共查询到20条相似文献,搜索用时 25 毫秒
1.
31P nuclear magnetic resonance spectroscopy (31P-MRS) was used to investigate the energy metabolism of the gastrocnemius muscle in 16 DMD/BMD female carriers. No significant difference was found with the controls in the resting muscle, while all carriers showed a decreased ability to perform work, and a higher Pi/PCr ratio for comparable relative levels of steady-state work. The rate of postexercise recovery of PCr/Pi ratio was lower in all carriers. The decreased rate of PCr/Pi recovery appears to be mainly due to a decreased rate of Pi recovery. Our findings show abnormal muscle energy metabolism in DMD/BMD female carriers. 相似文献
2.
Antonio Toscano Seiichi Tsujino Giuseppe Vita Sara Shanske Corrado Messina Salvatore DiMauro 《Muscle & nerve》1996,19(9):1134-1137
Human muscle phosphoglycerate mutase (PGAM-M) deficiency is associated with exercise intolerance, muscle cramps, chronic serum CK elevation, and recurrent episodes of myoglobinuria. Ten patients have been described: 7 African Americans, 1 African, and 2 Caucasians from the Italian kindred described here. Molecular genetic analysis has revealed three different mutations in the PGAM-M gene. The propositus of the Italian family was homozygous for a unique point mutation at condon 90 in exon 1, a C-to-T transition converting an encoded arginine to tryptophan. His sister, who had similar complaints, was also homozygous for this mutation while the paternal grandfather, both parents, a brother and a nephew of the propositus were heterozygous for the mutation. Our studies exclude that PGAM-M deficiency is limited to African Americans, and suggest that the molecular heterogeneity of this rare disorder may be due to a “founder effect” in different ethnic groups. © 1996 John Wiley & Sons, Inc Muscle & Nerve 19:1134–1137, 1996 相似文献
3.
A. Toscano M. C. Fazio G. Vita S. Cannavó N. Bresolin L. Bet A. Prelle B. Barbiroli S. Iotti P. Zaniol A. Magaudda F. Trimarchi C. Messina 《Journal of neurology》1995,242(4):203-209
A 16-year-old girl presented with early-onset cerebellar ataxia, myoclonus, elevated lactic acidosis and hypogonadotropic hypogonadism. Muscle biopsy specimens revealed fibres with a ragged appearance with increased mitochondria and lipid droplets. Biochemical investigation revealed a deficiency of complexbc
1 (complex III) of the mitochondrial respiratory chain. Genetic analysis did not show either deletions or known mutations of mitochondrial DNA (mtDNA). Phosphorus magnetic resonance spectroscopy (31P-MRS) showed defective energy metabolism in brain and gastrocnemius muscle. A decreased phosphocreatine (PCr) content was found in the occipital lobes accompanied by normal inorganic phosphate (Pi) and cytosolic pH. These findings represented evidence of a high cytosolic adenosine diphosphate concentration and a relatively high rate of metabolism accompanied by a low phosphorylation potential. Muscle31P-MRS showed a high Pi content at rest, abnormal exercise transfer pattern and a low rate of PCr post-exercise recovery. These findings suggested a deficit of mitochondrial function. Therapy with vitamins K3 and C normalized brain31P-MRS indices, whereas it did not affect muscle bioenergetic metabolism. In this patient, the endocrinological disorder is putatively due to a mitochondrial cytopathy. Although an unknown mtDNA mutation cannot be ruled out, the genetic defect may lie in the nuclear genome. 相似文献
4.
Summary The populations of cytochrome c oxidase (CCO)-positive and-negative mitochondria were analyzed in the elongated cells containing occasional multiple nuclei (myotubes) in primary muscle cultures derived from patients with various forms of mitochondrial encephalomyopathies with CCO deficiency. Even in control muscle cultures, CCO-positive (79.7%) and -negative (20.3%) mitochondria were distributed randomly, showing intracellular mosaicism. All mitochondria in all muscle cultures from two patients with clinical characteristics of Leigh's disease exhibited faint to negative CCO activity. In these patients no enzyme activity could be detected in any tissue including intrafusal fibers and fibroblasts in muscle biopsies. In patients with the fatal infantile and the encephalomyopathic forms of CCO deficiency, and myoclonic epilepsy with ragged-red fibers, two different types of myotubes containing mostly CCO-positive mitochondria and only negative mitochondria, respectively, representing intercellular mosaicism, were demonstrated. The intercellular mosaicism in biopsied and cultured muscles in the case of CCO deficiency supports the contention that both CCO-positive and -negative mitochondria coexist in the early myogenic cell and later randomly segregated during cell division (mitotic segregation), forming two different cells.Support in part by Grants-in-Aid for Scientific Research (No. 0267032), Scientific Research on Priority Areas (No. 62617523) and Developmental Scientific Research (No. 62870041) from the Ministry of Education, Science and Culture of Japan 相似文献
5.
Wenyan Li Tao Zheng Arun N. Babu Bella T. Altura Raj K. Gupta Burton M. Altura 《Brain research bulletin》2001,56(2):153-158
This study was designed to examine the roles of intracellular free magnesium ion concentration ([Mg(2+)](i)) in ethanol-induced intoxication and development of tolerance in cultured canine cerebral vascular smooth muscle cells and astrocytes as well as intact rat brain. The basal, resting level of [Mg(2+)](i) in cerebrovascular cells was 732.5 +/- 82.4 microM. Exposure of cultured canine cerebral vascular smooth muscle cells to ethanol (10 and 25 mM) for 24 h reduced the concentrations of [Mg(2+)](i) to 521.1 +/- 59.6 microM, and 308.2 +/- 37.8 microM, respectively. However, exposure of these cultured vascular cells to the same concentrations of ethanol, after initial pretreatment with ethanol for 24 h, failed to interfere with the levels of [Mg(2+)](i). Measurement of [Mg(2+)](i) at 48 h and 72 h indicated that the decreased levels of [Mg(2+)](i) induced by ethanol at 24 h treatment returned toward baseline. Similar experiments were performed in cultured type-2 astrocytes isolated from neonatal rat brain. The basal level of [Mg(2+)](i) in type-2 astrocytes was about 125 microM. Incubation of these cells with 10 mM ethanol for 10 min resulted in a 27% reduction in the level of [Mg(2+)](i), whereas incubation with 25 mM ethanol resulted in almost a 50% reduction in [Mg(2+)](i). The decreased levels of [Mg(2+)](i) lasted around 30 min, until the measurement finished. Continuous incubation of these cultured astrocytes, with ethanol (either 10 mM or 25 mM), for more than 24 h, indicated that the concentrations of [Mg(2+)](i) in type-2 astrocytes were equivalent to those at basal, resting levels. In vivo 31P-NMR spectroscopy, performed on intact rat brains, indicated that an initial administration of 4 mg/kg ethanol ( approximately 20-25 mM blood alcohol level) resulted (after 20-40 min of exposure) in severe deficits in whole brain [Mg(2+)](i) (550 +/- 33 microM to 358 +/- 24 microM). Repeated injections of ethanol (4 mg/kg) over the next 24-72 h resulted in progressively diminishing effects on brain [Mg(2+)](i). These experimental data indicate that chronic ethanol treatment can induce a tolerance to depletion of [Mg(2+)](i) in cerebrovascular smooth muscle cells, type-2 astrocytes as well as intact rat brain. The results suggest that [Mg(2+)](i) might play a major role in alcohol-induced tolerance in the brain. 相似文献
6.
Funicello R. Barbiroli B. Zaniol P. Martinelli P. 《The Italian Journal of Neurological Sciences》1993,14(3):263-267
We report a31P Magnetic Resonance Spectroscopy (31P-MRS) study on the changes of energy metabolism in human leg anterior and lateral compartment muscles with paresis due to
compression from a herniated lumbar disc at the L4-L5 level and recovery to normality. A low phosphocreatine to inorganic phosphate ratio due to both decreased phosphocreatine
and increased inorganic phosphate contents and a normal intracellular pH were the features of muscles with paresis. Changes
of31P-MRS parameters were followed during 18 weeks of treatment with physical therapy until complete recovery. Results show that31P-MRS is a useful clinical tool for detecting even small biochemical changes that may occur in muscles and for checking the
effects of therapy.
Sommario Abbiamo studiato in vivo con la spettroscopia NMR dei composti fosforilati il metabolismo energetico dei muscoli della loggia anterolaterale della gamba destra di un paziente affetto da paresi per ernia discale a livello di L4-L5 e le successive modificazioni durante il recupero alla normalità. I muscoli paretici erano caratterizzati da un basso rapporto fosfocreatina/fosfato inorganico dovuto sia a una diminuzione della fosfocreatina che ad un aumento del fosfato inorganico. I cambiamenti metabolici sono stati seguiti per 18 settimane durante i successivi cicli di terapia fisica fino al completo recupero. I risultati dimostrano, anche in questo caso, che la spettroscopia NMR è utile per valutare modeste modificazioni biochimiche che avvengono nei muscoli e per controllare l'effetto della terapia.相似文献
7.
B. Barbiroli R. Medori H. -J. Tritschler T. Klopstock P. Seibel H. Reichmann S. Iotti R. Lodi P. Zaniol 《Journal of neurology》1995,242(7):472-477
A woman affected by chronic progressive external ophthalmoplegia and muscle mitochondrial DNA deletion was studied by phosphorus magnetic resonance spectroscopy (31P-MRS) prior to and after 1 and 7 months of treatment with oral lipoic acid. Before treatment a decreased phosphocreatine (PCr) content was found in the occipital lobes, accompanied by normal inorganic phosphate (Pi) level and cytosolic pH. Based on these findings, we found a high cytosolic adenosine diphosphate concentration [ADP] and high relative rate of energy metabolism together with a low phosphorylation potential. Muscle MRS showed an abnormal work-energy cost transfer function and a low rate of PCr recovery during the post-exercise period. All of these findings indicated a deficit of mitochondrial function in both brain and muscle. Treatment with 600 mg lipoic acid daily for 1 month resulted in a 55% increase of brain [PCr], 72% increase of phosphorylation potential, and a decrease of calculated [ADP] and rate of energy metabolism. After 7 months of treatment MRS data and mitochondrial function had improved further. Treatment with lipoate also led to a 64% increase in the initial slope of the work-energy cost transfer function in the working calf muscle and worsened the rate of PCr resynthesis during recovery. The patient reported subjective improvement of general conditions and muscle performance after therapy. Our results indicate that treatment with lipoate caused a relevant increase in levels of energy available in brain and skeletal muscle during exercise. 相似文献
8.
Basal ganglia germinoma: diagnostic value of MR spectroscopy and (11)C-methionine positron emission tomography 总被引:2,自引:0,他引:2
Fujii Y Saito Y Ogawa T Fujii S Kamitani H Kondo S Horie Y Togawa M Senda M Maegaki Y Ohno K 《Journal of the neurological sciences》2008,270(1-2):189-193
We herein report a 12-year-old girl with a basal ganglia germinoma who presented with right-sided hemiparesis after a minor head trauma. Magnetic resonance (MR) imaging revealed a minimally enhanced lesion involving the left putamen, thalamus, and corona radiata. The lesion showed low-signal intensity on T1-, and high intensity on T2- and diffusion-weighted imaging. The MR signal in the adjacent globus pallidum was also low on T2-weighted imaging. MR spectroscopy on the lesion showed a large lactate/lipid/macromolecule peak with a decreased NAA/Cr ratio, but no increase in the Cho/Cr ratio. However, posttraumatic infarction at the territory of lateral lenticulostriate artery was ruled out 1 month later. This was based on progression of the hemiparesis and neuroimaging results, including an increased Cho/Cr ratio and weak uptake on (11)C-methionine positron emission tomography of the basal ganglia lesion. Stereotaxic brain biopsy confirmed the diagnosis of germinoma. 相似文献
9.
Chassain C Bielicki G Donnat JP Renou JP Eschalier A Durif F 《Experimental neurology》2005,191(2):276-284
The aim of this work was to explore in vivo the metabolism of the basal ganglia in a rat model of Parkinson's disease. (13)C NMR spectroscopy was used to monitor the synthesis of glutamate/glutamine from [2-(13)C] sodium acetate. (13)C label incorporation in glutamate at the carbon C4 was measured in the brain of rats in different physiopathological states and after antiparkinsonian treatment. Studies were performed in control rats (n = 6) and parkinsonian rats (n = 5) in a stable state and after acute levodopa administration (50 mg/kg iv). (13)C NMR spectra recorded using a (1)H/(13)C surface probe were acquired in the injured cerebral hemisphere. The sequence was a (13)C acquisition sequence with (1)H-decoupling during acquisition, which lasted 17 min, six spectra were obtained during the acetate infusion. Levels of glutamate C4 expressed as a percentage of the lipid resonance that appears in the same spectrum were significantly higher in parkinsonian rats than in controls after 34 min (45.1 +/- 12.8% vs. 32.0 +/- 3.7%; P < 0.05), 51 min (49.0 +/- 5.6% vs. 29.8 +/- 4.0%; P < 0.001), 68 min (61.6 +/- 12.5% vs. 43.5 +/- 13.7%; P < 0.01), and 85 min (46.8 +/- 5.8% vs. 27.4 +/- 7.4%; P < 0.05) of substrate infusion. In parkinsonian rats receiving an acute levodopa injection, the relative proportion of glutamate C4 was statistically lower than in parkinsonian rats receiving saline. Our results show that the metabolism of neuronal glutamate increases in dopamine-depleted striatum and that is restored by administration of levodopa. 相似文献
10.
Summary We investigated the effect of 30°C whole body hypothermia on neuronal injury, astroglial reactivity and intracellular pH in rats subjected to 15 min of forebrain ischemia. Experimental groups included: (1) normothermic ischemia (n=8), ischemia induced under 37°C body temperature, (2) hypothermic ischemia (n=6), ischemia induced under 30°C body temperature. Cerebral intracellular pH was measured using in vivo 31P NMR spectroscopy over 7 days. Neuronal injury and astrocytic reactivity were evaluated using hematoxylin and eosin staining, and immunoreactivity to glial fibrillary acidic protein, respectively. Normothermic animals revealed significant alkalosis (P<0.01) at 48 h after ischemia compared to the pre-ischemic value. No significant intracellular pH change was detected after ischemia in the hypothermic group. Ischemic neuronal injury was prevented in the hypothermic animals, compared to the severe neuronal injury found in the normothermic animals (P<0.01). The marked astrocytosis of normothermic animals was significantly inhibited in the hypothermic animals (P<0.01). Our data indicate, that hypothermia significantly inhibits neuronal injury as well as post-ischemic alkalois and astrocytosis, induced by 15 min of forebrain ischemia in the rat.Supported by NINDS grants NS23393 and NS29463 相似文献
11.
Giles MY Tan Felix Beacher Eileen Daly Jamie Horder Verinder Prasher Maria-Luisa Hanney Robin Morris Simon Lovestone Kieran C Murphy Andrew Simmons Declan GM Murphy 《Journal of Neurodevelopmental Disorders》2014,6(1)
Background
Down syndrome (DS), or trisomy 21, is one of the most common autosomal mutations. People with DS have intellectual disability (ID) and are at significantly increased risk of developing Alzheimer’s disease (AD). The biological associates of both ID and AD in DS are poorly understood, but glutamate has been proposed to play a key role. In non-DS populations, glutamate is essential to learning and memory and glutamate-mediated excitotoxicity has been implicated in AD. However, the concentration of hippocampal glutamate in DS individuals with and without dementia has not previously been directly investigated. Proton magnetic resonance spectroscopy (1H MRS) can be used to measure in vivo the concentrations of glutamate-glutamine (Glx). The objective of the current study was to examine the hippocampal Glx concentration in non-demented DS (DS-) and demented DS (DS+) individuals.Methods
We examined 46 adults with DS (35 without dementia and 11 with dementia) and 39 healthy controls (HC) using 1H MRS and measured their hippocampal Glx concentrations.Results
There was no significant difference in the hippocampal Glx concentration between DS+ and DS-, or between either of the DS groups and the healthy controls. Also, within DS, there was no significant correlation between hippocampal Glx concentration and measures of overall cognitive ability. Last, a sample size calculation based on the effect sizes from this study showed that it would have required 6,257 participants to provide 80% power to detect a significant difference between the groups which would indicate that there is a very low likelihood of a type 2 error accounting for the findings in this study.Conclusions
Individuals with DS do not have clinically detectable differences in hippocampal Glx concentration. Other pathophysiological processes likely account for ID and AD in people with DS. 相似文献12.
Glial contribution to seizure: K activation of (Na, K)-ATPase in bulk isolated glial cells and synaptosomes of epileptogenic cortex 总被引:7,自引:0,他引:7
Glial and neuronal (Na+, K+)-ATPase have dissimilar apparent affinities for K+ ions. Glial (Na+, K+)-ATPase is maximally activated by 20 mM K+ while neuronal (Na+, K+)-ATPase is maximally stimulated by 3–5 mM K+. Because this glial property may play an important role in the clearance of [K+]0 during seizures, we investigated the K+ activation of (Na+, K+)-ATPase within bulk isolated glial cells and synaptosomes isolated from epileptogenic brains. The primary focus (F), the homolateral brain area around the focus (PF) and the mirror (M) or secondary focus induced by freezing lesions were studied.Results show that both glial and synaptosomal enzyme activities in the epileptogenic state change in comparison with controls, i.e. sham-operated cats. In F and M., glial enzyme decreased reaction velocities between 3 and 18 mM K+. In PF, maximum velocities increased in glial (Na+, K+)-ATPase. These results indicate that in actively firing epileptogenic tissue (F, M), glial (Na+, K+)-ATPase decreased rate reactions while the catalytic activity was increased in cortical tissues surrounding the focus. These phenomena appeared early, i.e. 1–3 days after production of the freezing lesion, and was associated with a sharp decrease in absolute levels of enzyme activity.Synaptosomal (Na+, K+)-ATPase from controls always exhibited a saturation curve at 3–6 mM K+. Synaptosomal enzyme activities in the primary (F) lesion increased slightly 24 h after lesion production, then progressively decreased 3 days after lesion production. No significant changes were seen in M and PF. 相似文献
13.
Na+,K+ ATPase and myelin-associated glycoprotein (MAG) were studied by immunocytochemistry on paraffin sections of the spinal cord, optic nerve and trigeminal ganglion of adult control (+/+) and CNS myelin-deficient shiverer (shi/shi) mice. Immunostaining for Na+, K+-ATPase outlined the periphery of nerve fibers in the spinal cord white matter, optic nerve and trigeminal ganglion of +/+ and shi/shi mice. Immunostaining for Na+,K+-ATPase appeared somewhat denser in the optic nerve and spinal cord lateral funiculi of shi/shi than in +/+ mice. In addition, immunostaining for Na+,K+-ATPase was demonstrated at the plasmalemma of presumed satellite cells situated at the periphery of ganglion cell bodies in the trigeminal ganglion of both species of mice. Immunostaining for MAG was localized along the periphery of nerve fibers in the spinal cord funiculi (with little immunostaining within gray horns), optic nerve and trigeminal ganglion of both +/+ and shi/shi mice. The major differences between shi/shi and +/+ mice were that the number of MAG-immunostained nerve fibers was greatly reduced in the spinal cord funiculi and the density of immunostaining was slightly increased in the optic nerve of shi/shi mice. The numbers of MAG-immunostained nerve fibers in trigeminal ganglion were similar in both species. Also, the cytoplasm of some oligodendrocyte-like cells was found densely immunostained for MAG in the spinal cord and optic nerve of shi/shi mice, but not of +/+ mice. This light microscopic study provides evidence that the defective shiverer gene leads to a decrease in MAG deposition and to aggregations of MAG-like material within perikarya of oligodendrocyte-like cells in regions of the CNS. 相似文献
14.
Several studies have suggested that alcohol-induced brain injury is associated with generation of reactive oxygen species (ROS). The recent findings, that antioxidants (Vitamin E and pyrrolidine dithiocarbamate (PDTC)) prevent intracellular Ca(2+) ([Ca(2+)](i)) overload in cerebral vascular smooth muscle cells, induced by alcohol, demonstrate indirectly that ROS formation is related to cerebral vascular injury. The present experiments were designed to test the hypothesis that catalase, an hydrogen peroxide (H(2)O(2)) scavenging enzyme, can prevent or ameliorate alcohol-induced elevation of [Ca(2+)](i). Preincubation of cultured canine cerebral vascular smooth muscle cells with catalase (20-1000 units/ml) didn't produce any apparent changes from controls in resting levels of [Ca(2+)](i) after 1-3 days. Exposure of the cerebral vascular cells to culture media containing 10-100mM ethanol resulted in significant rises in [Ca(2+)](i) (p<0.01). Although exposure of these cells to a low concentration of catalase (20 units/ml) failed to prevent the increased level of [Ca(2+)](i) induced by ethanol, concomitant addition of higher concentrations of catalase (100-1000 units/ml) and ethanol (10-100mM) inhibited or ameliorated the rises of [Ca(2+)](i) induced by ethanol either at 24h or at 3 days, in a concentration-dependent manner. Catalase, in the range of 100-200 units/ml, inhibited approximately 50% of the [Ca(2+)](i) increases caused by ethanol in the first 24h. Catalase at a concentration of 1000 units/ml inhibited completely excessive [Ca(2+)](i) accumulation. The present results when viewed in light of other recently published data suggest that H(2)O(2) generation may be one of the earliest events triggered by alcohol in alcohol-induced brain-vascular damage, neurobehavioral actions and stroke. 相似文献
15.
Michael Aschner Dawn R Conklin Chang Ping Yao Jeffrey W Allen Kim H Tan 《Brain research》1998,813(2):444
Metallothionein (MT) proteins play an important role in the detoxification of heavy metals. Since methylmercury (MeHg) preferentially accumulates in astrocytes, we investigated the ability of the astrocyte-specific MT isoform, MT-I, to attenuate MeHg-induced cytotoxicity. Increased astrocytic MT expression was achieved by 24-h pretreatment of neonatal rat primary astrocyte cultures with 100 μM zinc (ZnSO4). Subsequently, the astrocytes were treated with MeHg (10 μM), and its toxic effects on cell volume, Na+ uptake, and K+ release were investigated and compared to cells treated with or without MeHg, but in the absence of Zn pretreatment. Pretreatment of astrocytes with Zn was associated with a 2.9-fold increase in MT protein levels (P<0.02), and a 5.6-fold increase in MT mRNA levels (p<0.002) compared to control astrocytes. Astrocytes expressing increased MT protein levels were resistant to MeHg-induced swelling. In isotonic buffer the effect of MeHg on swelling was abolished (p<0.01) by 24-h Zn pretreatment, in such a way that volume profiles in these cells did not differ from controls. Zn-induced increased expression of MTs was also associated with significant attenuation of astrocytic Na+ uptake (p<0.01) and Rb+ (a marker for K+) release (p<0.001) in response to treatment with MeHg. These results demonstrate (1) that astrocytes can be induced to express high levels of MT proteins by pretreatment with Zn, and (2) that Zn confers resistance against the acute effect of MeHg on astrocytic swelling and the associated changes in ion (Na+ and K+) transport. Taken together, the data suggest that astrocytic MT induction offers effective cellular adaptation to MeHg cytotoxicity. 相似文献
16.
The Leu-enkephalin analogue D-Ser2-Leu-Enk-Thr6 (DSLET) had been shown to enhance feeding in rats, increase dopaminergic activity in the striatum like other opiate agonists, and particularly to decrease dopaminergic activity in the hypothalamus. In this study, the latter effect was found to be localized in the hypothalamic nuclei involved in the regulation of feeding such as the paraventricular (PVN), ventromedian (VMH), dorsomedian (DMH) nuclei and the lateral hypothalamus (LH). DSLET produced the same decrease in dopaminergic activity in the LH as in the whole hypothalamus. In the median nuclei (PVN and VMH and to a lesser extent in the DMH), an opposite effect was observed, resembling that in the striatum. The relevance of these opposite variations with regard to the feeding effect of DSLET is discussed. The decreased dopaminergic activity in the LH would appear to be the most specifically related to the behavioural effect given the known role of dopamine in this region. These data reconcile apparently contradictory aspects of the role of dopamine and the functional opposition between the lateral and median hypothalamus in food intake control. 相似文献
17.
S Valdeolivas V Satta RG Pertwee J Fernández-Ruiz O Sagredo 《ACS chemical neuroscience》2012,3(5):400-406
We have investigated whether a 1:1 combination of botanical extracts enriched in either Δ(9)-tetrahydrocannabinol (Δ(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, is neuroprotective in Huntington's disease (HD), using an experimental model of this disease generated by unilateral lesions of the striatum with the mitochondrial complex II inhibitor malonate. This toxin damages striatal neurons by mechanisms that primarily involve apoptosis and microglial activation. We monitored the extent of this damage and the possible preservation of the striatal parenchyma by treatment with a Sativex-like combination of phytocannabinoids using different histological and biochemical markers. Results were as follows: (i) malonate increased the volume of edema measured by in vivo NMR imaging and the Sativex-like combination of phytocannabinoids partially reduced this increase; (ii) malonate reduced the number of Nissl-stained cells, while enhancing the number of degenerating cells stained with FluoroJade-B, and the Sativex-like combination of phytocannabinoids reversed both effects; (iii) malonate caused a strong glial activation (i.e., reactive microglia labeled with Iba-1, and astrogliosis labeled with GFAP) and the Sativex-like combination of phytocannabinoids attenuated both responses; and (iv) malonate increased the expression of inducible nitric oxide synthase and the neurotrophin IGF-1, and both responses were attenuated after the treatment with the Sativex-like combination of phytocannabinoids. We also wanted to establish whether targets within the endocannabinoid system (i.e., CB(1) and CB(2) receptors) are involved in the beneficial effects induced in this model by the Sativex-like combination of phytocannabinoids. This we did using selective antagonists for both receptor types (i.e., SR141716 and AM630) combined with the Sativex-like phytocannabinoid combination. Our results indicated that the effects of this combination are blocked by these antagonists and hence that they do result from an activation of both CB(1) and CB(2) receptors. In summary, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying signs of disease progression in a proinflammatory model of HD, which adds to previous data obtained in models priming oxidative mechanisms of striatal injury. However, the interest here is that, in contrast with these previous data, we have now obtained evidence that both CB(1) and CB(2) receptors appear to be involved in the effects produced by a Sativex-like phytocannabinoid combination, thus stressing the broad-spectrum properties of Sativex that may combine activity at the CB(1) and/or CB(2) receptors with cannabinoid receptor-independent actions. 相似文献
18.
Apoptosis has been shown to be induced by some pathological stimuli. MPP+ is a neurotoxin and an inducer of parkinsonism. When SH-SY5Y cells, human neuroblastoma cell line, were treated with MPP+, cell death estimated by lactate dehydrogenase (LDH) leakage assay occurred. The cell death was associated with the DNA fragmentation into nucleosomal fragments at 180 bp, suggesting that MPP+-induced cell death of SH-SY5Y cells occurs through apoptosis. Although SH-SY5Y cells natively express Bcl-2 protein, which inhibits apoptosis, the level of Bcl-2 protein in SH-SY5Y cells increased with increases in the treatment periods of MPP+. MPP+ inhibits the mitochondrial respiratory chain. The other inhibitors of the mitochondrial respiratory chain, antimycin A and oligomycin, also caused cell death associated with DNA fragmentation, but did not increase the Bcl-2 protein level, suggesting that an MPP+-induced apoptosis may be due to the inhibition of the mitochondrial respiratory chain but the MPP+-induced increase in the Bcl-2 protein level is not due to it. A protein kinase inhibitor, staurosporine, inhibited the MPP+-induced increase in the Bcl-2 protein level, but not the MPP+-induced cell death. These results also suggest that the mechanism by which MPP+ increases the Bcl-2 protein level is different from that of MPP+-induced cell death. 相似文献
19.
Prepulse inhibition of the acoustic startle response (PPI) is a cross-species measure of sensorimotor gating, which is severely disrupted in patients with schizophrenia. PPI deficits can be produced in experimental animals by administration of selective D(2)-like dopamine receptor agonists in the nucleus accumbens (NAc). G proteins coupled to these receptors reportedly are altered in the NAc of patients with schizophrenia. Therefore, we sought to determine whether experimental inactivation of intracellular G proteins in the NAc alters PPI. In adult male Sprague-Dawley rats, baseline PPI was determined by presenting acoustic pulse stimuli (120 dB) alone or preceded 100 ms earlier by prepulse stimuli (3, 6 or 12 dB above 70 dB ambient noise). PPI disruption was assessed in the presence of quinpirole (0.0, 0.05, 0.1, 0.5 mg/kg, sc), and pertussis toxin (PTX; 0.05 microg/side) was then infused into the NAc bilaterally. Ten days later, quinpirole-mediated disruption of PPI was significantly reduced; neither PTX alone, nor heat-inactivated PTX had any effect on quinpirole-induced PPI reductions. PPI was significantly higher after PTX infusion upon moderate quinpirole challenge, suggesting that D(2)-like receptors were less effective. PTX treatment significantly reduced basal and dopamine-stimulated [35S]GTPgammaS binding in the NAc core and shell, and reduced G(i)(alpha) protein immunoreactivity in the NAc. The results suggest that PPI disruption mediated by D(2)-like receptor activation in the NAc depends on coupling to G(i) and G(o) proteins, alteration of which could cause sensorimotor gating deficits in schizophrenia. 相似文献
20.
Intraretinal injections of high- and low-K+ Ringer's solutions generate potentials which are opposite in polarity but otherwise similar in both their shapes and retinal depth profiles. We provide evidence that the principal generator of the K+-mediated potential is the Mu¨ller (glial) cell, but that the ERG b-wave cannot be explained solely by this K+-mediated potential without considering involvement of the electrical activities of neuronal cells. 相似文献