共查询到20条相似文献,搜索用时 46 毫秒
1.
Purpera MN Shen L Taghavi M Münzberg H Martin RJ Hutson SM Morrison CD 《The Journal of endocrinology》2012,212(1):85-94
Elevation of dietary or brain leucine appears to suppress food intake via a mechanism involving mechanistic target of rapamycin, AMPK, and/or branched chain amino acid (BCAA) metabolism. Mice bearing a deletion of mitochondrial branched chain aminotransferase (BCATm), which is expressed in peripheral tissues (muscle) and brain glia, exhibit marked increases in circulating BCAAs. Here, we test whether this increase alters feeding behavior and brain neuropeptide expression. Circulating and brain levels of BCAAs were increased two- to four-fold in BCATm-deficient mice (KO). KO mice weighed less than controls (25·9 vs 20·4?g, P<0·01), but absolute food intake was relatively unchanged. In contrast to wild-type mice, KO mice preferred a low-BCAA diet to a control diet (P<0·05) but exhibited no change in preference for low- vs high-protein (HP) diets. KO mice also exhibited low leptin levels and increased hypothalamic Npy and Agrp mRNA. Normalization of circulating leptin levels had no effect on either food preference or the increased Npy and Agrp mRNA expression. If BCAAs act as signals of protein status, one would expect reduced food intake, avoidance of dietary protein, and reduction in neuropeptide expression in BCATm-KO mice. Instead, these mice exhibit an increased expression of orexigenic neuropeptides and an avoidance of BCAAs but not HP. These data thus suggest that either BCAAs do not act as physiological signals of protein status or the loss of BCAA metabolism within brain glia impairs the detection of protein balance. 相似文献
2.
Maple syrup urine disease (MSUD) was first recognized as an inherited lethal encephalopathy beginning in the first week of
life and associated with an unusual odor in the urine of affected children. It was later confirmed as a deficiency of branched-chain
keto acid dehydrogenase (BCKDH), which is the second step in branched-chain amino acid (BCAA) breakdown. MSUD is characterized
by BCAA and branched-chain keto acid (BCKA) accumulation. BCAAs are essential amino acids and powerful metabolic signals with
severe consequences of both deprivation and accumulation. Treatment requires life-long dietary restriction and monitoring
of BCAAs. However, despite excellent compliance, children commonly suffer metabolic decompensation during intercurrent illness
resulting in life-threatening cerebral edema and dysmyelination. The mechanisms underlying brain injury have been poorly understood.
Recent studies using newly developed mouse models of both classic and intermediate MSUD have yielded insight into the consequences
of rapid BCAA accumulation. Additionally, these models have been used to test preliminary treatments aimed at competing with
blood-brain barrier transport of BCAA using norleucine. Assessment of biochemical changes with and without treatment suggests
different roles for BCAA and BCKA in the mechanism of brain injury. 相似文献
3.
Dynamic changes in N-methyl-D-aspartate receptors after closed head injury in mice: Implications for treatment of neurological and cognitive deficits 下载免费PDF全文
Biegon A Fry PA Paden CM Alexandrovich A Tsenter J Shohami E 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(14):5117-5122
Traumatic brain injury is a leading cause of mortality and morbidity among young people. For the last couple of decades, it was believed that excess stimulation of brain receptors for the excitatory neurotransmitter glutamate was a major cause of delayed neuronal death after head injury, and several major clinical trials in severely head injured patients used blockers of the glutamate N-methyl-D-aspartate (NMDA) receptor. All of these trials failed to show efficacy. Using a mouse model of traumatic brain injury and quantitative autoradiography of the activity-dependent NMDA receptor antagonist MK801, we show that hyperactivation of glutamate NMDA receptors after injury is short-lived (<1 h) and is followed by a profound and long-lasting (> or =7 days) loss of function. Furthermore, stimulation of NMDA receptors by NMDA 24 and 48 h postinjury produced a significant attenuation of neurological deficits (blocked by coadministration of MK801) and restored cognitive performance 14 days postinjury. These results provide the underlying mechanism for the well known but heretofore unexplained short therapeutic window of glutamate antagonists after brain injury and support a pharmacological intervention with a relatively long (> or =24 h) time window easily attainable for treatment of human accidental head injury. 相似文献
4.
Role of branched chain amino acids in cerebral ammonia homeostasis related to hepatic encephalopathy
Lasse K. Bak Helle S. Waagepetersen Michael Sørensen Peter Ott Hendrik Vilstrup Susanne Keiding Arne Schousboe 《Metabolic brain disease》2013,28(2):209-215
Hepatic encephalopathy (HE) is associated with increased ammonia levels in plasma and brain. Different treatment strategies have been developed to ameliorate the detrimental effects of the ammonia load. One such strategy is based on the finding of a low level of the branched chain amino acids (BCAAs) in plasma of patients suffering from HE and the assumption that in particular isoleucine could be beneficial to brain energy metabolism as it is metabolized to the tricarboxylic acid cycle intermediate and precursor succinyl-CoA and acetyl-CoA, respectively. This would enable de novo synthesis of glutamine via α-ketoglutarate and glutamate and at the same time stimulate oxidative metabolism. The present mini-review summarizes the metabolic basis for this hypothesis delineating studies in the brain in vivo as well as in cultured neural cells aimed at elucidating the metabolism of the BCAAs focusing on isoleucine. The conclusion is that isoleucine appears at least partially to act in this fashion albeit its metabolism is quantitatively relatively modest. In addition, a short section on the role of the BCAAs in synaptic ammonia homeostasis is included along with some thoughts on the role of the BCAAs in other pathologies such as cancer. 相似文献
5.
Aged traumatic brain injury (TBI) patients suffer higher rates of mortality and disability than younger patients. Cognitive problems common to TBI patients are associated with damage to the hippocampus, a central locus of learning and memory. To investigate the molecular mechanisms of age-related vulnerability to brain injury in a mouse model of TBI, we studied the effects of TBI on hippocampal gene expression in young and aged mice. Young and aged male C57Bl/6 mice were subjected to sham injury or TBI and sacrificed 24 h post-injury. We used laser capture microdissection to obtain pure populations of neurons from the CA1, CA3, and dentate gyrus subfields of the hippocampus. We compared injury-induced gene expression in hippocampal neurons of young and aged mice using quantitative ribonuclease protection assay analysis of linearly amplified mRNA from laser captured neurons. Both increased age and TBI were associated with increased expression of neuroprotective (brain-derived neurotrophic factor), pro-inflammatory (interleukin-1beta), and proapoptotic (caspase-3) genes in mouse hippocampal neurons. Our data support previous reports that suggested the CA3 subregion is highly susceptible to fluid percussion TBI and that age-related changes in gene expression are one potential mechanism of increased vulnerability of the aged brain to TBI. 相似文献
6.
大量研究证实支链氨基酸(branched-chain amino acids,BCAAs)在心血管疾病如冠心病、动脉粥样硬化、高血压等的发生和发展中起着重要作用,且宿主BCAAs水平的升高与饮食、肠道菌群、疾病和遗传等因素均密切相关。从因果关系上看,肠道菌群紊乱促进了心血管疾病的发生发展,且部分肠道微生物参与BCAAs的生物合成,直接影响宿主外周BCAAs水平。近年来,从宿主和肠道菌群的角度干预BCAA代谢已成为国内外防治心血管疾病的研究热点。现就BCAAs与心血管疾病关系和肠道菌群-BCAAs代谢途径干预方法的研究进展进行综述。 相似文献
7.
Moussawi K Zhou W Shen H Reichel CM See RE Carr DB Kalivas PW 《Proceedings of the National Academy of Sciences of the United States of America》2011,108(1):385-390
Cocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. Vulnerability to relapse arises from an enduring impairment in cognitive control of motivated behavior, manifested in part by dysregulated synaptic potentiation and extracellular glutamate homeostasis in the projection from the prefrontal cortex to the nucleus accumbens. Here we show in rats trained to self-administer cocaine that the enduring cocaine-induced changes in synaptic potentiation and glutamate homeostasis are mechanistically linked through group II metabotropic glutamate receptor signaling. The enduring cocaine-induced changes in measures of cortico-accumbens synaptic and glial transmission were restored to predrug parameters for at least 2 wk after discontinuing chronic treatment with the cystine prodrug, N-acetylcysteine. N-acetylcysteine produced these changes by inducing an enduring restoration of nonsynaptic glutamatergic tone onto metabotropic glutamate receptors. The long-lasting pharmacological restoration of cocaine-induced glutamatergic adaptations by chronic N-acetylcysteine also caused enduring inhibition of cocaine-seeking in an animal model of relapse. These data mechanistically link nonsynaptic glutamate to cocaine-induced adaptations in excitatory transmission and demonstrate a mechanism to chronically restore prefrontal to accumbens transmission and thereby inhibit relapse in an animal model. 相似文献
8.
McNulty PH Jacob R Deckelbaum LI Young LH 《Metabolism: clinical and experimental》2000,49(10):1365-1369
Branched-chain amino acids (BCAAs) are oxidative energy substrates for the heart and may exert anabolic effects on myocardial protein. The factors regulating their myocardial uptake in patients with ischemic heart disease are therefore of interest. To examine whether myocardial BCAA utilization is influenced by the circulating insulin concentration, in 10 patients with chronic ischemic heart disease, we measured transmyocardial amino acid balance during fasting and again during a 90-minute euglycemic insulin infusion (plasma insulin, 218+/-25 microU x mL(-1)) with plasma BCAA concentrations held constant by coinfusion. In the fasting state, the myocardial fractional extraction of leucine (8%), isoleucine (9%), and valine (5%) from arterial plasma was slightly greater than that of glucose (3%), while net myocardial BCAA uptake (leucine, 409+/-207 nmol x min(-1); isoleucine, 220+/-144 nmol x min(-1); valine, 407+/-326 nmol x min(-1); and total BCAA uptake, 1.0+/-0.3 micromol x min(-1)) was about 13% that of glucose (8+/-2 micromol x min(-1)). During euglycemic hyperinsulinemia, myocardial glucose uptake increased 3-fold, but there was no change in the arterial-coronary sinus balance or net myocardial uptake of any BCAA under conditions where their plasma concentrations were held constant. Instead, the myocardial uptake of each BCAA correlated positively with its concentration in arterial plasma. These results demonstrate that in patients with cardiovascular disease, myocardial utilization of BCAAs is insensitive to the circulating insulin level and is regulated instead by their availability in arterial plasma. Hyperinsulinemia reduced the magnitude of both net glutamate uptake and alanine release, suggesting a possible salutary effect on myocardial oxidative efficiency. 相似文献
9.
Impairment of synaptic transmission by transient hypoxia in hippocampal slices: improved recovery in glutathione peroxidase transgenic mice 下载免费PDF全文
Furling D Ghribi O Lahsaini A Mirault ME Massicotte G 《Proceedings of the National Academy of Sciences of the United States of America》2000,97(8):4351-4356
There is increasing evidence that oxygen free radicals contribute to ischemic brain injury. It is unclear, however, to what extent specific antioxidant enzymes can prevent or reverse the impairment of synaptic function caused by transient hypoxia. In this study, we investigated in transgenic (Tg) mice whether a moderate increase in glutathione peroxidase-1 (GPx1) may improve the capacity of CA1 pyramidal cells to recover synaptic transmission after a short period of hypoxia in vitro. In control hippocampal slices, transient hypoxia (7-9 min) produced irreversible loss of excitatory postsynaptic potentials. Complete recovery of synaptic transmission was observed with homozygous Tg-MT-GPx-6 mice after reoxygenation, and, after repeated episodes of hypoxia, synaptic transmission was still viable in most Tg slices, in contrast to non-Tg slices. Moreover, hypoxic episodes abolished the capacity of hippocampal slices to generate long-term potentiation in area CA1 of control mice, whereas a significant extent of long-term potentiation expression was still preserved in Tg tissues. We also demonstrated that susceptibility to N-methyl-d-aspartate-mediated oxidative injury was reduced in Tg hippocampal slices. In conclusion, our results suggest that a moderate GPx increase can be sufficient to prevent irreversible functional damage produced by transient hypoxia in the hippocampus and to help maintain basic electrophysiological mechanisms involved in memory formation. 相似文献
10.
Pascal E. Sanchez Lei Zhu Laure Verret Keith A. Vossel Anna G. Orr John R. Cirrito Nino Devidze Kaitlyn Ho Gui-Qiu Yu Jorge J. Palop Lennart Mucke 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(42):E2895
In light of the rising prevalence of Alzheimer’s disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-β peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-β–induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by electroencephalography. Chronic treatment with LEV also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP mice. Our findings support the hypothesis that aberrant network activity contributes causally to synaptic and cognitive deficits in hAPP mice. LEV might also help ameliorate related abnormalities in people who have or are at risk for AD. 相似文献
11.
The effect of in vivo corticosterone manipulation on binding sites for the excitatory neurotransmitter glutamate was determined using radioligand binding to rat brain cryostat sections and crude synaptic membranes. 3H-glutamate binding to regions of the dorsal hippocampal formation was significantly decreased in adrenalectomized animals following 5-10 days of corticosterone treatment. Corticosterone did not alter 3H-glutamate binding in several other brain regions. The loss in 3H-glutamate binding appeared to be due to a decrease in the maximal number of binding sites, with little change in binding affinity. Both chloride-dependent and chloride-independent 3H-glutamate binding sites were decreased by corticosterone treatment. results indicate that corticosterone can selectively alter binding sites for excitatory amino acids in hippocampal tissue. 相似文献
12.
Malnutrition is common among older persons, with important consequences increasing frailty and morbidity and reducing health expectancy. On the contrary, calorie restriction (CR, a low-calorie dietary regimen with adequate nutrition) slows the progression of age-related diseases and extends the lifespan of many species. Identification of strategies mimicking key CR mechanisms - increased mitochondrial respiration and reduced production of oxygen radicals - is a hot topic in gerontology. Dietary supplementation with essential and/or branched chain amino acids (BCAAs) exerts a variety of beneficial effects in experimental animals and humans and has been recently demonstrated to support cardiac and skeletal muscle mitochondrial biogenesis, prevent oxidative damage, and enhance physical endurance in middle-aged mice, resulting in prolonged survival. Here we review recent studies addressing the possible role of BCAAs in energy metabolism and in the longevity of species ranging from unicellular organisms to mammals. We also summarize observations from human studies supporting the exciting hypothesis that dietary BCAA enriched mixture supplementation might be a health-promoting strategy in aged patients at risk. 相似文献
13.
Love-Gregory LD Dyer JA Grasela J Hillman RE Phillips CL 《Journal of inherited metabolic disease》2001,24(3):393-403
The turnaround time for diagnosis of maple syrup urine disease (MSUD) by classic serum amino acid analyses often requires 3-4 days. This is due to the need for branched-chain amino acids (BCAA) to accumulate in the serum of the newborn before testing. The accumulation of BCAAs in infants with MSUD during this time increases the risk of the infant becoming clinically symptomatic. We have developed a noninvasive DNA-based mismatch PCR-RFLP assay for the Y393N BCKDHA allele (E1alpha gene of the branched chain alpha-keto acid dehydrogenase complex), the primary cause of MSUD in Old Order Mennonite communities. The homozygosity and high frequency of this mutation in the Mennonite community and its prevalence in compound heterozygote non-Mennonite MSUD patients is of significance. We describe carrier testing, present the results of nine newborns diagnostically evaluated for the Y393N BCKDHA allele, and demonstrate the efficacy of this PCR-RFLP assay for determining clinical status within 24 h after birth. Analyses within the first 24 h of life allow for immediate diagnosis and treatment of infants homozygous for the Y393N MSUD defect. This is a significant improvement over the time required by current serum amino acid analysis methods. 相似文献
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15.
Volk L Kim CH Takamiya K Yu Y Huganir RL 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(50):21784-21789
AMPA-type glutamate receptors (AMPARs) mediate the majority of fast excitatory neurotransmission in the mammalian central nervous system. Modulation of AMPAR trafficking supports several forms of synaptic plasticity thought to underlie learning and memory. Protein interacting with C kinase 1 (PICK1) is an AMPAR-binding protein shown to regulate both AMPAR trafficking and synaptic plasticity at many distinct synapses. However, studies examining the requirement for PICK1 in maintaining basal synaptic transmission and regulating synaptic plasticity at hippocampal Schaffer collateral-cornu ammonis 1 (SC-CA1) synapses have produced conflicting results. In addition, the effect of PICK1 manipulation on learning and memory has not been investigated. In the present study we analyzed the effect of genetic deletion of PICK1 on basal synaptic transmission and synaptic plasticity at hippocampal Schaffer collateral-CA1 synapses in adult and juvenile mice. Surprisingly, we find that loss of PICK1 has no significant effect on synaptic plasticity in juvenile mice but impairs some forms of long-term potentiation and multiple distinct forms of long-term depression in adult mice. Moreover, inhibitory avoidance learning is impaired only in adult KO mice. These results suggest that PICK1 is selectively required for hippocampal synaptic plasticity and learning in adult rodents. 相似文献
16.
Giselli Scaini Clarissa M. Comim Giovanna M. T. Oliveira Matheus A. B. Pasquali João Quevedo Daniel P. Gelain José Cláudio F. Moreira Patrícia F. Schuck Gustavo C. Ferreira Maurício R. Bogo Emilio L. Streck 《Journal of inherited metabolic disease》2013,36(5):721-730
Maple syrup urine disease (MSUD) is a neurometabolic disorder that leads to the accumulation of branched-chain amino acids (BCAAs) and their α-keto branched-chain by-products. Because the neurotoxic mechanisms of MSUD are poorly understood, this study aimed to evaluate the effects of chronic administration of a BCAA pool (leucine, isoleucine and valine). This study examined the effects of BCAA administration on spatial memory and the levels of brain-derived neurotrophic factor (BNDF). We examined both pro-BDNF and bdnf mRNA expression levels after administration of BCAAs. Furthermore, this study examined whether antioxidant treatment prevented the alterations induced by BCAA administration. Our results demonstrated an increase in BDNF in the hippocampus and cerebral cortex, accompanied by memory impairment in spatial memory tasks. Additionally, chronic administration of BCAAs did not induce a detectable change in pro-BDNF levels. Treatment with N-acetylcysteine and deferoxamine prevented both the memory deficit and the increase in the BDNF levels induced by BCAA administration. In conclusion, these results suggest that when the brain is chronically exposed to high concentrations of BCAA (at millimolar concentrations) an increase in BDNF levels occurs. This increase in BDNF may be related to the impairment of spatial memory. In addition, we demonstrated that antioxidant treatment prevented the negative consequences related to BCAA administration, suggesting that oxidative stress might be involved in the pathophysiological mechanism(s) underlying the brain damage observed in MSUD. 相似文献
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Hiranya Pintana Wanpitak Pongkan Wasana Pratchayasakul Nipon Chattipakorn Siriporn C. Chattipakorn 《Age (Dordrecht, Netherlands)》2015,37(5)
Testosterone replacement improves metabolic parameters and cognitive function in hypogonadism. However, the effects of testosterone therapy on cognition in obese condition with testosterone deprivation have not been investigated. We hypothesized that testosterone replacement improves cognitive function in testosterone-deprived obese rats by restoring brain insulin sensitivity, brain mitochondrial function, and hippocampal synaptic plasticity. Thirty male Wistar rats had either a bilateral orchiectomy (ORX: O, n = 24) or a sham operation (S, n = 6). ORX rats were further divided into two groups fed with either a normal diet (NDO) or a high-fat diet (HFO) for 12 weeks. Then, ORX rats in each dietary group were divided into two subgroups (n = 6/subgroup) and were given either castor oil or testosterone (2 mg/kg/day, s.c.) for 4 weeks. At the end of this protocol, cognitive function, metabolic parameters, brain insulin sensitivity, hippocampal synaptic plasticity, and brain mitochondrial function were determined. We found that testosterone replacement increased peripheral insulin sensitivity, decreased circulation and brain oxidative stress levels, and attenuated brain mitochondrial ROS production in HFO rats. However, testosterone failed to restore hippocampal synaptic plasticity and cognitive function in HFO rats. In contrast, in NDO rats, testosterone decreased circulation and brain oxidative stress levels, attenuated brain mitochondrial ROS production, and restored hippocampal synaptic plasticity as well as cognitive function. These findings suggest that testosterone replacement improved peripheral insulin sensitivity and decreased oxidative stress levels, but failed to restore hippocampal synaptic plasticity and cognitive function in testosterone-deprived obese rats. However, it provided beneficial effects in reversing cognitive impairment in testosterone-deprived non-obese rats. 相似文献
19.
Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin 总被引:10,自引:0,他引:10 下载免费PDF全文
Merab Kokaia Kristina Holmberg Avtandil Nanobashvili Zhi-Qing D. Xu Zaal Kokaia Urban Lendahl Susanne Hilke Elvar Theodorsson Ulrika Kahl Tamas Bartfai Olle Lindvall Tomas Hkfelt 《Proceedings of the National Academy of Sciences of the United States of America》2001,98(24):14006-14011
The neuropeptide galanin has been shown to suppress epileptic seizures. In cortical and hippocampal areas, galanin is normally mainly expressed in noradrenergic afferents. We have generated a mouse overexpressing galanin in neurons under the platelet-derived growth factor B promoter. RIA and HPLC analysis revealed up to 8-fold higher levels of galanin in transgenic as compared with wild-type mice. Ectopic galanin overexpression was detected especially in dentate granule cells and hippocampal and cortical pyramidal neurons. Galanin-overexpressing mice showed retardation of seizure generalization during hippocampal kindling, a model for human complex partial epilepsy. The high levels of galanin in mossy fibers found in the transgenic mice were further increased after seizures. Frequency facilitation of field excitatory postsynaptic potentials, a form of short-term synaptic plasticity assessed in hippocampal slices, was reduced in mossy fiber-CA3 cell synapses of galanin-overexpressing mice, indicating suppressed glutamate release. This effect was reversed by application of the putative galanin receptor antagonist M35. These data provide evidence that ectopically overexpressed galanin can be released and dampen the development of epilepsy by means of receptor-mediated action, at least partly by reducing glutamate release from mossy fibers. 相似文献
20.
AIMS/HYPOTHESIS: Recent studies involving electrophysiology and immunolabelling indicate that short-term insulin treatment of hippocampal neurons in culture induces changes in glutamate receptor function, suggesting that this receptor system can be altered on a relatively rapid time scale during diabetic conditions. To investigate this hypothesis, we examined whether brain glutamate receptors and long-term potentiation are altered in the early stages of diabetes mellitus in non-obese diabetic mice, a genetic model of Type I (insulin-dependent) diabetes mellitus. METHODS: In vitro receptor autoradiography and immunoblotting were used to study the impact of diabetes on brain glutamate receptors. From an electrophysiological point of view, field potential recordings were also examined in area CA1 of hippocampal slices to determine the influence of diabetes on long-term potentiation. RESULTS: Quantitative autoradiographic analysis revealed enhanced 3H-glutamate binding to several brain regions of diabetes mice, with maximal increases in the cerebral cortex and hippocampus. Saturation kinetics within the cerebral cortex disclosed that this change of 3H-glutamate was possibly due to an increase in the maximal number of N-methyl- D-aspartate binding sites, an interpretation that was corroborated by Western blot analysis of N-methyl- D-aspartate 2A subunits. Impairment in the expression of hippocampal long-term potentiation was also observed in diabetic mice, while the failure to elicit synaptic potentiation was prevented by insulin treatment. CONCLUSION/INTERPRETATION: Because glutamate receptors are thought to be involved in several degenerative processes, our results suggest that up-regulation of these receptors in the early stages of diabetes could represent an important mechanism underlying neurological complications within the brain of diabetic patients. 相似文献