The role of growth factors as a therapeutic approach to demyelinating disease.
Abstract A variety of growth factors are being explored as therapeutic agents relevant to the axonal and oligodendroglial deficits that occur as a result of demyelinating lesions. This review focuses on five such proteins that are present in the lesion site and impact oligodendrocyte regeneration. It then presents approaches that are being exploited to manipulate the lesion environment affiliated with multiple neurodegenerative diseases and suggests that the utility of these approaches can extend to demyelination. Challenges are to further understand the roles of specific growth factors on a cellular and tissue le...
Source: Experimental Neurology - March 21, 2016 Category: Neurology Authors: Huang Y, Dreyfus CF Tags: Exp Neurol Source Type: research
Cellular and network-level adaptations to in utero methadone exposure along the ventral respiratory column in the neonate rat.
len N Abstract Neonatal abstinence syndrome (NAS) occurs in babies chronically exposed to opioids during pregnancy. NAS shares features with opioid withdrawal symptoms seen in adults, including autonomic dysregulation. Here, the effect of low-dose in utero methadone (MTD) exposure on respiration-modulated networks along the ventral respiratory column (VRC) in ventrolateral medulla was investigated in the neonate Sprague-Dawley rat. MTD was administered via drinking water (3mg/kg/day in drinking water of the mother E7-E21). Lower expression levels of myelin-associated proteins phosphorylated axonal neurofilament su...
Source: Experimental Neurology - March 19, 2016 Category: Neurology Authors: Gourévitch B, Cai J, Mellen N Tags: Exp Neurol Source Type: research
CB2 cannabinoid receptor is involved in the anti-inflammatory effects of leptin in a model of traumatic brain injury.
CONCLUSIONS AND IMPLICATIONS: Since some of the beneficial effects of leptin were not evident in the presence of AM630, our results suggest that CB2 receptor might be involved in the full expression of the neuroprotective effects of the hormone. These findings open new avenues for the study of leptin as a therapeutic treatment for TBI and enhance the importance of CB2 receptor in TBI pathophysiology and recovery. PMID: 27006282 [PubMed - as supplied by publisher] (Source: Experimental Neurology)
Source: Experimental Neurology - March 18, 2016 Category: Neurology Authors: Lopez-Rodriguez AB, Mela V, Acaz-Fonseca E, Garcia-Segura LM, Viveros MP Tags: Exp Neurol Source Type: research
Targeting human oligodendrocyte progenitors for myelin repair.
Abstract Oligodendrocyte development has been studied for several decades, and has served as a model system for both neurodevelopmental and stem/progenitor cell biology. Until recently, the vast majority of studies have been conducted in lower species, especially those focused on rodent development and remyelination. In humans, the process of myelination requires the generation of vastly more myelinating glia, occurring over a period of years rather than weeks. Furthermore, as evidenced by the presence of chronic demyelination in a variety of human neurologic diseases, it appears likely that the mechanisms that re...
Source: Experimental Neurology - March 17, 2016 Category: Neurology Authors: Dietz KC, Polanco JJ, Pol SU, Sim FJ Tags: Exp Neurol Source Type: research
Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice.
Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice. Exp Neurol. 2016 Mar 17; Authors: Guo C, Hao LJ, Yang ZH, Chai R, Zhang S, Gu Y, Gao HL, Zhong ML, Wang T, Li JY, Wang ZY Abstract Accumulating evidence suggests that an abnormal accumulation of iron in the substantia nigra (SN) is one of the defining characteristics of Parkinson's disease (PD). Accordingly, the potential neuroprotection of Fe chelators is widely acknowledged for the treatment of PD. Although desferrioxamine (DFO), an iron chelator w...
Source: Experimental Neurology - March 16, 2016 Category: Neurology Authors: Guo C, Hao LJ, Yang ZH, Chai R, Zhang S, Gu Y, Gao HL, Zhong ML, Wang T, Li JY, Wang ZY Tags: Exp Neurol Source Type: research
Models of axon regeneration in Drosophila.
Abstract Maintaining neuronal connectivity in the face of injury and disease is a major challenge for the nervous system. The great length of axons makes them particularly vulnerable to insult with dire consequences for neuronal function. In the peripheral nervous system there is a program of axonal regeneration that can reestablish connectivity. In the mammalian central nervous system, however, injured axons have little or no capacity to regenerate. The molecular mechanisms that promote axon regeneration have begun to be identified and many of the implicated pathways are evolutionarily conserved. Here we discuss ...
Source: Experimental Neurology - March 16, 2016 Category: Neurology Authors: Brace EJ, DiAntonio A Tags: Exp Neurol Source Type: research
Hippocampal Hyperexcitability in Fetal Alcohol Spectrum Disorder: Pathological Sharp Waves and Excitatory/Inhibitory Synaptic Imbalance.
Abstract Prenatal alcohol exposure (PAE) can lead to long-lasting neurological alterations that may predispose individuals to seizures and neurobehavioral dysfunction. To date, there exists limited information regarding the underlying pathophysiological mechanisms. The hippocampal CA3 region generates excitatory population activity, called sharp waves (SPWs), that provide an ideal model to study perturbations in neuronal excitability at the network and cellular levels. In the present study, we utilized a mouse model of PAE and used dual extracellular and whole-cell patch-clamp recordings from CA3 hippocampal pyram...
Source: Experimental Neurology - March 16, 2016 Category: Neurology Authors: Krawczyk M, Ramani M, Dian J, Florez CM, Mylvaganam S, Brien J, Reynolds J, Kapur B, Zoidl G, Poulter MO, Carlen PL Tags: Exp Neurol Source Type: research
Impact of rapamycin on status epilepticus induced hippocampal pathology and weight gain.
Abstract Growing evidence implicates the dentate gyrus in temporal lobe epilepsy (TLE). Dentate granule cells limit the amount of excitatory signaling through the hippocampus and exhibit striking neuroplastic changes that may impair this function during epileptogenesis. Furthermore, aberrant integration of newly-generated granule cells underlies the majority of dentate restructuring. Recently, attention has focused on the mammalian target of rapamycin (mTOR) signaling pathway as a potential mediator of epileptogenic change. Systemic administration of the mTOR inhibitor rapamycin has promising therapeutic potential...
Source: Experimental Neurology - March 16, 2016 Category: Neurology Authors: Hester MS, Hosford BE, Santos VR, Singh SP, Rolle I, LaSarge CL, Liska JP, Garcia-Cairasco N, Danzer SC Tags: Exp Neurol Source Type: research
The multifaceted role of astrocytes in regulating myelination.
Abstract Astrocytes are the major glial cell of the central nervous system (CNS), providing both metabolic and physical support to other neural cells. After injury, astrocytes become reactive and express a continuum of phenotypes which may be supportive or inhibitory to CNS repair. This review will focus on the ability of astrocytes to influence myelination in the context of specific secreted factors, cytokines and other neural cell targets within the CNS. In particular, we focus on how astrocytes provide energy and cholesterol to neurons, influence synaptogenesis, affect oligodendrocyte biology and instigate cros...
Source: Experimental Neurology - March 14, 2016 Category: Neurology Authors: Kiray H, Lindsay SL, Hosseinzadeh S, Barnett SC Tags: Exp Neurol Source Type: research
The multiple sclerosis drug fingolimod (FTY720) stimulates neuronal gene expression, axonal growth and regeneration.
l B Abstract Fingolimod (FTY720) is a new generation oral treatment for multiple sclerosis (MS). So far, FTY720 was mainly considered to target trafficking of immune cells but not brain cells such as neurons. Herein, we analyzed FTY720's potential to directly alter neuronal function. In CNS neurons, we identified a FTY720 governed gene expression response. FTY720 upregulated immediate early genes (IEGs) encoding for neuronal activity associated transcription factors such as c-Fos, FosB, Egr1 and Egr2 and induced actin cytoskeleton associated genes (actin isoforms, tropomyosin, calponin). Stimulation of primary neu...
Source: Experimental Neurology - March 12, 2016 Category: Neurology Authors: Anastasiadou S, Knöll B Tags: Exp Neurol Source Type: research
MLKL inhibition attenuates hypoxia-ischemia induced neuronal damage in developing brain.
Abstract Mixed lineage kinase domain-like protein (MLKL) is a critical molecule mediating cell necroptosis. However, its role in brain injury remains obscure. We first investigated the functions and mechanisms of MLKL in mediating neuronal damage in developing brain after hypoxia-ischemia. Neuronal necroptosis was induced by oxygen-glucose deprivation (OGD) plus caspase inhibitor zVAD treatment (OGD/zVAD). We found that two important necroptosis related proteins, receptor-interacting protein 1 and 3 (RIP1, RIP3) were upregulated. Furthermore, the interaction of RIP1-RIP3 with MLKL increased. Inhibition of MLKL thr...
Source: Experimental Neurology - March 12, 2016 Category: Neurology Authors: Qu Y, Shi J, Tang Y, Zhao F, Li S, Meng J, Tang J, Lin X, Peng X, Mu D Tags: Exp Neurol Source Type: research
High salt drives Th17 responses in experimental autoimmune encephalomyelitis without impacting myeloid dendritic cells.
nker RA Abstract Recently, we have shown that high dietary salt intake aggravates T helper cell (Th) 17 responses and neuroinflammation. Here, we employed in vitro assays for myeloid dendritic cell (mDC) maturation, DC cytokine production, T cell activation and ex vivo analyses in murine experimental autoimmune encephalomyelitis (EAE) to investigate whether the salt effect on Th17 cells is further mediated through DCs in vivo. In cell culture, an excess of 40mM sodium chloride did neither affect the generation, maturation nor the function of DCs, but, in different assays, significantly increased Th17 differentiati...
Source: Experimental Neurology - March 11, 2016 Category: Neurology Authors: Jörg S, Kissel J, Manzel A, Kleinewietfeld M, Haghikia A, Gold R, Müller DN, Linker RA Tags: Exp Neurol Source Type: research
Large-scale reconstitution of a retina-to-brain pathway in adult rats using gene therapy and bridging grafts: an anatomical and behavioral analysis.
AR Abstract Peripheral nerve (PN) grafts can be used to bridge tissue defects in the CNS. Using a PN-to-optic nerve (ON) graft model, we combined gene therapy with pharmacotherapy to promote the long-distance regeneration of injured adult retinal ganglion cells (RGCs). Autologous sciatic nerve was sutured onto the transected ON and the distal end immediately inserted into contralateral superior colliculus (SC). Control rats received intraocular injections of saline or adeno-associated virus (AAV) encoding GFP. In experimental groups, three bi-cistronic AAV vectors encoding ciliary neurotrophic factor (CNTF) were ...
Source: Experimental Neurology - March 9, 2016 Category: Neurology Authors: You SW, Hellström M, Pollett MA, LeVaillant C, Moses C, Rigby PJ, Penrose M, Rodger J, Harvey AR Tags: Exp Neurol Source Type: research
Intracellular signaling pathway regulation of myelination and remyelination in the CNS.
Abstract The restoration of myelin sheaths on demyelinated axons remains a major obstacle in the treatment of multiple sclerosis (MS). Currently approved therapies work by modulating the immune system to reduce the number and rate of lesion formation but are only partially effective since they are not able to restore lost myelin. In the healthy CNS, myelin continues to be generated throughout life and spontaneous remyelination occurs readily in response to insults. In patients with MS, however, remyelination eventually fails, at least in part as a result of a failure of oligodendrocyte precursor cell (OPC) differe...
Source: Experimental Neurology - March 5, 2016 Category: Neurology Authors: Gaesser JM, Fyffe-Maricich SL Tags: Exp Neurol Source Type: research
Tumor necrosis factor-inducible gene 6 protein: A novel neuroprotective factor against inflammation-induced developmental brain injury.
Abstract Inflammation is an important factor contributing to developmental brain injury in preterm infants. Although tumor necrosis factor-inducible gene 6 protein (TSG-6) has immunomodulatory effects in several inflammatory conditions of adult animals, nothing is currently known about the role of TSG-6 in the developing brain, its impact on perinatal inflammation and its therapeutic potential. The aim of the current work was 1) to characterize the developmental expression of TSG-6 in the newborn rat brain, 2) to evaluate the impact of LPS exposure on TSG-6 expression and 3) to assess the therapeutic potential of ...
Source: Experimental Neurology - March 4, 2016 Category: Neurology Authors: Bertling F, Bendix I, Drommelschmidt K, Wisniewski HG, Felderhoff-Mueser U, Keller U, Prager S Tags: Exp Neurol Source Type: research
Pre-ictal increase in theta synchrony between the hippocampus and prefrontal cortex in a rat model of temporal lobe epilepsy.
;o RN Abstract The pathologically synchronised neuronal activity in temporal lobe epilepsy (TLE) can be triggered by network events that were once normal. Under normal conditions, hippocampus and medial prefrontal cortex (mPFC) work in synchrony during a variety of cognitive states. Abnormal changes in this circuit may aid to seizure onset and also help to explain the high association of TLE with mood disorders. We used a TLE rat model generated by perforant path (PP) stimulation to understand whether synchrony between dorsal hippocampal and mPFC networks is altered shortly before a seizure episode. We recorded hi...
Source: Experimental Neurology - March 4, 2016 Category: Neurology Authors: Broggini AC, Esteves IM, Romcy-Pereira RN, Leite JP, Leão RN Tags: Exp Neurol Source Type: research
Loss of Ca(2+)-permeable AMPA receptors in synapses of tonic firing substantia gelatinosa neurons in the chronic constriction injury model of neuropathic pain.
Abstract Synapses transmitting nociceptive information in the spinal dorsal horn undergo enduring changes following peripheral nerve injury. Indeed, such injury alters the expression of the GluA2 subunit of glutamatergic AMPA receptors (AMPARs) in the substantia gelatinosa and this predicts altered channel conductance and calcium permeability, leading to an altered function of excitatory synapses. We therefore investigated the functional properties of synaptic AMPA receptors in rat substantia gelatinosa neurons following 10-20d chronic constriction injury (CCI) of the sciatic nerve; a model of neuropathic pain. We...
Source: Experimental Neurology - March 3, 2016 Category: Neurology Authors: Chen Y, Derkach VA, Smith PA Tags: Exp Neurol Source Type: research
Cognitive impairments following cranial irradiation can be mitigated by treatment with a tropomyosin receptor kinase B agonist.
Abstract Brain radiotherapy is frequently used successfully to treat brain tumors. However, radiotherapy is often associated with declines in short-term and long-term memory, learning ability, and verbal fluency. We previously identified a downregulation of the brain-derived neurotrophic factor (BDNF) following cranial irradiation in experimental animals. In the present study, we investigated whether targeting the BDNF high affinity receptor, tropomysin receptor kinase B (TrkB), could mitigate radiation-induced cognitive deficits. After irradiation, chronic treatment with a small molecule TrkB agonist, 7,8-dihydro...
Source: Experimental Neurology - March 2, 2016 Category: Neurology Authors: Yang P, Leu D, Ye K, Srinivasan C, Fike JR, Huang TT Tags: Exp Neurol Source Type: research
Physiological changes in the pallidum in a progressive model of Parkinson's disease: Are oscillations enough?
Abstract Neurophysiological changes in the basal ganglia thalamo-cortical circuit associated with the development of parkinsonian motor signs remain poorly understood. Theoretical models have ranged from those emphasizing changes in mean discharge rate to increased oscillatory activity within the beta range. The present study characterized neuronal activity within and across the internal and external segments of the globus pallidus as a function of motor severity using a staged, progressively severe 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinsonism in three rhesus monkeys. An increase in coherence...
Source: Experimental Neurology - March 2, 2016 Category: Neurology Authors: Muralidharan A, Jensen AL, Connolly A, Hendrix CM, Johnson MD, Baker KB, Vitek JL Tags: Exp Neurol Source Type: research
Comparison of trophic factors´ expression between paralyzed and recovering muscles after facial nerve injury. A quantitative analysis in time course.
Comparison of trophic factors´ expression between paralyzed and recovering muscles after facial nerve injury. A quantitative analysis in time course. Exp Neurol. 2016 Feb 29; Authors: Grosheva M, Nohroudi K, Schwarz A, Rink S, Bendella H, Sarikcioglu L, Klimaschewski L, Gordon T, Angelov DN Abstract After peripheral nerve injury, recovery of motor performance negatively correlates with the poly-innervation of neuromuscular junctions (NMJ) due to excessive sprouting of the terminal Schwann cells. Denervated muscles produce short-range diffusible sprouting stimuli, of which some are neurotrophic f...
Source: Experimental Neurology - February 29, 2016 Category: Neurology Authors: Grosheva M, Nohroudi K, Schwarz A, Rink S, Bendella H, Sarikcioglu L, Klimaschewski L, Gordon T, Angelov DN Tags: Exp Neurol Source Type: research
Learning to swim, again: Axon regeneration in fish.
Abstract Damage to the central nervous system (CNS) of fish can often be repaired to restore function, but in mammals recovery from CNS injuries usually fails due to a lack of axon regeneration. The relatively growth-permissive environment of the fish CNS may reflect both the absence of axon inhibitors found in the mammalian CNS and the presence of pro-regenerative environmental factors. Despite their different capacities for axon regeneration, many of the physiological processes, intrinsic molecular pathways, and cellular behaviors that control an axon's ability to regrow are conserved between fish and mammals. F...
Source: Experimental Neurology - February 29, 2016 Category: Neurology Authors: Rasmussen JP, Sagasti A Tags: Exp Neurol Source Type: research
Expression of galanin and its receptors are perturbed in a rodent model of mild, blast-induced traumatic brain injury.
t T Abstract The symptomatology, mood and cognitive disturbances seen in post-traumatic stress disorder (PTSD) and mild blast-induced traumatic brain injury (mbTBI) overlap considerably. However the pathological mechanisms underlying the two conditions are currently unknown. The neuropeptide galanin has been suggested to play a role in the development of stress and mood disorders. Here we applied bio- and histochemical methods with the aim to elucidate the nature of any changes in the expression of galanin and its receptors in a rodent model of mbTBI. In situ hybridization and quantitative polymerase chain reactio...
Source: Experimental Neurology - February 26, 2016 Category: Neurology Authors: Kawa L, Barde S, Arborelius UP, Theodorsson E, Agoston D, Risling M, Hökfelt T Tags: Exp Neurol Source Type: research
Transcranial direct current stimulation accelerates recovery of function, induces neurogenesis and recruits oligodendrocyte precursors in a rat model of stroke.
CONCLUSIONS: TDCS acts through multifaceted mechanisms that far exceed its primary neurophysiological effects, encompassing proliferation and migration of stem cells, their neuronal differentiation, and modulation of microglia responses. PMID: 26923911 [PubMed - as supplied by publisher] (Source: Experimental Neurology)
Source: Experimental Neurology - February 25, 2016 Category: Neurology Authors: Braun R, Klein R, Walter HL, Ohren M, Freudenmacher L, Getachew K, Ladwig A, Luelling J, Neumaier B, Endepols H, Graf R, Hoehn M, Fink GR, Schroeter M, Rueger MA Tags: Exp Neurol Source Type: research
Effect of zinc supplementation on neuronal precursor proliferation in the rat hippocampus after traumatic brain injury.
Abstract There is great deal of debate about the possible role of adult-born hippocampal cells in the prevention of depression and related mood disorders. We first showed that zinc supplementation prevents the development of the depression-like behavior anhedonia associated with an animal model of traumatic brain injury (TBI). This work then examined the effect of zinc supplementation on the proliferation of new cells in the hippocampus that have the potential to participate in neurogenesis. Rats were fed a zinc adequate (ZA, 30ppm) or zinc supplemented (ZS, 180ppm) diet for 4wk followed by TBI using controlled co...
Source: Experimental Neurology - February 19, 2016 Category: Neurology Authors: Cope EC, Morris DR, Gower-Winter SD, Brownstein NC, Levenson CW Tags: Exp Neurol Source Type: research
Sex- and isoform-specific mechanism of neuroprotection by transgenic expression of P450 epoxygenase in vascular endothelium.
Abstract OBJECTIVE: Cytochrome P450 epoxygenases (CYP) metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs), which exhibit vasodilatory, anti-inflammatory and neuroprotective actions in experimental cerebral ischemia. We evaluated the effect of endothelial-specific CYP overexpression on cerebral blood flow, inflammatory cytokine expression and tissue infarction after focal cerebral ischemia in transgenic mice. APPROACH AND RESULTS: Male and female wild-type and transgenic mice overexpressing either human CYP2J2 or CYP2C8 epoxygenases in vascular endothelium under control of the Tie2 promoter (Tie2-...
Source: Experimental Neurology - February 18, 2016 Category: Neurology Authors: Jia J, Davis CM, Zhang W, Edin ML, Jouihan S, Jia T, Bradbury JA, Graves JP, DeGraff LM, Lee CR, Ronnekleiv O, Wang R, Xu Y, Zeldin DC, Alkayed NJ Tags: Exp Neurol Source Type: research
Rho kinase inhibition following traumatic brain injury in mice promotes functional improvement and acute neuron survival but has little effect on neurogenesis, glial responses or neuroinflammation.
Abstract Inhibition of the Rho/Rho kinase pathway has been shown to be beneficial in a variety of neural injuries and diseases. In this manuscript we investigate the role of Rho kinase inhibition in recovery from traumatic brain injury using a controlled cortical impact model in mice. Mice subjected to a moderately severe TBI were treated for 1 or 4weeks with the Rho kinase inhibitor Y27632, and functional outcomes and neuronal and glial cell responses were analysed at 1, 7 and 35days post-injury. We hypothesised that Y27632-treated mice would show functional improvement, with augmented recruitment of neuroblasts ...
Source: Experimental Neurology - February 16, 2016 Category: Neurology Authors: Bye N, Christie KJ, Turbic A, Basrai HS, Turnley AM Tags: Exp Neurol Source Type: research
Long-term consequences of conditional genetic deletion of PTEN in the sensorimotor cortex of neonatal mice.
Abstract Targeted deletion of the phosphatase and tensin homolog on chromosome ten (PTEN) gene in the sensorimotor cortex of neonatal mice enables robust regeneration of corticospinal tract (CST) axons following spinal cord injury as adults. Here, we assess the consequences of long-term conditional genetic PTEN deletion on cortical structure and neuronal morphology and screen for neuropathology. Mice with a LoxP-flanked exon 5 of the PTEN gene (PTENf/f mice) received AAV-Cre injections into the sensorimotor cortex at postnatal day 1 (P1) and were allowed to survive for up to 18months. As adults, mice were assessed...
Source: Experimental Neurology - February 16, 2016 Category: Neurology Authors: Gutilla EA, Buyukozturk MM, Steward O Tags: Exp Neurol Source Type: research
Repeated low-dose kainate administration in C57BL/6J mice produces temporal lobe epilepsy pathology but infrequent spontaneous seizures.
Abstract More efficient or translationally relevant approaches are needed to model acquired temporal lobe epilepsy (TLE) in genetically tractable mice. The high costs associated with breeding and maintaining transgenic, knock-in, or knock-out lines place a high value on the efficiency of induction and animal survivability. Herein, we describe our approaches to model acquired epilepsy in C57BL/6J mice using repeated, low-dose kainate (KA) administration paradigms. Four paradigms (i.p.) were tested for their ability to induce status epilepticus (SE), temporal lobe pathology, and the development of epilepsy. All four...
Source: Experimental Neurology - February 16, 2016 Category: Neurology Authors: Umpierre AD, Bennett IV, Nebeker LD, Newell TG, Tian BB, Thomson KE, White HS, White JA, Wilcox KS Tags: Exp Neurol Source Type: research
Nerve growth factor alters microtubule targeting agent-induced neurotransmitter release but not MTA-induced neurite retraction in sensory neurons.
Abstract Peripheral neuropathy is a dose-limiting side effect of anticancer treatment with the microtubule-targeted agents (MTAs), paclitaxel and epothilone B (EpoB); however, the mechanisms by which the MTAs alter neuronal function and morphology are unknown. We previously demonstrated that paclitaxel alters neuronal sensitivity, in vitro, in the presence of nerve growth factor (NGF). Evidence in the literature suggests that NGF may modulate the neurotoxic effects of paclitaxel. Here, we examine whether NGF modulates changes in neuronal sensitivity and morphology induced by paclitaxel and EpoB. Neuronal sensitivi...
Source: Experimental Neurology - February 13, 2016 Category: Neurology Authors: Pittman SK, Gracias NG, Fehrenbacher JC Tags: Exp Neurol Source Type: research
A controlled spinal cord contusion for the rhesus macaque monkey.
Abstract Most in vivo spinal cord injury (SCI) experimental models use rodents.Due to the anatomical and functional differences between rodents and humans, reliable large animal models, such as non-human primates, of SCI are critically needed to facilitate translation of laboratory discoveries to clinical applications.Here we report the establishment of a controlled spinal contusion model that produces severity-dependent functional and histological deficits in non-human primates.Six adult male rhesus macaque monkeys underwent mild to moderate contusive SCI using 1.0 and 1.5mm tissue displacement injuries at T9 or ...
Source: Experimental Neurology - February 11, 2016 Category: Neurology Authors: Ma Z, Zhang YP, Liu W, Yan G, Li Y, Shields LB, Walker M, Chen K, Huang W, Kong M, Lu Y, Brommer B, Chen X, Xu XM, Shields CB Tags: Exp Neurol Source Type: research
Molecular, Cellular and Functional Events in Axonal Sprouting after Stroke.
Abstract Stroke is the leading cause of adult disability. Yet there is a limited degree of recovery in this disease. One of the mechanisms of recovery is the formation of new connections in the brain and spinal cord after stroke: post-stroke axonal sprouting. Studies indicate that post-stroke axonal sprouting occurs in mice, rats, primates and humans. Inducing post-stroke axonal sprouting in specific connections enhances recovery; blocking axonal sprouting impairs recovery. Behavioral activity patterns after stroke modify the axonal sprouting response. A unique regenerative molecular program mediates this aspect o...
Source: Experimental Neurology - February 10, 2016 Category: Neurology Authors: Carmichael ST, Kathirvelu B, Schweppe CA, Nie EH Tags: Exp Neurol Source Type: research
Longitudinal measures of cognition in the Ts65Dn mouse: Refining windows and defining modalities for therapeutic intervention in down syndrome.
Abstract Mouse models have provided insights into adult changes in learning and memory in Down syndrome, but an in-depth assessment of how these abnormalities develop over time has never been conducted. To address this shortcoming, we conducted a longitudinal behavioral study from birth until late adulthood in the Ts65Dn mouse model to measure the emergence and continuity of learning and memory deficits in individuals with a broad array of tests. Our results demonstrate for the first time that the pace at which neonatal and perinatal milestones are acquired is correlated with later cognitive performance as an adul...
Source: Experimental Neurology - February 5, 2016 Category: Neurology Authors: Olmos-Serrano JL, Tyler WA, Cabral HJ, Haydar TF Tags: Exp Neurol Source Type: research
Reducing synuclein accumulation improves neuronal survival after spinal cord injury.
This study is the first to reveal that reducing synuclein accumulation is a novel strategy for improving neuronal survival after spinal cord injury. PMID: 26854933 [PubMed - as supplied by publisher] (Source: Experimental Neurology)
Source: Experimental Neurology - February 5, 2016 Category: Neurology Authors: Fogerson SM, van Brummen AJ, Busch DJ, Allen SR, Roychaudhuri R, Banks SM, Klärner FG, Schrader T, Bitan G, Morgan JR Tags: Exp Neurol Source Type: research
Adult skin-derived precursor Schwann cells exhibit Superior myelination and regeneration supportive properties compared to chronically denervated nerve-derived Schwann cells.
Abstract Functional outcomes following delayed peripheral nerve repair are poor. Schwann cells (SCs) play key roles in supporting axonal regeneration and remyelination following nerve injury, thus understanding the impact of chronic denervation on SC function are critical toward developing therapies to enhance regeneration. To improve our understanding of SC function following acute versus chronic-denervation, we performed functional assays of SCs from adult rodent sciatic nerve with acute- (Day5 post) or chronic-denervation (Day56 post), versus embryonic nerves. We also compared Schwann cells derived from adult s...
Source: Experimental Neurology - February 5, 2016 Category: Neurology Authors: Kumar R, Sinha S, Hagner A, Stykel M, Raharjo E, Singh K, Midha R, Biernaskie J Tags: Exp Neurol Source Type: research
Abnormal response of distal Schwann cells to denervation in a mouse model of motor neuron disease.
Abstract In several animal models of motor neuron disease, degeneration begins in the periphery. Clarifying the possible role of Schwann cells remains a priority. We recently showed that terminal Schwann cells (TSCs) exhibit abnormalities in postnatal mice that express mutations of the SOD1 enzyme found in inherited human motor neuron disease. TSC abnormalities appeared before disease-related denervation commenced and the extent of TSC abnormality at P30 correlated with the extent of subsequent denervation. Denervated neuromuscular junctions (NMJs) were also observed that lacked any labeling for TSCs. This suggest...
Source: Experimental Neurology - February 4, 2016 Category: Neurology Authors: Carrasco DI, Bahr BA, Seburn KL, Pinter MJ Tags: Exp Neurol Source Type: research
Exercise leads to the re-emergence of the cholinergic/nestin neuronal phenotype within the medial septum/diagonal band and subsequent rescue of both hippocampal ACh efflux and spatial behavior.
Abstract Exercise has been shown to improve cognitive functioning in a range of species, presumably through an increase in neurotrophins throughout the brain, but in particular the hippocampus. The current study assessed the ability of exercise to restore septohippocampal cholinergic functioning in the pyrithiamine-induced thiamine deficiency (PTD) rat model of the amnestic disorder Korsakoff Syndrome. After voluntary wheel running or sedentary control conditions (stationary wheel attached to the home cage), PTD and control rats were behaviorally tested with concurrent in vivo microdialysis, at one of two time poi...
Source: Experimental Neurology - January 30, 2016 Category: Neurology Authors: Hall JM, Savage LM Tags: Exp Neurol Source Type: research
The role of the PI3K/Akt/mTOR pathway in glial scar formation following spinal cord injury.
This study's findings thus have positive implications for patients who are unable to receive immediate medical attention after SCI. PMID: 26828688 [PubMed - as supplied by publisher] (Source: Experimental Neurology)
Source: Experimental Neurology - January 29, 2016 Category: Neurology Authors: Chen CH, Sung CS, Huang SY, Feng CW, Hung HC, Yang SN, Chen NF, Tai MH, Wen ZH, Chen WF Tags: Exp Neurol Source Type: research
In vitro models of axon regeneration.
Abstract A variety of in vitro models has been developed to understand the mechanisms underlying the regenerative failure of central nervous system (CNS) axons, and to guide pre-clinical development of regeneration-promoting therapeutics. These range from single-cell based assays that typically focus on molecular mechanisms to organotypic assays aimed at recapitulating in vivo behavior. By utilizing a combination of models, researchers can balance the speed, convenience, and mechanistic resolution of simpler models with the biological relevance of more complex models. This review will discuss a number of the model...
Source: Experimental Neurology - January 27, 2016 Category: Neurology Authors: Al-Ali H, Beckerman S, Bixby JL, Lemmon VP Tags: Exp Neurol Source Type: research
Therapy induces widespread reorganization of motor cortex after complete spinal transection that supports motor recovery.
In this study we assessed the effect of passive exercise and serotonergic (5-HT) pharmacological therapies on behavioral recovery and organization of the motor cortex. We compared the effects of passive hindlimb bike exercise to bike exercise combined with daily injections of 5-HT agonists in a rat model of complete mid-thoracic transection. 5-HT pharmacotherapy combined with bike exercise allowed the animals to achieve unassisted weight support in the open field. This combination of therapies also produced extensive expansion of the axial trunk motor cortex into the deafferented hindlimb motor cortex and, surprisingly, re...
Source: Experimental Neurology - January 27, 2016 Category: Neurology Authors: Ganzer PD, Manohar A, Shumsky JS, Moxon KA Tags: Exp Neurol Source Type: research
Use of human stem cells in Huntington disease modeling and translational research.
Abstract Huntington disease (HD) is a devastating neurological disorder caused by an extended CAG repeat in exon 1 of the gene that encodes the huntingtin (HTT) protein. HD pathology involves a loss of striatal medium spiny neurons (MSNs) and progressive neurodegeneration affects the striatum and other brain regions. Because HTT is involved in multiple cellular processes, the molecular mechanisms of HD pathogenesis should be investigated on multiple levels. On the cellular level, in vitro stem cell models, such as induced pluripotent stem cells (iPSCs) derived from HD patients and HD embryonic stem cells (ESCs), h...
Source: Experimental Neurology - January 27, 2016 Category: Neurology Authors: Golas MM, Sander B Tags: Exp Neurol Source Type: research
Treatment with the MAO-A inhibitor clorgyline elevates monoamine neurotransmitter levels and improves affective phenotypes in a mouse model of Huntington disease.
This study supports a potential therapeutic use for MAO-A inhibitors in the treatment of depression and anxiety in patients with HD. PMID: 26825854 [PubMed - as supplied by publisher] (Source: Experimental Neurology)
Source: Experimental Neurology - January 26, 2016 Category: Neurology Authors: Garcia-Miralles M, Ooi J, Bardile CF, Tan LJ, George M, Drum CL, Lin RY, Hayden MR, Pouladi MA Tags: Exp Neurol Source Type: research
Respiratory outcomes after mid-cervical transplantation of embryonic medullary cells in rats with cervical spinal cord injury.
Abstract Respiratory motor output after cervical spinal cord injury (cSCI) is profoundly influenced by spinal serotonin. We hypothesized that intraspinal transplantation of embryonic midline brainstem (MB) cells rich in serotonergic raphé neurons would improve respiratory outcomes after cSCI. One week after hemisection of the 2nd cervical segment (C2Hx) a suspension of either embryonic (E14) MB cells, fetal spinal cord cells (FSC), or media only (sham) was delivered to the dorsal C3 spinal cord of adult male rats. Six weeks later, ventilation was evaluated using plethysmography; phrenic nerve activity was e...
Source: Experimental Neurology - January 22, 2016 Category: Neurology Authors: Dougherty BJ, Gonzalez-Rothi EJ, Lee KZ, Ross HH, Reier PJ, Fuller DD Tags: Exp Neurol Source Type: research
Analysis of the behavioral, cellular and molecular characteristics of pain in severe rodent spinal cord injury.
Abstract Human SCI is frequently associated with chronic pain that is severe and refractory to medical therapy. Most rodent models used to assess pain outcomes in SCI apply moderate injuries to lower thoracic spinal levels, whereas the majority of human lesions are severe in degree and occur at cervical or upper thoracic levels. To better model and understand mechanisms associated with chronic pain after SCI, we subjected adult rats to T3 severe compression or complete transection lesions, and examined pain-related behaviors for three months. Within one week after injury, rats developed consistent forepaw pain-rel...
Source: Experimental Neurology - January 22, 2016 Category: Neurology Authors: Lee-Kubli CA, Ingves M, Henry KW, Shiao R, Collyer E, Tuszynski MH, Campana WM Tags: Exp Neurol Source Type: research
Anti-glycan antibodies halt axon regeneration in a model of guillain Barrè syndrome axonal neuropathy by inducing microtubule disorganization via RhoA-ROCK-dependent inactivation of CRMP-2.
Anti-glycan antibodies halt axon regeneration in a model of guillain Barrè syndrome axonal neuropathy by inducing microtubule disorganization via RhoA-ROCK-dependent inactivation of CRMP-2. Exp Neurol. 2016 Jan 21; Authors: Salvador VR, Heredia F, Berardo A, Palandri A, Wojnacki J, Vivinetto AL, Sheikh KA, Caceres A, Lopez PH Abstract Several reports have linked the presence of high titers of anti-Gg Abs with delayed recovery/poor prognosis in GBS. In most cases, failure to recover is associated with halted/deficient axon regeneration. Previous work identified that monoclonal and patient-derive...
Source: Experimental Neurology - January 21, 2016 Category: Neurology Authors: Salvador VR, Heredia F, Berardo A, Palandri A, Wojnacki J, Vivinetto AL, Sheikh KA, Caceres A, Lopez PH Tags: Exp Neurol Source Type: research
Postnatal glucocorticoid-induced hypomyelination, gliosis, and neurologic deficits are dose-dependent, preparation-specific, and reversible.
PMID: 26795086 [PubMed - as supplied by publisher] (Source: Experimental Neurology)
Source: Experimental Neurology - January 18, 2016 Category: Neurology Authors: Malaeb SN, Stonestreet BS Tags: Exp Neurol Source Type: research
The use of the rat as a model for studying peripheral nerve regeneration and sprouting after complete and partial nerve injuries.
Abstract Rat models of complete and partial injuries are the most frequently used models for analysis of the cellular and molecular processes of nerve regeneration and axon sprouting. Studies of nerve regeneration and axon sprouting after complete and partial nerve injuries, respectively, are reviewed. Special consideration is made of the peripheral nerves chosen for the studies and the outcome measures that were utilized in the studies. The studies have made important contributions to our knowledge of the degenerative and regenerative processes that occur after the peripheral nerve injuries, why functional recove...
Source: Experimental Neurology - January 18, 2016 Category: Neurology Authors: Gordon T, Borschel GH Tags: Exp Neurol Source Type: research
Inhibition of CRMP2 phosphorylation repairs CNS by regulating neurotrophic and inhibitory responses.
Abstract Central nervous system (CNS) regeneration is restricted by both the lack of neurotrophic responses and the presence of inhibitory factors. As of yet, a common mediator of these two pathways has not been identified. Microtubule dynamics is responsible for several key processes after CNS injuries: intracellular trafficking of receptors for neurotrophic factors, axonal retraction by inhibitory factors, and secondary tissue damages by inflammation and scarring. Kinases regulating microtubule organization, such as Cdk5 or GSK3β, may play pivotal roles during CNS recovery, but the molecular mechanisms rema...
Source: Experimental Neurology - January 18, 2016 Category: Neurology Authors: Nagai J, Owada K, Kitamura Y, Goshima Y, Ohshima T Tags: Exp Neurol Source Type: research
Systemic inflammation affects reperfusion following transient cerebral ischaemia.
Abstract Reperfusion after stroke is critical for improved patient survival and recovery and can be achieved clinically through pharmacological (recombinant tissue plasminogen activator) or physical (endovascular intervention) means. Yet these approaches remain confined to a small percentage of stroke patients, often with incomplete reperfusion, and therefore there is an urgent need to learn more about the mechanisms underlying the no-reflow phenomenon that prevents restoration of adequate microvascular perfusion. Recent evidence suggests systemic inflammation as an important contributor to no-reflow and to furthe...
Source: Experimental Neurology - January 18, 2016 Category: Neurology Authors: Burrows F, Haley MJ, Scott E, Coutts G, Lawrence CB, Allan SM, Schiessl I Tags: Exp Neurol Source Type: research
Neuroinflammation in primary blast neurotrauma: Time course and prevention by torso shielding.
In this study, we investigated the temporal dynamics of microglial activation in the brain of mice exposed to mild-moderate blast in a shock tube. Because, in our previous work, we had found that torso shielding with rigid Plexiglas attenuates traumatic axonal injury in the brain, we also evaluated neuroinflammatory microglial responses in animals with torso protection at 7days post blast injury. Because of the prominent involvement of the visual system in blast TBI in rodents, activated microglial cells were counted in the optic tract at various time points post-injury with stereological methods. Cell counts (activated mi...
Source: Experimental Neurology - January 16, 2016 Category: Neurology Authors: Xu L, Schaefer ML, Linville RM, Aggarwal A, Mbuguiro W, Wester BA, Koliatsos VE Tags: Exp Neurol Source Type: research
Generation of Highly Enriched V2a Interneurons from Mouse Embryonic Stem Cells.
In this study, we employed a genetic strategy to obtain large quantities of highly enriched mouse embryonic stem cell (ESC)-derived V2a INs, an excitatory glutamatergic IN population that is defined by expression of the homeodomain protein Chx10 during development. Puromycin N-acetyltransferase expression was driven by the native gene regulatory elements of Chx10 in the transgenic ESC line, resulting in positive selection of V2a INs after induction and treatment with puromycin. Directly after selection, approximately 80% of cells are Chx10(+), with 94% Lhx3(+); after several weeks, cultures remain free of proliferative cel...
Source: Experimental Neurology - January 16, 2016 Category: Neurology Authors: Iyer NR, Huettner JE, Butts JC, Brown CR, Sakiyama-Elbert SE Tags: Exp Neurol Source Type: research