共查询到20条相似文献,搜索用时 15 毫秒
1.
Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis
Miyazaki K Ohta Y Nagai M Morimoto N Kurata T Takehisa Y Ikeda Y Matsuura T Abe K 《Journal of neuroscience research》2011,89(5):718-728
Recent reports suggest that functional or structural defect of vascular components are implicated in amyotrophic lateral sclerosis (ALS) pathology. In the present study, we examined a possible change of the neurovascular unit consisting of endothelium (PCAM-1), tight junction (occludin), and basement membrane (collagen IV) in relation to a possible activation of MMP-9 in ALS patients and ALS model mice. We found that the damage in the neurovascular unit was more prominent in the outer side and preferentially in the anterior horn of ALS model mice. This damage occurred prior to motor neuron degeneration and was accompanied by MMP-9 up-regulation. We also found the dissociation between the PCAM-1-positive endothelium and GFAP-positive astrocyte foot processes in both humans and the animal model of ALS. The present results indicate that perivascular damage precedes the sequential changes of the disease, which are held in common between humans and the animal model of ALS, suggesting that the neurovascular unit is a potential target for therapeutic intervention in ALS. 相似文献
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《Neurological research》2013,35(7):744-754
AbstractObjective: There is increasing evidence to support that altered RNA processing is implicated in the pathogenesis of motor neuron degeneration of amyotrophic lateral sclerosis (ALS). We evaluate the expression of three RNA processing-related proteins in ALS model mice in this study.Methods: We analyzed expression and distribution patterns of three RNA processing-related proteins, nucleolar protein (NOP) 56 (identified as causative gene for spinocerebellar ataxia (SCA) 36, nicknamed Asidan), TDP-43, and fused in sarcoma/translocated in liposarcoma (FUS) in lumbar and cervical cords, hypoglossal nucleus, cerebral motor cortex, and cerebellum of transgenic (Tg) SOD1 G93A ALS model mice throughout the course of motor neuron degeneration.Results: Compared to age-matched wild type (WT) mice, Tg mice showed progressive reduction of NOP56 levels in the large motor neurons of lumbar and cervical cords from the early-symptomatic stage (14 weeks of age) to the end stage of the disease (18 weeks). TDP-43 and FUS protein levels showed a later decrease in the nucleus of large motor neuron at 18 weeks (end stage of the disease). These changes were not observed in the primary motor cortex of the cerebrum as well as molecular and granular layers and Purkinje cells in the cerebellum.Discussion: The present study suggests a progressive loss of these three nuclear proteins and subsequent RNA processing problems including a novel gene relating to ALS (NOP56) under the motor neuron degeneration. 相似文献
3.
Sugai F Yamamoto Y Miyaguchi K Zhou Z Sumi H Hamasaki T Goto M Sakoda S 《The European journal of neuroscience》2004,20(11):3179-3183
Valproic acid (VPA) has long been used as an antiepileptic drug and recently as a mood stabilizer, and evidence is increasing that VPA exerts neuroprotective effects through changes in a variety of intracellular signalling pathways including upregulation of Bcl-2 protein with an antiapoptotic property and inhibiting glycogen synthase kinase 3-beta, which is considered to promote cell survival. Although the neuroprotective effects of VPA have been demonstrated in a murine model of human immunodeficiency virus-1 encephalitis, there have been no reports on the effect of VPA in chronic progressing neurodegenerative disease models including amyotrophic lateral sclerosis (ALS). ALS is a devastating disease selectively affecting motoneurons, and its disease model mice bear a close resemblance to ALS symptomatically and pathologically. First, we used an organotypic slice culture using mouse spinal cord, and showed that VPA protected spinal motoneurons against death from glutamate toxicity in vitro. Then, we treated ALS model mice with VPA at the dose effective level for epileptic model mice after 45 days of age (pre-onset treatment) or the day of the disease onset (post-onset treatment). We found a significant prolongation of the disease duration in ALS model mice in both methods of treatment. Considering the long usage of VPA for epileptic patients with good tolerance and safety, these data strongly support the clinical application of VPA for ALS treatment. 相似文献
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Kathryn L West Dinesh K Sivakolundu Mark D Zuppichini Monroe P Turner Jeffrey S Spence Hanzhang Lu Darin T Okuda Bart Rypma 《Journal of cerebral blood flow and metabolism》2021,41(1):182
The neural mechanisms underlying motor impairment in multiple sclerosis (MS) remain unknown. Motor cortex dysfunction is implicated in blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies, but the role of neural–vascular coupling underlying BOLD changes remains unknown. We sought to independently measure the physiologic factors (i.e., cerebral blood flow (ΔCBF), cerebral metabolic rate of oxygen (ΔCMRO2), and flow–metabolism coupling (ΔCBF/ΔCMRO2), utilizing dual-echo calibrated fMRI (cfMRI) during a bilateral finger-tapping task. We utilized cfMRI to measure physiologic responses in 17 healthy volunteers and 32 MS patients (MSP) with and without motor impairment during a thumb-button-press task in thumb-related (task-central) and surrounding primary motor cortex (task-surround) regions of interest (ROIs). We observed significant ΔCBF and ΔCMRO2 increases in all MSP compared to healthy volunteers in the task-central ROI and increased flow–metabolism coupling (ΔCBF/ΔCMRO2) in the MSP without motor impairment. In the task-surround ROI, we observed decreases in ΔCBF and ΔCMRO2 in MSP with motor impairment. Additionally, ΔCBF and ΔCMRO2 responses in the task-surround ROI were associated with motor function and white matter damage in MSP. These results suggest an important role for task-surround recruitment in the primary motor cortex to maintain motor dexterity and its dependence on intact white matter microstructure and neural–vascular coupling. 相似文献
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Hedlund E Hefferan MP Marsala M Isacson O 《The European journal of neuroscience》2007,26(7):1721-1737
Amyotrophic lateral sclerosis (ALS), spinal bulbar muscular atrophy (or Kennedy's disease), spinal muscular atrophy and spinal muscular atrophy with respiratory distress 1 are neurodegenerative disorders mainly affecting motor neurons and which currently lack effective therapies. Recent studies in animal models as well as primary and embryonic stem cell models of ALS, utilizing over-expression of mutated forms of Cu/Zn superoxide dismutase 1, have shown that motor neuron degeneration in these models is in part a non cell-autonomous event and that by providing genetically non-compromised supporting cells such as microglia or growth factor-excreting cells, onset can be delayed and survival increased. Using models of acute motor neuron injury it has been shown that embryonic stem cell-derived motor neurons implanted into the spinal cord can innervate muscle targets and improve functional recovery. Thus, a rationale exists for the development of cell therapies in motor neuron diseases aimed at either protecting and/or replacing lost motor neurons, interneurons as well as non-neuronal cells. This review evaluates approaches used in animal models of motor neuron disorders and their therapeutic relevance. 相似文献
7.
The ability of thyrotropin releasing hormone (TRH) or naloxone to reduce the motor function deficit and to improve the spinal cord blood flow (SCBF) was investigated in a rat spinal cord compression injury model. Spinal cord injury was induced by compression for 5 min with a load of 35 g on a 2.2 x 5.0 mm sized compression plate causing a transient paraparesis. One group of animals was given TRH, one group naloxone and one group saline alone. Each drug was administered intravenously as a bolus dose of 2 mg/kg 60 min after injury followed by a continuous infusion of 2 mg/kg/h for 4 h. The motor performance was assessed daily on the inclined plane until Day 4, when SCBF was measured with the 14C-iodoantipyrine autoradiographic method. It was found that neither TRH nor naloxone had promoted motor function recovery or affected SCBF 4 days after spinal cord injury. 相似文献
8.
Yasushi Ito Mitsunori Yamada Hirotaka Tanaka Kazunari Aida Kazuhiro Tsuruma Masamitsu Shimazawa Isao Hozumi Takashi Inuzuka Hitoshi Takahashi Hideaki Hara 《Neurobiology of disease》2009,36(3):470-476
Endoplasmic reticulum (ER) stress-induced neuronal death may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, whether CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP), an ER-stress apoptotic mediator, is involved in the pathogenesis of ALS is controversial. Here we demonstrate the expression levels and localization of CHOP in spinal cords of both sporadic ALS patients and ALS transgenic mice by immunohistochemistry. In the spinal cords of sporadic ALS patients, CHOP was markedly up-regulated but typically expressed at low levels in those of the control. Likewise, CHOP expression increased at 14 (symptomatic stage) and 18 to 20 weeks (end stage) in ALS transgenic mice spinal cords. Furthermore, localizations of CHOP were merged in motor neurons and glial cells, such as oligodendrocytes, astrocytes, and microglia. These results indicate that the up-regulation of CHOP in motor neurons and glial cells may play pivotal roles in the pathogenesis of ALS. 相似文献
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We sought to determine whether the global increase in regional cerebral blood flow (rCBF) produced by electrical stimulation of the rostral cerebellar fastigial nucleus (FN) is a consequence of excitation of intrinsic neurons of the FN or of axons of fibers passing through or projecting into it. Studies were conducted in rats anesthetized with chloralose, paralyzed and ventilated. rCBF was measured with [14C]iodoantipyrine as tracer and regional cerebral glucose utilization (rCGU) by [14C]2-deoxyglucose in homogenates of 11 brain regions. Neuronal perikarya in FN were excited chemically by local microinjection of the glutamate analogue kainic acid (KA) (5 nmol in 100 nl). KA elicited a transient and significant fall of arterial pressure and heart rate, the fastigial depressor response (FDR). Associated was a significant and symmetrical reduction in rCBF, to 44% of control in all regions except medulla. The response was site- and agent-specific and unrelated to the hypotension. KA also significantly and proportionally reduced, to 52% of control, rCGU in the same 10 areas of brain. In all regions the magnitudes of the reductions in rCBF and rCGU elicited by KA were linearly related. Intrinsic neurons of FN were chronically destroyed by local microinjection of the excitotoxin ibotenic acid (IBO) (10 μg/μl in 0.4 μl). Destruction of intrinsic FN neurons had no effect on resting rCBF nor on the global cerebrovascular vasodilation elicited by electrical stimulation of the FN. We conclude that: (a) excitation of intrinsic neurons of FN elicits a widespread reduction of cerebral metabolism and, secondarily, blood flow; (b) FN neurons do not exert a long-term tonic influence on brain blood flow nor metabolism; (c) the global increase in rCBF elicited by electrical stimulation of the FN is a consequence of excitation of axons projecting into or through the nucleus. 相似文献
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Matthew J Farrar Jonathan D Rubin Darcy M Diago Chris B Schaffer 《Journal of cerebral blood flow and metabolism》2015,35(4):667-675
The availability of transgenic strains has made the laboratory mouse a popular model for the study of healthy and diseased state spinal cord (SC). Essential to identifying physiologic and pathologic events is an understanding of the microvascular network and flow patterns of the SC. Using 2-photon excited fluorescence (2PEF) microscopy we performed in vivo measurements of blood flow in the lower thoracic portion of the mouse dorsal spinal vein (dSV) and in the first upstream branches supplying it, denoted as dorsal ascending venules (dAVs). We found that the dSV had large radiculomedullary veins (RMVs) exiting the SC, and that flow in the dSV between pairs of RMVs was bidirectional. Volumetric flow increased in each direction away from the point of bifurcation. Flow in the upstream dAVs varied with diameter in a manner consistent with a constant distal pressure source. By performing ex vivo 2PEF microscopy of fluorescent-gel perfused tissue, we created a 3-D map of the dorsal spinal vasculature. From these data, we constructed a simple model that predicted changes in the flow of upstream branches after occlusion of the dSV in different locations. Using an atraumatic model of dSV occlusion, we confirmed the predictions of this model in vivo. 相似文献
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Intracerebroventricular (ICV) injection of streptozotocin (STZ) has been reported to impair cerebral glucose utilization and energy metabolism (Nitsch and Hoyer: Neurosci Lett, 128:199-202, 1991) and also to prejudice passive avoidance learning in adult rats (Mayer et al.: Brain Res 532:95-100, 1990). It is well established that the forebrain cholinergic system, whose integrity is essential for learning and memory functions, depends on the target-derived retrograde messenger nerve growth factor (NGF). Therefore, we measured NGF and choline acetyltransferase (ChAT) activity levels in the forebrain cholinergic system in adult rats that had received a single injection of either STZ or artificial cerebrospinal fluid into the left ventricle 1 or 3 weeks prior to sacrifice. One week after ICV STZ treatment, NGF content was significantly decreased (-32%) in the septal region, where NGF-responsive cell bodies are located and NGF exerts its neurotrophic action after retrograde transport from NGF-producing targets. In contrast, NGF levels in the cortex and hippocampus, which are target regions for the basal forebrain cholinergic neurons, and in the brainstem and cerebellum were increased (+12% to +47%) within 3 weeks after ICV STZ treatment. The alterations in NGF levels were not related to changes in ChAT activity that decreased in the hippocampus by only 15%. This might be due to masking effects exerted by compensatory NGF-mediated stimulation of ChAT activity in remaining functional neurons. It is suggested that impaired behavior which has been observed after STZ-induced impairment of cerebral glucose and energy metabolism may be at least partially related to a diminished capacity of central NGF-responsive neurons to bind and/or transport NGF.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
14.
In-vivo measurements of regional acetylcholine esterase activity in degenerative dementia: comparison with blood flow and glucose metabolism 总被引:5,自引:0,他引:5
K. Herholz B. Bauer K. Wienhard L. Kracht R. Mielke O. Lenz T. Strotmann W.-D. Heiss 《Journal of neural transmission (Vienna, Austria : 1996)》2000,107(12):1457-1468
Summary. Memory and attention are cognitive functions that depend heavily on the cholinergic system. Local activity of acetylcholine
esterase (AChE) is an indicator of its integrity. Using a recently developed tracer for positron emission tomography (PET),
C-11-labeled N-methyl-4-piperidyl-acetate (C-11-MP4A), we measured regional AChE activity in 4 non-demented subjects, 4 patients
with dementia of Alzheimer type (DAT) and 1 patient with senile dementia of Lewy body type (SDLT), and compared the findings
with measurements of blood flow (CBF) and glucose metabolism (CMRGlc). Initial tracer extraction was closely related to CBF.
AChE activity was reduced significantly in all brain regions in demented subjects, whereas reduction of CMRGlc and CBF was
more limited to temporo-parietal association areas. AChE activity in SDLT was in the lower range of values in DAT. Our results
indicate that, compared to non-demented controls, there is a global reduction of cortical AChE activity in dementia.
Received November 13, 1999; accepted May 15, 2000 相似文献
15.
Elevated extracellular glutamate, resulting from a loss of astrocytic glutamate transport capacity, may contribute to excitotoxic motor neuron (MN) damage in ALS. Accounting for their high excitotoxic vulnerability, MNs possess large numbers of unusual Ca(2+)-permeable AMPA channels (Ca-AMPA channels), the activation of which triggers mitochondrial Ca(2+) overload and strong reactive oxygen species (ROS) generation. However, the causes of the astrocytic glutamate transport loss remain unexplained. To assess the role of Ca-AMPA channels on the evolution of pathology in vivo, we have examined effects of prolonged intrathecal infusion of the Ca-AMPA channel blocker, 1-naphthyl acetylspermine (NAS), in G93A transgenic rat models of ALS. In wild-type animals, immunoreactivity for the astrocytic glutamate transporter, GLT-1, was particularly strong around ventral horn MNs. However, a marked loss of ventral horn GLT-1 was observed, along with substantial MN damage, prior to onset of symptoms (90-100 days) in the G93A rats. Conversely, labeling with the oxidative marker, nitrotyrosine, was increased in the neuropil surrounding MNs in the transgenic animals. Compared to sham-treated G93A animals, 30-day NAS infusions (starting at 67+/-2 days of age) markedly diminished the loss of both MNs and of astrocytic GLT-1 labeling. These observations are compatible with the hypothesis that activation of Ca-AMPA channels on MNs contributes, likely in part through oxidative mechanisms, to loss of glutamate transporter in surrounding astrocytes. 相似文献
16.
Fei Du Yi Zhang Xiao-Hong Zhu Wei Chen 《Journal of cerebral blood flow and metabolism》2012,32(9):1778-1787
Cerebral glucose consumption and glucose transport across the blood–brain barrier are crucial to brain function since glucose is the major energy fuel for supporting intense electrophysiological activity associated with neuronal firing and signaling. Therefore, the development of noninvasive methods to measure the cerebral metabolic rate of glucose (CMRglc) and glucose transport constants (KT: half-saturation constant; Tmax: maximum transport rate) are of importance for understanding glucose transport mechanism and neuroenergetics under various physiological and pathological conditions. In this study, a novel approach able to simultaneously measure CMRglc, KT, and Tmax via monitoring the dynamic glucose concentration changes in the brain tissue using in-vivo
1H magnetic resonance spectroscopy (MRS) and in plasma after a brief glucose infusion was proposed and tested using an animal model. The values of CMRglc, Tmax, and KT were determined to be 0.44±0.17 μmol/g per minute, 1.35±0.47 μmol/g per minute, and 13.4±6.8 mmol/L in the rat brain anesthetized with 2% isoflurane. The Monte-Carlo simulations suggest that the measurements of CMRglc and Tmax are more reliable than that of KT. The overall results indicate that the new approach is robust and reliable for in-vivo measurements of both brain glucose metabolic rate and transport constants, and has potential for human application. 相似文献
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The regional cerebral blood flow (rCBF) response to vibrotactile stimulation was compared in conscious young (5.9+/-1.8 years old) and aged (18.0+/-3.3 years old) monkeys using [15O]H(2)O and high-resolution positron emission tomography (PET). In addition, the effects of docosahexaenoic acid (DAH), an n-3 polyunsaturated fatty acid (PUFA), on the rCBF response to stimulation were evaluated in aged monkeys. Soybean milk (SBM) or DHA-containing SBM (DHA/SBM) was supplied to aged monkeys for 1 and 4 weeks. Under control conditions, vibrotactile stimulation elicited an increase in the rCBF response in the contralateral somatosensory cortices of both young and aged monkeys, but the degree of increase in the rCBF response was significantly lower in aged monkeys (116% of corresponding 'rest' condition) than that in young animals (141%). The regional cerebral metabolic rate of glucose (rCMRglc) response to the stimulation, an index of neuronal activation, was not significantly different between young and aged monkeys as measured by [18F]-2-fluoro-2-deoxy-D-glucose (FDG). Supply of DHA/SBM at a dose of 150 mg/kg/day as DHA for 1 week resulted in a significant increase in rCBF response to stimulation (127%) in aged monkeys, and 4-week supply of DHA induced further facilitation of the rCBF response (133%). In contrast, the reduced rCBF response in the aged monkeys was not affected by SBM alone for either 1 or 4 weeks. The neuronal activation itself elicited by the stimulation, as measured by [18F]FDG, was not affected by SBM or DHA/SBM. These results suggested the involvement of DHA in the coupling mechanism between the neuronal activation and rCBF response, possibly by modulation of cholinergic neuronal transmission. 相似文献
18.
Spalloni A Geracitano R Berretta N Sgobio C Bernardi G Mercuri NB Longone P Ammassari-Teule M 《Experimental neurology》2006,197(2):505-514
Although amyotrophic lateral sclerosis (ALS) is mainly considered as a motor disease, extramotor neural and cognitive alterations have also been reported in ALS patients. There is evidence that mutations in the Cu/Zn superoxide dismutase (SOD1) gene are implicated in about 20% of familiar ALS and transgenic mice overexpressing the human Cu/Zn superoxide dismutase (GLY(93) --> ALA) mutation show an ALS-like phenotype. However, while motor behavior has been extensively analyzed in these mutants, little is known on their cognitive abilities. To characterize the pre-symptomatic cognitive profile of G93A+/+ mice, we estimated their capability to detect spatial novelty and examined several indexes of their hippocampal function. We found an enhancement of spatial abilities in mutant mice associated with (1) a higher expression of hippocampal AMPA subunit GluR1 mRNA and of GluR1 protein levels, and (2) an increased induction and maintenance of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses. Thus, before leading to extensive neuronal excitotoxicity, the high endogenous levels of glutamate present in the brain of pre-symptomatic G93A+/+ mice could mediate site-specific molecular and synaptic changes providing favorable conditions to spatial information processing. These findings suggest that identification of pre-symptomatic behavioral changes in murine models of ALS may point to early neural abnormalities selectively associated with mutations in the Cu/Zn superoxide dismutase (SOD1) gene. 相似文献
19.
Costantino Iadecola Masatsugu Nakai Sima Mraovitch David A. Ruggiero Lewis W. Tucker Donald J. Reis 《Brain research》1983,272(1)
We sought to determine whether the increases in local cerebral blood flow (LBCF) elicited by focal electrical stimulation within the dorsal medullary reticular formation (DMRF), are secondary to or independent of, increased local cerebral glucose utilization (LCGU).Rats were anesthetized (chloralose), paralyzed, artificially ventilated and arterial pressure and blood gases controlled. LCBF and LCGU were determined in two separate groups of animals, using the autoradiographic [14C]iodoantipyrine and [14C]2-deoxyglucose methods, respectively. In unstimulated controls, LCBF (n= 5) and LCGU (n= 5) were linearly related (r = 0.780; P < 0.001) in the 27 brain regions studied. During DMRF stimulation LCGU increased significantly in 21 of the 27 regions, including cerebral cortex (up to 168% of control), thalamic nuclei (up to 161%) and selected ponto-medullary regions (e.g. parabrachial complex: 212%; vestibular complex: 147%). Along with LCGU, LCBF rose significantly in 25 regions (sensory motor cortex: 163%; anterior thalamus: 161%; parabrachial complex: 186%). Correlation analysis demonstrated that, during DMRF stimulation, the close relationship between LCBF and LCGU is preserved (r = 0.845; P < 0.001) and that, in addition, the increase in LCBF (δ LCBF) is proportional to the increase in LCGU (δ LCGU) (δLCGU+ 6.92; r = 0.7729; P < 0.001).Excitation of neurons or fibers within DMRF increases brain metabolism globally and blood flow secondarily. The DMRF appears to modulate cerebral metabolism globally, by as yet undefined pathways. 相似文献
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