precise causes of stroke-induced brain edema. Many studies report that AVP receptors (V1a and V2) mediate cascades of events that result in vasoconstriction, platelet aggregation, water retention, and hyponatremia. V1a receptors are found primarily in vascular smooth muscle cells and platelets, and activation of V1a receptors by AVP induces vasoconstriction and platelet aggregation. Therefore, blocking of V1a receptors after ischemic brain injury may potentially prevent vasoconstriction and clot formation, which may also improve regional cerebral blood flow (rCBF), and lower the magnitude of brain edema. V2 receptors are localized in the collecting ducts of the kidneys, and activation of V2 receptors by AVP leads to increased water reabsorption and reduction of plasma sodium and osmolality. Pharmacological inhibition of V2 receptors has been shown to increase water secretion (aquaresis) in the kidneys, raising sodium concentration in the blood and thus may help control brain edema. Related Articles | Metrics

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The role of the unfolded protein response in myelination Michelle C. Naughton, Jill M. McMahon, Una F. FitzGerald 2016, 11 (3):  394-395.  doi: 10.4103/1673-5374.179036 Abstract ( 262 )   PDF (756KB) ( 576 )   Save The production, transport and integration of myelin components into the membrane during development is a highly coordinated and regulated process that relies heavily on the endoplasmic reticulum (ER), a sub-cellular organelle that is the principal site of membrane assembly. Ribosomes on the rough ER allow translation of proteins such as proteolipid protein (PLP) (comprising 50% of total myelin protein) prior to correct folding, post-translational modifications and eventual complexing with nascent smooth ER-synthesised lipids. We hypothesise that oligodendrocytes may make use of a specialised UPR during developmental myelination to cope with exceptional synthetic demand in a manner similar to that employed by differentiating B lymphocytes, where the three arms of the UPR are differentially activated and there is a notable suppression of the PERK pathway. Such a strategy would probably be beneficial in the instance of high protein and membrane manufacture, such as myelination, since PERK signalling is known to result in a significant and global reduction in protein translation. Suppression of this arm, in conjunction with the increase in molecules that improve both the capacity and efficiency of the ER, afforded by signalling through ATF6 and IRE1, can only be of benefit during a period of such intense bioactivity. The question of whether or not activation of the IRE1 and ATF6 arms of the UPR can be boosted therapeutically in an effort to promote remyelination in diseases such as MS, merits further investigation. Related Articles | Metrics

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Dimethyltryptamine (DMT): a biochemical Swiss Army knife in neuroinflammation and neuroprotection? Attila Szabo, Ede Frecska 2016, 11 (3):  396-397.  doi: 10.4103/1673-5374.179041 Abstract ( 395 )   PDF (136KB) ( 556 )   Save The inflammatory theory of many neuropsychiatric illnesses has become an emerging trend in modern medicine. Various immune mechanisms – mainly via the activity of microglia – may contribute to the etiology and symptomatology of diseases, such as schizophrenia, bipolar disorder, depression, or Alzheimer’s disease. They act as ’gatekeepers’ continuously monitoring the tissue microenvironment for potential ’danger signals’ by means of their pattern recognition receptors, such as Toll-like receptors or RIG-I-like receptors. Tryptaminergic trace amines (e.g., N,N-dimethyltryptamine; DMT) as well as neurosteroids (e.g., dehydroepiandrosterone) are endogenous ligands of the Sig-1R. DMT was shown to be endogenously present in the human brain and in other tissues of the body, however the exact physiological role of this tryptamine has not been identified yet. This wide-spectrum agonist activity may allow DMT to modulate several physiological processes and regulate inflammation through the Sig-1R and 5-HTRs. Protective and neuroregenerative effects of Sig-1R agonists have been reported in several in vitro and in vivo studies. The selective Sig-1R agonists 2-(4-morpholinethyl)1 phenylcyclohexanecarboxylate (PRE084) and cutamesine have been shown to strongly promote neuroprotective mechanisms and significantly increase neuronal cell survival and regeneration under various conditions, such as traumas, autoimmunity, and neurodegenerative disorders. Specific Sig-1R stimulation has also been found to greatly increase the levels of the glial cell-derived neurotrophic factor (GDNF) that promotes neuronal cell survival and differentiation. The neuroregenerative potential of DMT through the Sig-1R has been suggested earlier as multiple biochemical and physiological mechanisms exist, which facilitate the transportation and binding of DMT to the Sig-1R in the mammalian brain. Thus DMT – as a natural, endogenous agonist atboth the Sig-1R and 5-HTRs – is hypothesized to be an unique, many-faced pharmacological entity, which has many important roles in the immunoregulatory processes of peripheral and brain tissues, as well as involved in the promotion and induction of neuroregeneration in the mammalian nervous system. Related Articles | Metrics

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Inhibition of the AMPK/nNOS pathway for neuroprotection in stroke Mushfiquddin Khan, Inderjit Singh 2016, 11 (3):  398-399.  doi: 10.4103/1673-5374.179039 Abstract ( 227 )   PDF (680KB) ( 545 )   Save Stroke ranks fourth among all causes of death and is the major cause of long-term disability in the United States. Other than thrombolysis by tissue plasminogen activator (tPA), which offers only a short window of treatment (~3-4 hours), an effective neuroprotective or functional recovery therapy is not available mainly because of limited understanding of the signaling mechanisms of stroke disease. After stroke, the nitric oxide (NO) metabolome is derailed due to aberrant activities of nitric oxide synthases (NOS). In neurons, peroxynitrite production comes to dominate the metabolome rather than S-Nitrosoglutathione (GSNO). In spite of peroxynitrite’s major, causal role in stroke, neuronal peroxynitrite- or nNOS-targeted therapy does not exist due to limited mechanistic understanding of nNOS regulation/signaling and peroxynitrite-modified targets. In order to tease out the roles of GSNO and peroxynitrite in stroke and their potential links to outcomes after IR, research needs to elucidate the complex interplay between phosphorylation/dephosphoryaltion and S-nitrosylation/denitrosylation and/or nitrotyrosination of nNOS and its regulatory enzymes. Undoubtedly, these reactions determine the role of nNOS and the potential effects of excess peroxynitrite and GSNO on outcomes following stroke. Both wild type mice treated with nNOS specific inhibitors and nNOS KO mice show reduced levels of IR injury and improved neurological functions following IR, supporting the need to investigate the nNOS-mediated injury mechanisms and to develop an nNOS targeted stroke therapy for neuroprotection and recovery of functions. nNOS activity is regulated by several mechanisms/mediators, including S-nitrosylation (NO/GSNO), AMP kinase, and peroxynitrite. Therefore, the focus of this perspective is to examine both mechanisms of the NOS-dependent stroke disease and its amelioration by novel S-nitrosylation mechanisms using GSNO in an animal model of transient cerebral ischemia reperfusion (IR). Perhaps discoveries in this realm could offer new opportunities for drug development that could widen or open new therapeutic windows for stroke. Related Articles | Metrics

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Intranasal insulin neuroprotection in ischemic stroke Vasileios-Arsenios Lioutas, Vera Novak 2016, 11 (3):  400-401.  doi: 10.4103/1673-5374.179040 Abstract ( 272 )   PDF (377KB) ( 526 )   Save Acute ischemic stroke (AIS) is a leading cause of death and long-term disability in the USA and worldwide. Significant advances in the last two decades have resulted in introduction of intravenous tissue plasminogen activator and more recently catheter based endovascular interventions in selected patients. These interventions are applicable to a limited number of patients fulfilling specific criteria; therefore neuroprotection has attracted significant attention. Neuroprotection refers to strategies and interventions aiming to limit the extent of AIS-related injury and facilitate the naturally occurring regenerative mechanisms. Acute ischemic injury triggers a series of events in a cellular and molecular level, resulting in energy failure and ultimately neuronal death: Inflammation, excitotoxicity, apoptosis, reactive oxygen and nitrogen species formation, mitochondrial failure have been implicated in the ischemic cascade. In contrast to many other neuroprotective agents used in past clinical trials targeting specific single steps along the process, insulin’s effects are pleiotropic: It suppresses pro-inflammatory transcription factors and might limit the detrimental effect of the inflammatory response. It produces an antithrombotic effect by decreasing the tissue factor and plasminogen activator inhibitor-1 levels and a vasodilatory effect by promoting activation of endothelial nitric oxide synthase; both actions could facilitate recruitment of collateral vessels and enhance the effect of thrombolysis, ultimately reducing the final infarct volume and improving long-term functional outcome. Insulin also favorably regulates cerebral energy homeostasis. In addition to the acute phase, insulin’s effects extend to the subacute and chronic phase, exerting a potent antiapoptotic effect and promoting myelin and neurite regeneration, neurotransmission and functional connectivity of the brain. The intranasal route presents significant advantages: The absorption occurs mostly through paracellular transport and endocytosis, following the course of olfactory and trigeminal neurons that are present in the nasal cavity. This offers the significant advantage of bypassing the blood-brain barrier and achieving rapid, widespread CNS penetration (detected in the CNS within 1 hour from administration). Intranasally administered insulin possesses many of the ideal properties for acute stroke neuroprotection, due to it plurifunctional mechanism of action, wide applicability, safety and simplicity of CNS distribution. Well-designed animal and phase I human studies are necessary to improve our understanding of its neuroprotective potential in acute stroke. Related Articles | Metrics

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Estrogen/Huntingtin: a novel pathway involved in neuroprotection Maria Teresa Nuzzo, Maria Marino 2016, 11 (3):  402-403.  doi: 10.4103/1673-5374.179045 Abstract ( 213 )   PDF (140KB) ( 519 )   Save The pathogenesis of these diseases involves mitochondrial dysfunction/oxidative stress, programmed cell death, abnormal protein aggregation, trafficking, and/or degradation. In most cases, the end stage neuropathology is characterized by a highly specific distribution of abnormal protein aggregates in disease specific patterns in the affected neuronal populations. Although clinical treatments for neurodegenerative disorders have progressed over the years with some promising results, the availability of treatments that can limit or halt neurodegenerative disorders continues to remain limited. A challenging approach to obtain results more close to the patient's treatment could be to dissect the role and the action mechanisms of endogenous substances well known for their neuroprotective effects. Sex steroid hormone estrogens, prevalent in women, seem to be good candidates for these studies. Indeed, a growing number of evidence concerning structural, cellular, and molecular differences in diverse male and female brain regions could explain male and female diverse response to environmental challenges and different vulnerabilities to behavioral and neurological disorders. Striking differences in symptomatology, prevalence, progression, and severity between sexes occur in several neurodegenerative diseases. Although potential sex differences concerning HD are poorly defined, few reports suggest that the age of onset of HD is higher and the course of disease is more moderate in women compared with men. In addition, animal models of HD indicate sex-related differences in the HD phenotype (www.epicentro.iss.it). As a whole, these evidences point to a substantial beneficial influence of 17β-estradiol (the most efficient within estrogens; E2) against the development and progression of neurodegenerative diseases. As a whole, these results allow us to define a novel neuroprotective axis, consisting of E2 induction of Htt and Ngb expression levels by two different and parallel mechanisms with a convergent outcome: the arrest of apoptotic cascade and the neuron survival against oxidative stress injury. The first step depends on the mediation of ERα and culminates in Htt up-regulation. Htt expression results crucial for the realization of the other step, consisting in the increase of Ngb expression through ERβ. The existence of an E2/Htt/Ngb axis supports our working hypothesis that neuroprotection in HD could be renewed by restoring neuroglobin levels with drugs that mimickingE2-induced signal pathways can alleviate symptoms or slow the progression of HD. Related Articles | Metrics

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Glial plasticity after hexahydrobenzene exposure Tania Campos-Ordonez, Oscar Gonzalez-Perez 2016, 11 (3):  404-405.  doi: 10.4103/1673-5374.179042 Abstract ( 193 )   PDF (357KB) ( 546 )   Save Parkinson disease (PD) is a progressive neurodegenerative disorder clinically characterized by motor symptoms (bradykinesia, tremor, rigidity, postural instability) and non-motor symptoms (hyposmia, sleep disorders, autonomic and sphincteric dysfunctions, fatigue, pain, depression, and cognitive disorders). At the onset of parkinsonian symptoms, the neuron loss is quite 70% in the lateral ventral part and 50% in the caudal part of substantia nigra. For this reason, and for the long time between the cellular onset and the clinical onset of the disease, it is mandatory to develop new therapies with disease-modifying and neuroprotective actions. The gold standard therapy for PD is always levodopa, while other currently validated treatments are dopamine agonists, cathecol-O-methyltransferase inhibitors, monoamine-oxidase-B inhibitors, and amantadine. Recent data showed that in some inherited and degenerative diseases of the nervous system the pathogenesis of the symptoms could be linked to a focal deficiency of thiamine (vitamin B1) due either to dysfunction of intracellular thiamine transport or to structural enzymatic abnormalities. Thiamine is a cofactor of enzymes involved in fundamental pathways of energetic cell metabolism, particularly critical in glucose metabolism. Recent clinical studies showed a considerable and stable improvement of motor and non-motor symptoms in patients affected by PD with intramuscular high-dose thiamine (100 mg) administered twice a week. Therefore, we decided to extend the treatment with high doses of thiamine to a series of PD patients in order to clarify the potential effect of thiamine in this disease. We found that long-term treatment with intramuscular administration of thiamine has led to significant improvement of motor and non-motor symptoms of patients with PD; this improvement was stable during time and without side effects. Our report represents an important contribution to PD therapy, although further experience is necessary to exclude placebo effect and to confirm the present observation, with clinical, cellular, and molecular data. The aim of future studies will be to investigate the clinical, restorative, and neuroprotective effects of long-term treatment with thiamine in PD. Related Articles | Metrics

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An open-label pilot study with high-dose thiamine in Parkinson’s diseas Antonio Costantini, Roberto Fancellu 2016, 11 (3):  406-407.  doi: 10.4103/1673-5374.179047 Abstract ( 740 )   PDF (135KB) ( 1279 )   Save Parkinson disease (PD) is a progressive neurodegenerative disorder clinically characterized by motor symptoms (bradykinesia, tremor, rigidity, postural instability) and non-motor symptoms (hyposmia, sleep disorders, autonomic and sphincteric dysfunctions, fatigue, pain, depression, and cognitive disorders). At the onset of parkinsonian symptoms, the neuron loss is quite 70% in the lateral ventral part and 50% in the caudal part of substantia nigra. For this reason, and for the long time between the cellular onset and the clinical onset of the disease, it is mandatory to develop new therapies with disease-modifying and neuroprotective actions. The gold standard therapy for PD is always levodopa, while other currently validated treatments are dopamine agonists, cathecol-O-methyltransferase inhibitors, monoamine-oxidase-B inhibitors, and amantadine. Recent data showed that in some inherited and degenerative diseases of the nervous system the pathogenesis of the symptoms could be linked to a focal deficiency of thiamine (vitamin B1) due either to dysfunction of intracellular thiamine transport or to structural enzymatic abnormalities. Thiamine is a cofactor of enzymes involved in fundamental pathways of energetic cell metabolism, particularly critical in glucose metabolism. Recent clinical studies showed a considerable and stable improvement of motor and non-motor symptoms in patients affected by PD with intramuscular high-dose thiamine (100 mg) administered twice a week. Therefore, we decided to extend the treatment with high doses of thiamine to a series of PD patients in order to clarify the potential effect of thiamine in this disease. We found that long-term treatment with intramuscular administration of thiamine has led to significant improvement of motor and non-motor symptoms of patients with PD; this improvement was stable during time and without side effects. Our report represents an important contribution to PD therapy, although further experience is necessary to exclude placebo effect and to confirm the present observation, with clinical, cellular, and molecular data. The aim of future studies will be to investigate the clinical, restorative, and neuroprotective effects of long-term treatment with thiamine in PD. Related Articles | Metrics

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Enzymatic remodeling of heparan sulfate: a therapeutic strategy for systemic and localized amyloidoses? Kazuchika Nishitsuji, Hiroyuki Saito, Kenji Uchimura 2016, 11 (3):  408-409.  doi: 10.4103/1673-5374.179043 Abstract ( 192 )   PDF (458KB) ( 472 )   Save The term “amyloidosis” today refers to diseases in which amyloidogenic proteins deposit as insoluble fibrils in many tissues and organs. Thus far, many in vivo observations revealed that amyloid deposits contain, besides protein fibrils, carbohydrate and other protein components derived from intra- and extracellular spaces. These non-amyloid components may be involved in the pathogenesis and pathology of amyloidosis, such as amyloid formation and amyloid-induced tissue damage. In the 1980s, Snow and Kisilevsky found that glycosaminoglycans (GAGs) were associated with tissue amyloid deposits. They identified the GAG as heparan sulfate (HS), which is a component of heparan sulfate proteoglycan (HSPG) and a member of the GAG family. HS is now known to be associated with different types of amyloid in systemic and localized amyloidoses. From this perspective, we will discuss here the possible roles of HS and its highly sulfated domains in the pathogenesis and pathology of amyloidosis. As described above, HSulf-1 and HSulf-2 degraded RB4CD12 epitopes that had accumulated in amyloid plaques of AD modelmice. HSulf-1 and HSulf-2 also interfered with the cellular interaction and cytotoxicity of apoA-I fibrils. An ex vivo study showed that amyloid plaques were retained after degradation of RB4CD12 epitopes, so whether these “post-treated” amyloid plaques areunstable or vulnerable to proteolytic degradation and/or microglial clearance requires clarification. These results suggest a novel concept that enzymatic remodeling of HS may be a therapeutic strategy for systemic and localized amyloidoses. We previously showed that sulfate moieties of HS affected cytotoxicity and degradation of amyloid or amyloidogenic proteins by regulating their cellular interactions. Additional studies to elucidate the roles of highly sulfated domains of HS in amyloid formation, interaction of amyloid with cells in various tissues and organs, and subsequent cytotoxicity or degradation are ongoing. Related Articles | Metrics

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Multiple sclerosis and neuromyelitis optica spectrum disorders: some similarities in two distinct diseases Hiroaki Yokote, Hidehiro Mizusawa 2016, 11 (3):  410-411.  doi: 10.4103/1673-5374.179048 Abstract ( 306 )   PDF (218KB) ( 603 )   Save There are some similarities between MS and NMOSD, although these 2 diseases are essentially distinct. Understanding the similarities between MS and NMOSD helps us to see an atypical case that is the borderline between MS and NMOSD. It is essential to choose carefully an appropriate treatment based on the nature of the lesion and the pathophysiological background: IFN-β should be avoided for this borderline patient at least since the disease can be mediated by Th17. Related Articles | Metrics

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ApoE2 and Alzheimer’s disease: time to take a closer look Long Wu, Liqin Zhao 2016, 11 (3):  412-413.  doi: 10.4103/1673-5374.179044 Abstract ( 164 )   PDF (356KB) ( 661 )   Save Alzheimer’s disease (AD) is the most common form of dementia among the elderly. It currently affects approximately 5.1 million Americans, a number predicted to triple by 2050. AD is clinically manifested as progressive loss of memory and cognitive function, and is characterized pathologically by the formation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFT). Since its discovery in 1906, extensive research has been undertaken to define AD pathogenesis and to develop treatments; however, the cause of AD remains largely unknown and no therapeutic success has been achieved in over 200 AD drug trials conducted in the past decade. These challenges underscore the need for increased research focus to better understand AD risk mechanisms that would allow for the development of strategies aimed at AD prevention and early intervention. In the past 20 years, ApoE2 has been increasingly recognized as a neuroprotective variant; however, the underlying mechanisms have been largely unexplored. Our recent findings offer new perspectives for further in-depth studies that will increase our understanding of the roles of ApoE2 and of how ApoE genotypes interact with sex to modulate the adaptation and defense mechanisms in the aging brain. The insights gained from these mechanistic investigations could potentially be translated into therapeutic strategies aimed to transform an aging —in particular, an ApoE4 brain—into an ApoE2-like brain, thereby preventing and reducing the risk for AD. Related Articles | Metrics

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Ischemia and reperfusion injury of the spinal cord: experimental strategies to examine postischemic paraplegia Florian Simon, Alexander Oberhuber 2016, 11 (3):  414-415.  doi: 10.4103/1673-5374.179050 Abstract ( 209 )   PDF (211KB) ( 429 )   Save There are several aspects one should consider if thinking about building up an animal model. First of all it is important to understand that experimental models are only an attempt to mimic clinical situation and require a lot of discussion when conclusions are to be drawn with a view to humans. There will never be an ideal model. For a deeper understanding of a clinic problem or side-effect several models are needed so that the best fitting one can be chosen. This indicates that a precise formulation of the question to be answered is needed in advance. It requires a rather big budget, a lot of time and manpower to realise a large animal model that should take place in an animal intensive care. At the same time this has the benefit of more clinical relevant data acquisition. For those needing a simple model that is easy to learn and only needs an animal operation theatre but no animal intensive care unit, the rabbit model might be the right choice. It combines the small surgical impact with the possibility of long-time postoperative observation. When looking at questions dealing with DNA focus or needing animals of genetically altered strains the mouse model will fit best as it offers these advantages that normally cannot be found in other animal models. Eventually, when building up a new model one should take into account that research in literature will not replace teamwork with already experienced scientists in this field. Results will always differ from literature of other groups, because micromanagement differs. So each new experiment, especially when using a new animal model, needs a learning curve for building up one’s own know-how. Related Articles | Metrics

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Drosophila neuronal injury model allows for temporal dissection of neurodegenerative events Barron L. Lincoln II, Lani C. Keller 2016, 11 (3):  416-417.  doi: 10.4103/1673-5374.179046 Abstract ( 229 )   PDF (453KB) ( 509 )   Save Drosophila melanogaster have become one of the preeminent model systems to study neurodegeneration due to their short life cycle, exemplar genetics, vast array of available reagents and most importantly the similarities to the human neurodegenerative process. Drosophila provide researchers with several simple model systems from which to study a variety of neurodegenerative diseases ranging from Alzheimer’s Disease and Tauopathies to Amyotrophic Lateral Sclerosis and Prion Diseases. Forward and reverse genetic screens, the use of transgenic animals, and the ability to test candidate therapeutics by pharmacological approaches have allowed researchers to make great strides in determining the molecular signaling involved in the neural injury response. These simple models are capable of reproducing many complex neurodegenerative phenotypes also observed in humans. The trauma seen in spinal cord injuries or traumatic brain injuries can be replicated using both mechanical and genetically induced injuries. The significant progress in neurodegeneration research would not be possible without the technological advances in imagery and staining. The advanced development of fluorescent proteins, anti-body staining techniques, live cell imaging technology, and super resolution microscopy have increased the rate of scientific discovery in the fields of neurodegenerative research. Related Articles | Metrics

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Contribution of purinergic receptors to spinal cord injury repair: stem cell- based neuroregeneration Rosa Gomez-Villafuertes 2016, 11 (3):  418-419.  doi: 10.4103/1673-5374.179049 Abstract ( 211 )   PDF (275KB) ( 410 )   Save Traumatic spinal cord injury (SCI), defined as physical trauma to the spinal column yielding altered motor, sensory, or autonomic function, is a devastating neurological disease causing major impact at both personal and societal level. Unfortunately, to date no effective treatment exists for the major neurological deficits of SCI. However, there are several hopeful neuroprotective agents beingcurrently investigated in ongoing preclinical and clinical trials. The aim of neuroprotective treatments is not only to reduce cell death and reduce mechanisms of secondary injury, but also to promote regeneration and tissue repair. One of these promising therapeutic strategies consists on cell transplantation to replace dead or damaged cells and provide trophic support. In particular, adult neural stem/progenitor cells (NSPCs) are especially attractive to promote tissue repair after SCI, since they readily expand in vitro forming colonies of undifferentiated cells called neurospheres, and are committed to the neural lineage.Adult NSPCs may have advantages over embryonic or fetal cells: 1) in some cases it will be possible to harvest them in an autologous fashion; 2) they may have less oncogenic potential than embryonic stem cells; and 3) the avoidance of some of the ethical issues surrounding the use of stem cells of embryonic or fetal origin. Related Articles | Metrics

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Vasopressor administration in spinal cord injury: should we apply a universal standard to all injury patterns? William J. Readdy, Sanjay S. Dhall 2016, 11 (3):  420-421.  doi: 110.4103/1673-5374.179051 Abstract ( 341 )   PDF (235KB) ( 788 )   Save Spinal cord injury (SCI) is a devastating in pathology, with significant physical, psychosocial, and financial burdens. Despite the severity of this disease, and our deepening understanding of the pathophysiology, we remain limited in our treatment options. Recent well-publicized studies have focused on the benefit of early surgical decompression in this patient population, but fewer studies have focused on the medical management of these patients. In light of the recent controversy surrounding methylprednisolone administration, many believe that supraphysiologic mean arterial pressure (MAP) maintenance offers the best hope for improving outcomes through medical management. The 2013 guidelines recommend the maintenance of MAP between 85 and 90 mm Hg for the first seven days following acute cervical SCI. Although limited by the paucity of current literature on the topic, this recommendation provides the foundation for medical management of SCI at many institutions. Given the devastating nature of this injury pattern, the long term sequelae of injury, and the limited number of interventions, we continue to search for alternative and improved therapies to reduce the burden of disease. While research in MAP therapy is promising, it must be viewed contextually. Throughout these studies, spinal cord injury is treated as a homogenous injury pattern, when SCIs can vary extensively in prognosis. Variables including level of injury, mechanism of injury, presence of hemorrhagic spinal cord trauma, and pattern of intraspinal injury can all impact long-term outcomes. Applying universal standards to what must be considered a heterogeneous patient population may not be the best approach. In a 2015 study, Readdy et al. show that patients with acute traumatic central cord injury (ATCCS) who received vasopressors for MAP goal maintenance suffered high rates of cardiogenic complications (76%). Results indicate that vasopressor administration was associated with significant and preventable adverse outcomes. It is our belief that these discrepancies highlight the continued importance of clinical decision-making. The implementation of the 2013 AANS Guidelines on the administration of vasopressors in acute SCI shows promise, but clinicians must continue to exercise situational judgment. Universal application of guidelines to the heterogeneous mixture of spinal cord injury patients may result in concerning risk-benefit ratios in certain patient populations. Additionally, a multicenter study is needed to elucidate the proper management of acute SCI. To date, a major limitation in the development of such a study has been the incongruence amongst SCI data recording methods across centers. We recommend that members of the clinical SCI research community begin to adapt a standardized data collection approach, such as the National Institute of Health/National Institute of Neurologic Disorders and Stroke (NIH/NINDS) Common Data Elements to facilitate multi-center studies. Expanding the current single-institutional studies to larger multi-institutional collaborations is essential, given the limited incidence of acute SCI. These subpopulation analyses will allow for clearer, personalized guidelines while also elucidating the true risk-benefit ratio of vasopressor administration in each group. Related Articles | Metrics

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Peripheral nerve regeneration monitoring using multilayer microchannel scaffolds Yoonsu Choi, Hongseok (Moses) Noh 2016, 11 (3):  422-423.  doi: 10.4103/1673-5374.179052 Abstract ( 199 )   PDF (264KB) ( 698 )   Save After a systemic study with a wide range of the temporal and structural variation, promising clinical applications can be pursued using this temporal structural nerve regeneration; forinstance, a guided nerve regeneration from the proximal nerve to the severed target distal nerve. This is dependent on a proper nerve regeneration where enough number of axonal growth should be initiated and guided to the target nerve stump using scaffolding materials and finally reinnervate to the target muscles. For final clinical uses, the scaffolding material will be switched with biodegradable materials using the same fabrication technique. While the well guided regenerated nerves regain the functional control on the target muscles, the biodegradable scaffolds will also disappear. The other benefit of the temporal and structural guidance of the growth cone and axonal branching is the selective nerve regeneration to the specific nerves and proper sensory and motor axonal connection to improve misdirection of the regenerated nerves. This could be achieved with an additional capability of the multilayer microchannel scaffolds with biochemical guidance. Related Articles | Metrics

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Neuroinflammation in glaucoma: soluble tumor necrosis factor alpha and the connection with excitotoxic damage Jorge L. Cueva Vargas, Adriana Di Polo 2016, 11 (3):  424-426.  doi: 10.4103/1673-5374.179053 Abstract ( 176 )   PDF (419KB) ( 680 )   Save Inflammation is a complex and highly regulated response that occurs early after infection or injury. The inflammatory response in the central nervous system (CNS), known as neuroinflammation, is achieved by activation of resident glia and monocyte-derived cells. Accumulating evidence indicates that this cellular response occurs in the early stages of numerous neurodegenerative diseases, triggering a cascade of events that converge to promote neuronal damage. Indeed, neuroinflammation has been reported in a host of CNS disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, stroke, and glaucoma. Glaucoma is a prevalent neurodegenerative disease and characterized by the progressive degeneration of retinal ganglion cells (RGC) and their axons in the optic nerve resulting in gradual vision loss. High intraocular pressure is the most significant known risk factor for developing the disease, but the mechanism by which elevated pressure promotes RGC damage is currently unknown. Current therapies are aimed at lowering intraocular pressure, but many patients continue to experience visual field loss even when pressure lowering treatments are implemented. A better understanding of the mechanisms causing glaucomatous neurodegeneration triggered by ocular hypertension injury is, therefore, essential to develop effective therapies. Accumulating evidence indicates that neuroinflammation plays a key role in RGC damage in glaucoma. A number of studies have confirmed the presence of hallmark features of neuroinflammation in glaucoma animal models and human specimens including glial cell activation, upregulation of proinflammatory cytokines, induction of the complement cascade, and trans-endothelial cell migration of leukocytes. A critical modulator of the neuroinflammatory response in glaucoma is tumor necrosis factor alpha (TNFα). RGCs express the TNFα receptors 1 and 2 (TNFR1/2) and TNFα signaling has been linked to RGC death. For example, exogenous administration of TNFα promotes RGC loss and optic nerve degeneration, and genetic or pharmacological depletion of TNFα or its receptors stimulates RGC survival. High-throughput characterization of the retinal proteome revealed significant upregulation of TNFα signaling in human glaucoma. Notably, TNFα levels are elevated in aqueous humor samples from glaucoma patients and TNFα gene polymorphisms are associated with primary open angle glaucoma. In conclusion, while endogenous TNFα plays critical physiological roles in retinal homeostasis and neurotransmission. These findings suggest that modulation of soluble TNFα signaling might be beneficial to counter the harmful effect of neuroinflammation and synaptic alterations in glaucomatous optic neuropathies. Related Articles | Metrics

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GIT1 enhances neurite outgrowth by stimulating microtubule assembly Yi-sheng Li, Li-xia Qin, Jie Liu, Wei-liang Xia, Jian-ping Li, Hai-lian Shen, Wei-Qiang Gao 2016, 11 (3):  427-434.  doi: 10.4103/1673-5374.179054 Abstract ( 245 )   PDF (1397KB) ( 782 )   Save  GIT1, a G-protein-coupled receptor kinase interacting protein, has been reported to be involved in neurite outgrowth. However, the neurobiological functions of the protein remain unclear. In this study, we found that GIT1 was highly expressed in the nervous system, and its expression was maintained throughout all stages of neuritogenesis in the brain. In primary cultured mouse hippocampal neurons from GIT1 knockout mice, there was a significant reduction in total neurite length per neuron, as well as in the average length of axon-like structures,which could not be prevented by nerve growth factor treatment. Overexpression of GIT1 significantly promoted axon growth and fully rescued the axon outgrowth defect in the primary hippocampal neuron cultures from GIT1 knockout mice. The GIT1 N terminal region, including the ADP ribosylation factor-GTPase activating protein domain, the ankyrin domains and the Spa2 homology domain, were sufficient to enhance axonal extension. Importantly, GIT1 bound to many tubulin proteins and microtubule-associated proteins, and it accelerated microtubule assembly in vitro. Collectively, our findings suggest that GIT1 promotes neurite outgrowth, at least partially by stimulating microtubule assembly. This study provides new insight into the cellular and molecular pathogenesis of GIT1-associated neurological diseases. Related Articles | Metrics

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Buyanghuanwu decoction promotes angiogenesis after cerebral ischemia/reperfusion injury: mechanisms of brain tissue repair Zhen-qiang Zhang, Jun-ying Song, Ya-quan Jia, Yun-ke Zhang 2016, 11 (3):  435-440.  doi: 10.4103/1673-5374.179055 Abstract ( 239 )   PDF (1017KB) ( 1041 )   Save Buyanghuanwu decoction has been shown to protect against cerebral ischemia/reperfusion injury, but the underlying mechanisms remain unclear. In this study, rats were intragastrically given Buyanghuanwu decoction, 15 mL/kg, for 3 days. A rat model of cerebral ischemia/reperfusion injury was established by middle cerebral artery occlusion. In rats administered Buyanghuanwu decoction, infarct volume was reduced, serum vascular endothelial growth factor and integrin αvβ3 levels were increased, and brain tissue vascular endothelial growth factor and CD34 expression levels were increased compared with untreated animals. These effects of Buyanghuanwu decoction were partially suppressed by an angiogenesis inhibitor (administered through the lateral ventricle for 7 consecutive days). These data suggest that Buyanghuanwu decoction promotes angiogenesis, improves cerebral circulation, and enhances brain tissue repair after cerebral ischemia/reperfusion injury. Related Articles | Metrics

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Radix Ilicis Pubescentis total flavonoids ameliorates neuronal damage and reduces lesion extent in a mouse model of transient ischemic attack Ming-san Miao, Lin Guo, Rui-qi Li, Xiao-lei Zhang 2016, 11 (3):  441-446.  doi: 10.4103/1673-5374.179056 Abstract ( 271 )   PDF (783KB) ( 1005 )   Save Flavonoids are a major component in the traditional Chinese medicine Radix Ilicis Pubescentis. Previous studies have shown that the administration of Radix Ilicis Pubescentis total flavonoids is protective in cerebral ischemia. However, to our knowledge, no studies have examined whether the total flavonoids extracted from Radix Ilicis Pubescentis prevent or ameliorate neuronal damage following transient ischemic attacks. Therefore, Radix Ilicis Pubescentis total flavonoids question and the potential underlying mechanisms. Thus, beginning 3 days before the induction of a mouse model of transient ischemic attack using tert-butyl hydroperoxide injections, mice were intragastrically administered 0.3, 0.15, or 0.075 g/kg of Radix Ilicis Pubescentis total flavonoids daily for 10 days. The results of spectrophotometric analyses demonstrated that Radix Ilicis Pubescentis total flavonoids enhanced oxygen free radical scavenging and reduced pathological alterations in the brain. Hematoxylin-eosin staining results showed that Radix Ilicis Pubescentis total flavonoids reduced hippocampal neuronal damage and cerebral vascular injury in this mouse model of transient ischemic attack. These results suggest that the antioxidant effects of Radix Ilicis Pubescentis total flavonoids alleviate the damage to brain tissue caused by transient ischemic attack. Related Articles | Metrics

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BACE1 in the retina: a sensitive biomarker for monitoring early pathological changes in Alzheimer’s disease Lan Li, Jia Luo, Dan Chen, Jian-bin Tong, Le-ping Zeng, Yan-qun Cao, Jian Xiang, Xue-gang Luo, Jing-ming Shi, Hui Wang,Ju-fang Huang 2016, 11 (3):  447-453.  doi: 10.4103/1673-5374.179057 Abstract ( 269 )   PDF (1968KB) ( 858 )   Save Because of a lack of sensitive biomarkers, the diagnosis of Alzheimer’s disease (AD) cannot be made prior to symptom manifestation. Therefore, it is crucial to identify novel biomarkers for the presymptomatic diagnosis of AD. While brain lesions are a major feature of AD, retinal pathological changes also occur in patients. In this study, we investigated the temporal changes in β-site APP-cleaving enzyme 1 (BACE1) expression in the retina and brain to determine whether it could serve as a suitable biomarker for early monitoring of AD. APP/PS-1 transgenic mice, 3, 6 and 8 months of age, were used as an experimental group, and age-matched C57/BL6 wild-type mice served as the control group. In the Morris water maze test, there were no significant differences in escape latency or in the number of crossings in the target area among mice of different ages. Compared with wild-type mice, no changes in learning or memory abilities were detected in transgenic mice at 3 months of age. However, compared with wild-type mice, the escape latency was significantly increased in transgenic mice at 6 months, starting on day 3, and at 8 months, starting on day 2, during Morris water maze training. In addition, the number of crossings of the target area was significantly decreased in transgenic mice. The learning and memory abilities of transgenic mice were further worsened at 8 months of age. Immunohistochemical staining revealed no BACE1 plaques in wild-type mice at 3, 6 or 8 months or in transgenic mice at 3 months, but they were clearly found in the entorhinal cortex, hippocampus and prefrontal cortex of transgenic mice at 6 and 8 months. BACE1 expression was not detected in the retina of wild-type mice at 3 months, but weak BACE1 expression was detected in the ganglion cell layer, inner plexiform layer and outer plexiform layer at 6 and 8 months. In transgenic mice, BACE1 expression in the ganglion cell layer was increased at 3 months, and BACE1 expression in the ganglion cell layer, inner plexiform layer and outer plexiform layer was significantly increased at 6 and 8 months, compared with age-matched wild-type mice. Taken together, these results indicate that changes in BACE1 expression appear earlier in the retina than in the brain and precede behavioral deficits. Our findings suggest that abnormal expression of BACE1 in the retina is an early pathological change in APP/PS-1 transgenic mice, and that BACE1 might have potential as a biomarker for the early diagnosis of AD in humans. Related Articles | Metrics

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Neuroprotective effects of tetrandrine against vascular dementia Yan-ling Lv, Ze-zhi Wu, Li-xue Chen, Bai-xue Wu, Lian-lian Chen, Guang-cheng Qin, Bei Gui, Ji-ying Zhou 2016, 11 (3):  454-459.  doi: 10.4103/1673-5374.179058 Abstract ( 322 )   PDF (802KB) ( 800 )   Save Tetrandrine is one of the major active ingredients in Menispermaceae Stephania tetrandra S. Moore, and has specific therapeutic effects in ischemic cerebrovascular disease. Its use in vascular dementia has not been studied fully. Here, we investigated whether tetrandrine would improve behavioral and cellular impairments in a two-vessel occlusion rat model of chronic vascular dementia. Eight weeks after model establishment, rats were injected intraperitoneally with 10 or 30 mg/kg tetrandrine every other day for 4 weeks. Behavioral assessment in the Morris water maze showed that model rats had longer escape latencies in training trials, and spent less time swimming in the target quadrant in probe trials, than sham-operated rats. However, rats that had received tetrandrine showed shorter escape latencies and longer target quadrant swimming time than untreated model rats. Hematoxylin-eosin and Nissl staining revealed less neuronal necrosis and pathological damage, and more living cells, in the hippocampus of rats treated with tetrandrine than in untreated model rats. Western blot assay showed that interleukin-1β expression, and phosphorylation of the N-methyl-D-aspartate 2B receptor at tyrosine 1472, were lower in model rats that received tetrandrine than in those that did not. The present findings suggest that tetrandrine may be neuroprotective in chronic vascular dementia by reducing interleukin-1β expression, N-methyl-D-aspartate receptor 2B phosphorylation at tyrosine 1472, and neuronal necrosis. Related Articles | Metrics

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Neuroprotection against vascular dementia after acupuncture combined with donepezil hydrochloride: P300 event related potential Qiang Liu, Xiu-juan Wang,Zhe-cheng Zhang, Rong Xue, Ping Li, Bo Li 2016, 11 (3):  460-464.  doi: 10.4103/1673-5374.179059 Abstract ( 206 )   PDF (335KB) ( 751 )   Save Acupuncture can be used to treat various nervous system diseases. Here, 168 vascular dementia patients were orally administered donepezil hydrochloride alone (5 mg/day, once a day for 56 days), or combined with acupuncture at Shenting (DU24), Tianzhu (BL10), Sishencong (Extra), Yintang (Extra), Renzhong (DU26), Neiguan (PC6), Shenmen (HT7), Fengchi (GB20), Wangu (GB12) and Baihui (DU20) (once a day for 56 days). Compared with donepezil hydrochloride alone, P300 event related potential latency was shorter with an increased amplitude in patients treated with donepezil hydrochloride and acupuncture. Mini-Mental State Examination score was also higher. Moreover, these differences in P300 latency were identified within different infarcted regions in patients treated with donepezil hydrochloride and acupuncture. These findings indicate that acupuncture combined with donepezil hydrochloride noticeably improves cognitive function in patients with vascular dementia, and exerts neuroprotective effects against vascular dementia. Related Articles | Metrics

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“Warming yang and invigorating qi” acupuncture alters acetylcholine receptor expression in the neuromuscular junction of rats with experimental autoimmune myasthenia gravis Hai-peng Huang, Hong Pan, Hong-feng Wang 2016, 11 (3):  465-468.  doi: 10.4103/1673-5374.179060 Abstract ( 240 )   PDF (1432KB) ( 799 )   Save Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction. “Warming yang and invigorating qi” acupuncture treatment has been shown to reduce serum inflammatory cytokine expression and increase transforming growth factor beta expression in rats with experimental autoimmune myasthenia gravis. However, few studies have addressed the effects of this type of acupuncture on the acetylcholine receptors at the neuromuscular junction. Here, we used confocal laser scanning microscopy to examine the area and density of immunoreactivity for an antibody to the nicotinic acetylcholine receptor at the neuromuscular junction in the phrenic nerve of rats with experimental autoimmune myasthenia gravis following “warming yang and invigorating qi” acupuncture therapy. Needles were inserted at acupressure points Shousanli(LI10), Zusanli (ST36), Pishu (BL20), and Shenshu (BL23) once daily for 7 consecutive days. The treatment was repeated after 1 day of rest. We found that area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve was significantly increased following acupuncture treatment. This outcome of the acupuncture therapy was similar to that of the cholinesterase inhibitor pyridostigmine bromide. These findings suggest that “warming yang and invigorating qi” acupuncture treatment increases acetylcholine receptor expression at the neuromuscular junction in a rat model of autoimmune myasthenia gravis. Related Articles | Metrics

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Macular thickness as a predictor of loss of visual sensitivity in ethambutol-induced optic neuropathy Chun-xia Peng, Ai-di Zhang, Bing Chen, Bing-jian Yang, Qiu-hong Wang, Mo Yang, Shi-hui Wei 2016, 11 (3):  469-475.  doi: 10.4103/1673-5374.179061 Abstract ( 298 )   PDF (947KB) ( 1093 )   Save Ethambutol is a common cause of drug-related optic neuropathy. Prediction of the onset of ethambutol-induced optic neuropathy and consequent drug withdrawal may be an effective method to stop visual loss. Previous studies have shown that structural injury to the optic nerve occurred earlier than the damage to visual function. Therefore, we decided to detect structural biomarkers marking visual field loss in early stage ethambutol-induced optic neuropathy. The thickness of peripapillary retinal nerve fiber layer, macular thickness and visual sensitivity loss would be observed in 11 ethambutol-induced optic neuropathy patients (22 eyes) using optical coherence tomography. Twenty-four healthy age- and sex-matched participants (48 eyes) were used as controls. Results demonstrated that the temporal peripapillary retinal nerve fiber layer thickness and average macular thickness were thinner in patients with ethambutol-induced optic neuropathy compared with healthy controls. The average macular thickness was strongly positively correlated with central visual sensitivity loss (r2=0.878, P=0.000). These findings suggest that optical coherence tomography can be used to efficiently screen patients. Macular thickness loss could be a potential factor for predicting the onset of ethambutol-induced optic neuropathy. Related Articles | Metrics

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Imipramine protects retinal ganglion cells from oxidative stress through the tyrosine kinase receptor B signaling pathway Ming-lei Han, Guo-hua Liu, Jin Guo, Shu-juan Yu, Jing Huang 2016, 11 (3):  476-479.  doi: 10.4103/1673-5374.179066 Abstract ( 210 )   PDF (540KB) ( 489 )   Save Retinal ganglion cell (RGC) degeneration is irreversible in glaucoma and tyrosine kinase receptor B (TrkB)-associated signaling pathways have been implicated in the process. In this study, we attempted to examine whether imipramine, a tricyclic antidepressant, may protect hydrogen peroxide (H2O2)-induced RGC degeneration through the activation of the TrkB pathway in RGC-5 cell lines. RGC-5 cell lines were pre-treated with imipramine 30 minutes before exposure to H2O2. Western blot assay showed that in H2O2-damaged RGC-5 cells, imipramine activated TrkB pathways through extracellular signal-regulated protein kinase/TrkB phosphorylation. TUNEL staining assay also demonstrated that imipramine ameliorated H2O2-induced apoptosis in RGC-5 cells. Finally, TrkB-IgG intervention was able to reverse the protective effect of imipramine on H2O2-induced RGC-5 apoptosis. Imipramine therefore protects RGCs from oxidative stress-induced apoptosis through the TrkB signaling pathway. Related Articles | Metrics

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Characteristics of mRNA dynamic expression related to spinal cord ischemia/reperfusion injury: a transcriptomics study Zhi-ping Qi, Peng Xia, Ting-ting Hou, Ding-yang Li, Chang-jun Zheng, Xiao-yu Yang 2016, 11 (3):  480-486.  doi: 10.4103/1673-5374.179067 Abstract ( 223 )   PDF (1338KB) ( 587 )   Save Following spinal cord ischemia/reperfusion injury, an endogenous damage system is immediately activated and participates in a cascade reaction. It is difficult to interpret dynamic changes in these pathways, but the examination of the transcriptome may provide some information. The transcriptome reflects highly dynamic genomic and genetic information and can be seen as a precursor for the proteome. We used DNA microarrays to measure the expression levels of dynamic evolution-related mRNA after spinal cord ischemia/reperfusion injury in rats. The abdominal aorta was blocked with a vascular clamp for 90 minutes and underwent reperfusion for 24 and 48 hours. The simple ischemia group and sham group served as controls. After rats had regained consciousness, hindlimbs showed varying degrees of functional impairment, and gradually improved with prolonged reperfusion in spinal cord ischemia/reperfusion injury groups. Hematoxylin-eosin staining demonstrated that neuronal injury and tissue edema were most severe in the 24-hour reperfusion group, and mitigated in the 48-hour reperfusion group. There were 8,242 differentially expressed mRNAs obtained by Multi-Class Dif in the simple ischemia group, 24-hour and 48-hour reperfusion groups. Sixteen mRNA dynamic expression patterns were obtained by Serial Test Cluster. Of them, five patterns were significant. In the No. 28 pattern, all differential genes were detected in the 24-hour reperfusion group, and their expressions showed a trend in up-regulation. No. 11 pattern showed a decreasing trend in mRNA whereas No. 40 pattern showed an increasing trend in mRNA from ischemia to 48 hours of reperfusion, and peaked at 48 hours. In the No. 25 and No. 27 patterns, differential expression appeared only in the 24-hour and 48-hour reperfusion groups. Among the five mRNA dynamic expression patterns, No. 11 and No. 40 patterns could distinguish normal spinal cord from pathological tissue. No. 25 and No. 27 patterns could distinguish simple ischemia from ischemia/reperfusion. No. 28 pattern could analyze the need for inducing reperfusion injury. The study of specific pathways and functions for different dynamic patterns can provide a theoretical basis for clinical differential diagnosis and treatment of spinal cord ischemia/reperfusion injury. Related Articles | Metrics

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Salvianolic acid B protects the myelin sheath around injured spinal cord axons Zhe Zhu, Lu Ding, Wen-feng Qiu, Hong-fu Wu, Rui Li 2016, 11 (3):  487-492.  doi: 10.4103/1673-5374.179068 Abstract ( 245 )   PDF (1158KB) ( 602 )   Save Salvianolic acid B, an active pharmaceutical compound present in Salvia miltiorrhiza, exerts a neuroprotective effect in animal models of brain and spinal cord injury. Salvianolic acid B can promote recovery of neurological function; however, its protective effect on the myelin sheath after spinal cord injury remains poorly understood. Thus, in this study, in vitro tests showed that salvianolic acid B contributed to oligodendrocyte precursor cell differentiation, and the most effective dose was 20 μg/mL. For in vivo investigation, rats with spinal cord injury were intraperitoneally injected with 20 mg/kg salvianolic acid B for 8 weeks. The amount of myelin sheath and the number of regenerating axons increased, neurological function recovered, and caspase-3 expression was decreased in the spinal cord of salvianolic acid B-treated animals compared with untreated control rats. These results indicate that salvianolic acid B can protect axons and the myelin sheath, and can promote the recovery of neurological function. Its mechanism of action is likely to be associated with inhibiting apoptosis and promoting the differentiation and maturation of oligodendrocyte precursor cells. Related Articles | Metrics

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Substance P combined with epidermal stem cells promotes wound healing and nerve regeneration in diabetes mellitus Fei-bin Zhu, Xiang-jing Fang, De-wu Liu, Ying Shao, Hong-yan Zhang, Yan Peng, Qing-ling Zhong, Yong-tie Li,De-ming Liu 2016, 11 (3):  493-501.  doi: 10.4103/1673-5374.179073 Abstract ( 276 )   PDF (6772KB) ( 983 )   Save Exogenous substance P accelerates wound healing in diabetes, but the mechanism remains poorly understood. Here, we established a rat model by intraperitoneally injecting streptozotocin. Four wounds (1.8 cm diameter) were drilled using a self-made punch onto the back, bilateral to the vertebral column, and then treated using amniotic membrane with epidermal stem cells and/or substance P around and in the middle of the wounds. With the combined treatment the wound-healing rate was 100% at 14 days. With prolonged time, type I collagen content gradually increased, yet type III collagen content gradually diminished. Abundant protein gene product 9.5- and substance P-immunoreactive nerve fibers regenerated. Partial nerve fiber endings extended to the epidermis. The therapeutic effects of combined substance P and epidermal stem cells were better than with amniotic membrane and either factor alone. Our results suggest that the combination of substance P and epidermal stem cells effectively contributes to nerve regeneration and wound healing in diabetic rats. Related Articles | Metrics

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Altered microRNA expression profiles in a rat model of spina bifida Pan Qin, Lin Li, Da Zhang, Qiu-liang Liu, Xin-rang Chen, He-ying Yang, Ying-zhong Fan, Jia-xiang Wang 2016, 11 (3):  502-507.  doi: 10.4103/1673-5374.179070 Abstract ( 437 )   PDF (819KB) ( 476 )   Save MicroRNAs (miRNAs) are dynamically regulated during neurodevelopment, yet few reports have examined their role in spina bifida. In this study, we used an established fetal rat model of spina bifida induced by intragastrically administering olive oil-containing all-trans retinoic acid to dams on day 10 of pregnancy. Dams that received intragastric administration of all-trans retinoic acid-free olive oil served as controls. The miRNA expression profile in the amniotic fluid of rats at 20 days of pregnancy was analyzed using an miRNA microarray assay. Compared with that in control fetuses, the expression of miRNA-9, miRNA-124a, and miRNA-138 was significantly decreased (> 2-fold), whereas the expression of miRNA-134 was significantly increased (> 4-fold) in the amniotic fluid of rats with fetuses modeling spina bifida. These results were validated using real-time quantitative reverse-transcription polymerase chain reaction. Hierarchical clustering analysis of the microarray data showed that these differentially expressed miRNAs could distinguish fetuses modeling spina bifida from control fetuses. Our bioinformatics analysis suggested that these differentially expressed miRNAs were associated with many cytological pathways, including a nervous system development signaling pathway. These findings indicate that further studies are warranted examining the role of miRNAs through their regulation of a variety of cell functional pathways in the pathogenesis of spina bifida. Such studies may provide novel targets for the early diagnosis and treatment of spina bifida. Related Articles | Metrics

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Verapamil inhibits scar formation after peripheral nerve repair in vivo A-chao Han, Jing-xiu Deng, Qi-shun Huang, Huai-yuan Zheng, Pan Zhou, Zhi-wei Liu, Zhen-bing Chen 2016, 11 (3):  508-511.  doi: 10.4103/1673-5374.179075 Abstract ( 312 )   PDF (748KB) ( 663 )   Save The calcium channel blocker, verapamil, has been shown to reduce scar formation by inhibiting fibroblast adhesion and proliferation in vitro. It was not clear whether topical application of verapamil after surgical repair of the nerve in vivo could inhibit the formation of excessive scar tissue. In this study, the right sciatic nerve of adult Sprague-Dawley rats was transected and sutured with No. 10-0 suture. The stoma was wrapped with gelfoam soaked with verapamil solution for 4 weeks. Compared with the control group (stoma wrapped with gelfoam soaked with physiological saline), the verapamil application inhibited the secretion of extracellular matrix from fibroblasts in vivo, suppressed type I and III collagen secretion and increased the total number of axons and the number of myelinated axons. These findings suggest that verapamil could reduce the formation of scar tissue and promote axon growth after peripheral nerve repair. Related Articles | Metrics

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Cartilage oligomeric matrix protein enhances the vascularization of acellular nerves Wei-ling Cui, Long-hai Qiu, Jia-yan Lian, Jia-chun Li, Jun Hu, Xiao-lin Liu 2016, 11 (3):  512-518.  doi: 10.4103/1673-5374.179078 Abstract ( 260 )   PDF (1121KB) ( 682 )   Save Vascularization of acellular nerves has been shown to contribute to nerve bridging. In this study, we used a 10-mm sciatic nerve defect model in rats to determine whether cartilage oligomeric matrix protein enhances the vascularization of injured acellular nerves. The rat nerve defects were treated with acellular nerve grafting (control group) alone or acellular nerve grafting combined with intraperitoneal injection of cartilage oligomeric matrix protein (experimental group). As shown through two-dimensional imaging, the vessels began to invade into the acellular nerve graft from both anastomotic ends at day 7 post-operation, and gradually covered the entire graft at day 21. The vascular density, vascular area, and the velocity of revascularization in the experimental group were all higher than those in the control group. These results indicate that cartilage oligomeric matrix protein enhances the vascularization of acellular nerves. Related Articles | Metrics

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Recovery of an injured corticospinal tract during the early stage of rehabilitation following pontine infarction Sung Ho Jang, Hyeok Gyu Kwon 2016, 11 (3):  519-520.  doi: 10.4103/1673-5374.179080 Abstract ( 223 )   PDF (344KB) ( 519 )   Save Related Articles | Metrics