Abstract:
:Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative syndrome characterized by the systemic loss of motor neurons with prominent astrocytosis and microgliosis in the spinal cord and brain. Astrocytes play an essential role in maintaining extracellular microenvironments that surround motor neurons, and are activated by various insults. Growing evidence points to a non-cell autonomous neurotoxicity caused by chronic and sustained astrocytic activation in patients with neurodegenerative diseases, including ALS. However, the mechanisms that underlie the harmful effects of astrocytosis in patients with ALS remain unresolved. We focused on bone morphogenetic proteins as a major soluble factor that promotes astrocytogenesis and its activation in the adult spinal cord. In a transgenic rat model with ALS-linked mutant Cu/Zn superoxide dismutase gene, BMP4 was progressively up-regulated in reactive astrocytes of the spinal ventral horns, whereas the BMP-antagonist noggin was decreased in association with neuronal degeneration. Continuous intrathecal noggin supplementation after disease onset significantly ameliorated motor dysfunction symptoms, neurogenic muscle atrophy, and extended survival of symptomatic ALS model rats, despite lack of deterrence against neuronal death itself. The exogenous noggin inhibited astrocytic hypertrophy, astrocytogenesis, and neuroinflammation by inactivating both Smad1/5/8 and p38 mitogen-activated protein kinase pathways. Moreover, intrathecal infusion of a Bmp4-targeted antisense oligonucleotides and provided selective Bmp4 knockdown in vivo, which suppressed astrocyte and microglia activation, reproducing the aforementioned results by noggin treatment. Collectively, we clarified the involvement of BMP4 in the processes of excessive gliosis that exacerbate the disease progression of the ALS model rats. Our study demonstrated that BMP4, with its downstream signaling, might be a novel therapeutic target for disease-modifying therapies in ALS.
journal_name
Exp Neuroljournal_title
Experimental neurologyauthors
Shijo T,Warita H,Suzuki N,Ikeda K,Mitsuzawa S,Akiyama T,Ono H,Nishiyama A,Izumi R,Kitajima Y,Aoki Mdoi
10.1016/j.expneurol.2018.06.009subject
Has Abstractpub_date
2018-09-01 00:00:00pages
164-179eissn
0014-4886issn
1090-2430pii
S0014-4886(18)30199-7journal_volume
307pub_type
杂志文章abstract::Diffuse and neuritic plaques are sites of accumulation of beta-amyloid peptides (A beta) in the brains of Alzheimer's disease (AD) patients. Although amyloid fibrils are formed from A beta, the contribution of other plaque-associated proteins and peptides to the pathogenesis of AD amyloidosis is unknown. To pursue thi...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1006/exnr.1994.1209
更新日期:1994-12-01 00:00:00
abstract::Our previous studies showed that Insulin-like Growth Factor (IGF)-1 reduced blood brain barrier permeability and decreased infarct volume caused by middle cerebral artery occlusion (MCAo) in middle aged female rats. Similarly, cultures of primary brain microvessel endothelial cells from middle-aged female rats and exp...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/j.expneurol.2018.09.016
更新日期:2019-01-01 00:00:00
abstract::Anatomic and electrophysiologic evidence suggests there is a vestibular input to eye movement-related pause neurons in the midline of the pontine reticular formation of the cat. The present investigation sought to explore the functional significance of this vestibular drive by examining pause neuron response to horizo...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/0014-4886(87)90300-1
更新日期:1987-03-01 00:00:00
abstract::Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for motoneurons (MNs), and is considered a potential agent for the treatment of amyotrophic lateral sclerosis (ALS) and other MN diseases. The effectiveness of GDNF may depend significantly upon its route of delivery to MNs. In this study w...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/j.expneurol.2006.08.028
更新日期:2007-02-01 00:00:00
abstract::Our previous study demonstrates that delayed (initiated 24h post injury) erythropoietin (EPO) therapy for traumatic brain injury (TBI) significantly improves spatial learning. In this study, we investigated the impact of inhibition of EPO treatment-mediated neurogenesis on spatial learning after experimental TBI. Youn...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/j.expneurol.2012.02.015
更新日期:2012-05-01 00:00:00
abstract::Oxidative stress has been implicated in several neurodegenerative diseases affecting both neuronal and glial cells. The aim of this study was to investigate the involvement of reactive oxygen species in glutamate-evoked activation of NF-kappaB in primary astrocytes. A prolonged exposure to glutamate (24 h) caused a de...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/j.expneurol.2005.01.014
更新日期:2005-06-01 00:00:00
abstract::Blood flow in the feline thoracic spinal cord was measured, using a laser-Doppler flowmetry. Rhythmic changes in the spinal cord blood flow were repeatedly observed with a frequency of about three to eight cycles per minute, unrelated to the respiratory or cardiac cycles. These changes were unaffected by hypertension ...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/0014-4886(88)90009-x
更新日期:1988-08-01 00:00:00
abstract::Peripheral nerve injury can result in formation of a neuroma, which is often associated with heightened sensitivity to normally innocuous stimuli as well as spontaneous dysesthesia and pain. The onset and persistence of neuropathic pain have been linked to spontaneous ectopic electrogenesis in axons within neuromas, s...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/j.expneurol.2011.05.005
更新日期:2011-08-01 00:00:00
abstract::These studies have examined the extent to which intrastriatal grafts of embryonic mesencephalic neurons induce recovery of normal discharge patterns in striatal neurons of rats after a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal dopamine (DA) pathway. Lesioned rats were tested for rotational beha...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1006/exnr.1996.0070
更新日期:1996-04-01 00:00:00
abstract::The aim of this study was to compare the physiological properties of single neurons in the glabrous (G) and heterogeneous (H) subdivisions of primary somatosensory digit 3 cortex of adult raccoons. Extracellular recordings were obtained from 50 G neurons whose receptive fields (RFs) were confined to the glabrous skin ...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/0014-4886(92)90059-y
更新日期:1992-02-01 00:00:00
abstract::Status epilepticus (SE) is an acute event, characterized by repeated or continuous seizures, which alters neuronal properties of the brain and can promote the epileptic disorder. Experimental observations indicate that SE becomes progressively less responsive to anti-epileptic drugs, suggesting changes in the underlyi...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/j.expneurol.2012.01.020
更新日期:2012-04-01 00:00:00
abstract::Previous work utilizing the 2-deoxyglucose (2-DG) technique demonstrated that denervation, both direct (enucleation) or indirect (retinal receptor destruction, leaving ganglion cells intact), resulted in a depression followed by an increase in glucose metabolism in the superior colliculus (SC) of the mature hooded rat...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/0014-4886(89)90040-x
更新日期:1989-06-01 00:00:00
abstract::Intracerebral transplants of ventral mesencephalic (VM) tissue have been well characterized. VM grafts contain numerous tyrosine hydroxylase immunoreactive neurons which send axons into the host brain. Transplanted neurons in VM grafts develop normally in that they contain tyrosine hydroxylase and GAP43. An overlooked...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1006/exnr.1994.1144
更新日期:1994-09-01 00:00:00
abstract::Alpha-synuclein (alphaSN) is implicated in Parkinson's disease (PD) and is the major component of Lewy bodies (LBs). Although alphaSN is mainly expressed in neuronal cells and exists as a cytoplasmic protein, it has been found in body fluids including cerebrospinal fluid and blood. This study explored plasma alphaSN a...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/j.expneurol.2006.12.006
更新日期:2007-04-01 00:00:00
abstract::The clinical outcome of peripheral nerve injuries requiring surgical repair is usually poor and efficient therapies do not exist. Recent work has suggested that low-frequency electrical stimulation of the severed nerve which produces repeated discharges of the parent motoneuron perikarya positively influences axonal r...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/j.expneurol.2007.08.005
更新日期:2007-11-01 00:00:00
abstract::Dementia and parkinsonism are late-onset symptoms associated with repetitive head injury, as documented in multiple contact-sport athletes. Clinical symptomatology is the likely phenotype of chronic degeneration and circuit disruption in the substantia nigra (SN). To investigate the initiating neuropathology, we hypot...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/j.expneurol.2011.12.003
更新日期:2012-03-01 00:00:00
abstract::Urotensin-II (U-II) is a cyclic peptide identified recently in many mammalian species including man. U-II and its receptor are expressed in the central nervous system, in the cardiovascular system and in other peripheral tissues. Although this peptide has been reported initially to be a potent vasoconstrictor, increas...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/j.expneurol.2007.12.004
更新日期:2008-04-01 00:00:00
abstract::delta-Aminolevulinic acid (ALA), a toxic precursor of porphyrin, when injected i.v. failed to enter most brain structures, such as the cortex, thalamus, midbrain, and others, as determined by the autoradiographic technique. However, the choroid plexus, median eminence, and a narrow strip of the periventricular zone, w...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/0014-4886(83)90234-0
更新日期:1983-02-01 00:00:00
abstract::Recent studies have implicated nitric oxide (NO) in several mechanisms related to neuronal degeneration and synaptic plasticity. In the present study, two models of traumatic neuronal injury were used to examine the expression of NOS following neuronal injury and its relationship to axonal sprouting and neuronal degen...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1006/exnr.1993.1050
更新日期:1993-04-01 00:00:00
abstract::Given the profound negative public health effects of major depressive disorder (MDD), and data suggesting only modest effectiveness of existing psychological and pharmacological treatments for this condition, there has been increasing interest in exploring the antidepressant potential of non-pharmacological, brain-bas...
journal_title:Experimental neurology
pub_type: 杂志文章,评审
doi:10.1016/j.expneurol.2009.04.028
更新日期:2009-09-01 00:00:00
abstract::This study characterizes the impact of increasing-intensity treadmill exercise (iTR) on noradrenergic (NE) and serotonergic (5HT) modulation of neuropathic pain. Following sciatic nerve transection and repair (SNTR) rats developed significant mechanical and thermal hyperalgesia that was partially prevented by iTR perf...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/j.expneurol.2017.10.007
更新日期:2018-01-01 00:00:00
abstract::Primary spinal cord trauma can initiate a cascade of pathophysiologic events which markedly contribute to the expansion and amplification of the primary insult. The detailed mechanisms of these secondary neurochemical reactions are largely unknown; however, they involve membrane lipid derangements with the release of ...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1006/exnr.1999.7308
更新日期:2000-02-01 00:00:00
abstract::NMDA receptors in postmortem human spinal cord were analyzed using [3H]MK-801 ligand binding and immunoblotting with NMDA receptor subunit-specific antibodies. The average KD for [3H]MK-801 binding was 1.77 nM with a Bmax of 0.103 pmol/mg. The EC50 for stimulation of -3H-MK-801 binding with L-glutamate was 0.34 microM...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1006/exnr.1997.6691
更新日期:1997-12-01 00:00:00
abstract::Olfactory ensheathing cells (OECs) are unique glia that support axon outgrowth in the olfactory system, and when used as cellular therapy after spinal cord injury, improve recovery and axon regeneration. Here we assessed the effects of combining OEC transplantation with another promising therapy, epidural electrical s...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/j.expneurol.2018.07.015
更新日期:2018-11-01 00:00:00
abstract::The accumulation of damage to DNA plays a significant role in the etiology of the aging process. The importance of nutrition in delaying the aging process is well recognized. L-carnitine is a quaternary ammonium compound heterogeneously distributed in the brain. In the present study the effect of L-carnitine on DNA da...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/j.expneurol.2004.09.009
更新日期:2005-01-01 00:00:00
abstract::Peripheral nerve regeneration following injury occurs spontaneously, but many of the processes require metabolic energy. The mechanism of energy supply to axons has not previously been determined. In the central nervous system, monocarboxylate transporter 1 (MCT1), expressed in oligodendroglia, is critical for supplyi...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/j.expneurol.2014.10.018
更新日期:2015-01-01 00:00:00
abstract::Functional regeneration of brainstem-spinal pathways occurs in the developing chick when the spinal cord is severed prior to embryonic day (E) 13. Functional spinal cord regeneration is not observed in animals injured after E13. This developmental transition from a permissive to a restrictive repair period may be due ...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1006/exnr.2000.7496
更新日期:2000-11-01 00:00:00
abstract::The present experiments focused on the morphological interaction between serotonergic (5-HT) and noradrenergic (NA) axons during regeneration following partial axonal denervation in the cerebral cortex in adult rats. The denervation paradigm used employed two neurotoxins, one for 5-HT and one for NA axons, infused tog...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/s0014-4886(03)00221-8
更新日期:2003-11-01 00:00:00
abstract::Hydrocephalic mutant mice and matched siblings at different ages were used to measure the pressure and the resistance to drainage of the cerebrospinal fluid (CSF) from the lateral ventricles and from the cisterna magna with glass micropipets. The resting CSF pressure in normal mice increased between 1 to 2 and 4 to 8 ...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1016/0014-4886(85)90049-4
更新日期:1985-10-01 00:00:00
abstract::Microglia express cytokines, major histocompatibility (MHC) loci, and several other immunologically important constituents. The aim of this study was to detect immunological responses of microglial cells following allogeneic dopaminergic transplantation using active and adoptive immunizations. Adult inbred Fisher 344 ...
journal_title:Experimental neurology
pub_type: 杂志文章
doi:10.1006/exnr.1996.0151
更新日期:1996-10-01 00:00:00