Glutamate neurotoxicity has been hypothesized to underlie several types of acute brain injury. Free radical reactions are implicated in a variety of physiological and pathological processes and abnormalities associated with superoxide dismutase (SOD) have been recently documented in several neurodegenerative processes. We investigated superoxide production and MnSOD activity after kainate injection into the CA3 region of the rat hippocampus. The measurements take place at different times in the hippocampus, forebrain cortex, straitum and cerebellum homogenates. Free radicals including superoxide are responsible for postlesional cytotoxicity. The increase of MnSOD in distinct brain regions, which are functionally connected via afferents and efferents, suggests that these regions are affected by the injury. It suggests that MnSOD protects the cells in these regions from superoxide-induced damage and therefore may limit the retrograde and anterograde spread of neurotoxicity.
To elucidate the role of the serotonin (5-HT)(2A/2C) receptors in 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity, MDMA was administered to rats and the presence of the serotonin transporter (5-HTT) was assessed at the protein level with immunohistochemistry (IHC), and the RNA level with a Northern blotting technique. d-lysergic acid diethylamide (LSD) and MDL 11,939 were given in conjunction with MDMA in order to assess the importance of 5-HT receptors in MDMA-induced neurotoxicity. The hypothesis is that the MDMA + LSD-treated animals should have more neurotoxicity as measured by loss of 5-HTTs compared to the MDMA-treated animals. Moreover, the loss of 5-HTTs should be attenuated in animals given the combination of MDMA + MDL 11,939, as the latter drug is a selective 5-HT2A/2c antagonist. The results showed that MDMA-induced neurotoxicity was dose dependently increased by LSD. Moreover, the drug MDL 11,939 attenuated MDMA-induced neurotoxicity, suggesting that 5-HT2A/2C receptors are involved in MDMA-induced neurotoxicity.
Nitric oxide is synthesized from L-arginine by nitric oxide synthase (NOS), and it is a free radical with signaling functions. Neuronal nitric oxide synthase (nNOS) is mainly expressed in the central nervous system, and it has been implicated in the pathogenesis of brain injury such as ischemia. In the present study, the effects of 7-nitroindazole, which specifically inhibits nNOS, on apoptosis and cell proliferation int he dentate gyrus after transient global ischemia in gerbils were investigated. Enhanced apoptotic neuronal cell death and cell proliferation were observed in the dentate gyrus of ischemic gerbils. However, 7-nitroindazole suppressed the ischemia-induced apoptosis and cell proliferation. These results suggest that 7-nitroindazole has an inhibitive effect on apoptosis and cell proliferation following transient global ischemia. The present study shows that nitric oxide, the synthesis of which is augmented by ischemia, plays an important role in the regulation of apoptosis and cell proliferation following ischemic injury.
To elucidate the region within the somatosensory cortex that receives inputs from the horizontal semicircular canal (HSC) in rats, we used a multichannel recording system to measure evoked potentials in the parietal cortex in response to electrical stimulation of the HSC nerve. The recordings suggested that the HSC nerves projected bilaterally into the somatosensory cortex, with a contralateral predominance. The territory within the somatosensory cortex that responded to the stimulation of the HSC nerve was as follows: mediolateral 6.0 mm and anteroposterior –1.3 ∼ –2.3 mm from the bregma, and depth 1.4 ∼ 1.6 mm from the cortex surface horizontally by stereotaxic atlas. The evoked potential in the parietal cortex that was induced by electrical stimulation was abolished after the administration of tetrodotoxin into the oval window of the vestibular system. These results suggest that the horizontal semicircular nerve projects bilaterally into the deep layers of the secondary somatosensory cortex.
The cytokines interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha), produced by glial cells within the brain, appear to contribute to the neuropathogenesis of several inflammatory neurodegenerative diseases. However, little is known about the mechanism underlying cytokine-induced neurotoxicity. Using astroglial cultures obtained from fetal rat brain, we investigated the effects of lipopolysacchanides (LPS) and cytokines (IL-1beta and TNF-alpha). Primary cell cultures treated with LPS, IL-1beta plus TNF-alpha generated substantial amounts of nitric oxide (NO), elevated interleukin 6 (IL-6) levels and caused astroglial injury measured by lactate dehydrogenase (LDH) activity. However, blockade of NO production with nitric oxide synthase (NOS) inhibitors did not affect cell death, suggesting that NO is not responsible for cytokine-induced astroglial cell death under the experimental conditions employed.
We investigated whether the role of the astrocytic glutamate transporter GLT-1 is reversed when the ionic gradient across plasma membrane has collapsed, and if so, whether the reversal is crucial to neuronal death. To estimate the direction of glutamate transport by GLT-1, Na+ movement coupled with glutamate transport in astrocytes was analyzed in mixed astrocyte/neuron cultures. The rise in astrocytic intracellular Na+ due to glutamate exposure was suppressed by co-treatment with dihydrokainate (DHK). In contrast, the ouabain-induced rise in Na+ was significantly enhanced by DHK, suggesting that the role of GLT-1 was reversed. We then analyzed whether the reversal increased the amount of extracellular glutamate, and was crucial to excitotoxic neuronal death. Ouabain treatment resulted in a marked rise in glutamate and in neuronal death, and both the rise and cell death were significantly attenuated by DHK treatment.
We investigated for aneuploidy of chromosomes 7, 9, 10, 17, and p-53 gene deletions in 36 glial tumor tissues, using interphase fluorescence in sity hybridization (FISH), and compared the frequencies of abnormalities between low and high grade tumors. Among the 13 low grade tumors; 1 had trisomy 7, 1 had monosomy 9, 2 had monosomy 10, 1 had monosomy 17, 1 had p53 deletion, and among the 23 high grade tumors; 10 had trisomy 7, 1 had monosomy 9, 7 had monosomy 10, 2 had monosomy 17, 6 had p 53 deletion. The results indicated that neither aneuploidy of chromosome 9, nor chromosome 17 are prominent findings between low or high grade of glial tumors, although high-grade glial tumors have higher rates of trisomy 7 (43.5%), monosomy 10 (30.4%) and p53 (26%) deletion than low-grade ones. Statistical results showed significant difference between trisomy 7 and high grade astorocytomas (p=0.031). Considering these chromosomal abnormalities we suggest that trisomy 7, loss of chromosome 10 and alterations of the p53 gene have important role associated with glial tumor development and trisomy 7 is the most important genetic changes associated with glial tumor progression.
Oxcarbazepine (OXC) is a widely used novel antiepileptic drug that has been available for routine prescription for 10 years. To examine low dose OXC-induced neurotoxic effects on cerebellar development, we administered 25 mg/kg OXC orally to newbom Wistar rats once a day on postnatal days 2-14. Microscopic processed cerebellar sections of the control and treated groups were examined by volumetric analysis. Volume estimations were obtained using the Cavalieri's principle using a computerized stereological image analyzer (CAST-GRID). The total volume of the cerebellum, white matter and the various cerebellar layers (except extragranular layer) were significantly increased in the treated animals. These data may provide useful implications for the management of OXC-induced developmental neurotoxicity in children exposed to OXC during the late fetal period. Our finings suggest that women suffering from epilepsy should be given OXC carefully only at the lowest effective doses during pregnancy.
The laminar distribution of the neurofilament inclusions (NI) and swollen achromatic neurons (SN) was studied in gyri of the temporal cortex in four patients with neurofilament inclusion disease (NID). In 84% of gyri analysed, the density of the NI was maximal in the lower cortical laminae. The distribution of the SN was more variable than the NI. Density was maximal in the lower cortex in 46% of gyri, in the upper cortical laminae in 8% of gyri, and a bimodal distribution in 15% of gyri. In the remaining gyri, there was a more even distribution of SN with cortical depth. In 31% of gyri, the vertical density of the NI was positively correlated with that of the SN. The data suggest that cortical degeneration in the temporal lobe of NID initially affects neurons in the lower laminae. Subsequently, the pathology may spread to affect much of the cortical profile, the SN preceding the appearance of the NI.
The aim of this study is to explore the action of 5-HT1 receptor on spontaneous firing activity of the rat medial vestibular nuclear neurons by patch clamp experiments. The spontaneous firing was increased in 45.5% and decreased in 54.5% of the neurons tested with 5-carboxamidotryptamine, non-selective 5-HT1 receptor agonist. And the whole potassium currents of medial vestibular nuclear neurons was decreased in 64% and increased in 36% of cells tested with 5-carboxamidotryptamine. The spontaneous firing rate was increased by 8-OH-DPAT, selective 5-HT1A receptor agonist in 73.3% and was not changed in 26.7%. Whole potassium currents were decreased in 84.2% and was not affected in 15.8% by 8-OH-DPAT. These results suggest that 5-HT1A receptor of the medial vestibular nuclear neurons mediates excitatory effects whereas inhibitory effects are mediated by other 5-HT1 receptors.
Previous studies have demonstrated that estrogen alters the responsiveness of subfornical organ (SFO) neurons projecting to the hypothalamic paraventricular nucleus (PVN) to angiotensin II (ANG II) and activation of the SFO facilitates noradrenaline (NA) release in the PVN area. The present study was carried out to investigate whether estrogen elicits alterations in the NA release in the PVN area induced by electrical and chemical activation of the SFO. Intracerebral microdialysis techniques were utilized to quantify the extracellular content of NA in the region of the PVN in ovariectomized (OVX) female rats that were treated with either propylene glycol (PG) vehicle or estradiol benzoate (EB). In both groups, electrical stimulation (5-20 Hz, 600 muA) of the SFO significantly increased the NA concentration in the PVN area. Injections of ANG II (10(-8) M, 0.2 mul) into the stimulation site significantly enhanced the release of NA in the PVN area. The NA release to either electrical or chemical stimulation of the SFO was much greater in the PG-treated than in the EB-treated rats. These results suggest that estrogen may decrease the NA release in the PVN area caused by ANG II acting at the SFO.
Following a direct insult to the central nervous system, ciliary neurotrophic factor (CNTF) is induced in reactive astrocytes adjacent to the injury, where it participates in functional recovery. On the other hand, the role of CNTF in spinal cord plasticity after peripheral nerve injury is unclear. Hence, CNTF immunoreactivity (IR) was evaluated in rat spinal cords following unilateral spinal nerve ligation. CNTF-IR was found in GFAP-negative white matter cells exhibiting oligodendrocyte-like morphology. While GFAP labeling was increased in spinal cords of ligated animals, CNTF-IR was unchanged, suggesting that CNTF does not regulate spinal astrocyte reactivity generated by peripheral nerve ligation.
Neuroscience Research CommunicationsVolume 34, Issue 3 p. 121-121 In Memoriam: David de Wied, 1925–2004 W.H. Gispen, W.H. GispenSearch for more papers by this authorP.R. Bär, P.R. BärSearch for more papers by this authorG.J. Biessels, G.J. BiesselsSearch for more papers by this author W.H. Gispen, W.H. GispenSearch for more papers by this authorP.R. Bär, P.R. BärSearch for more papers by this authorG.J. Biessels, G.J. BiesselsSearch for more papers by this author First published: 23 June 2004 https://doi.org/10.1002/nrc.20006AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume34, Issue3May/June 2004Pages 121-121 RelatedInformation
Vascular disease probably plays an important role in the pathogenesis of cerebral complications that are associated with diabetes mellitus. Previous studies showed that treatment with the angiotensin converting enzyme-inhibitor enalapril (24 mg/kg) prevented neurophysiological and cognitive deficits in streptozotocin diabetic rats, and improved cerebral blood flow, despite a reduction in systemic mean arterial blood pressure. The present study examined if these effects could be sustained with long-term treatment, and if treatment with a lower dose (12 mg/kg) could prevent peripheral and central neurophysiological deficits without causing hypotension. Sciatic nerve conduction velocities were measured every three weeks after diabetes induction, until 24 weeks. Brain stem auditory (BAEP) and visual evoked potentials (VEP) were measured every three weeks from 10 weeks after diabetes induction, until 25 weeks. Nerve conduction velocity was decreased, and BAEP and VEP latencies increased in untreated diabetic rats. At the end of follow-up 12 mg/kg enalapril partially prevented evoked potential abnormalities, but not nerve conduction deficits, whereas 24 mg/kg enalapril largely prevented deficits in nerve conduction velocity (p<0.001), as well as BAEP (p<01) and VEP latencies (p<0.05). Mean arterial blood pressure was 122 mmHg in the untreated diabetic group, 75 mmHg in the 24 mg/kg group and 112 mmHg in the 12 mg/kg group. Sustained treatment with enalapril at 24 mg/kg was associated with increased mortality, which may be related to the marked hypotension at this dosage. We conclude that long-term treatment with enalapril at a dose of 24 mg/kg can prevent peripheral and central neurophysiological deficits in streptozotocin diabetic rats, but that adverse effects preclude sustained treatment.
In the present study, we identified the key protein that modulates the initiation of functional glutamatergic synapses in developing cortical neurons. First, we found a day in vitro that marked a critical increase in the number of functional synapses by the application of cyclic AMP, as demonstrated with Ca2+ imaging. We then examined the changes in the expression levels of proteins, which were expected to play a role in glutamatergic synapses, by the application of cyclic AMP. Our findings suggest that the expression of the α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors modulates the initiation of functional synapses in developing neurons, and that immature neurons already contain N-methyl d-aspartate (NMDA) receptors and presynaptic proteins such as synaptophysin.
Objective: Aim of this study was to compare ADAS-Cog and MDB, instruments usually used in cognitive assessment of AD patients, relative to: 1) diagnostic sensitivity for dementia of AD; 2) ability to rate the progression of cognitive decline and ability to detect the qualitative characteristics of cognitive decline. Material and methods: A sample of 54 AD patients was submitted to a cognitive assessment with both battery at time of study entry (T 0) and after 12 months (T 12). Results: This study showed: 1) a better diagnostic sensitivity of MDB respect to ADAS-Cog in diagnosing patients affected by mild to moderate levels of AD; 2) a better sensitivity of ADAS-Cog to follow the cognitive decline over a twelve-months period Conclusion: These results supports the use of the MDB in the screening phase of AD patients and of ADAS-Cog to follow the progression of cognitive decline over time.
This review discusses the phosphorylation of the Amyloid Precursor Protein (APP) and the possible role of this phosphorylation in Alzheimer's disease (AD). AD is a neurodegenerative disorder characterized by the deposition of β-amyloid plaques in the brain parenchyma and neurofibrillary tangles comprised of hyperphosphorylated tau. APP plays a primary role in the pathogenesis of AD, because its processing generates the amyloid beta peptide (Aβ), the core of the amyloid plaque. APP has a large N-terminal extracellular domain and a short intracellular C-terminal domain that can be phosphorylated by various protein kinases. This review summarized recent work describing the phsphorylation of APP and the downstream events induced by this phosphorylation as well as the impact of APP phosphorylation on APP function and on the production of Aβ peptide.
Calexcitin (CE) is a low molecular weight Ca2+- and guanosine triphosphate- binding protein, which is phosphorylated during associative learning in both vertebrates and invertebrates. The purpose of this study was to determine the presence of CE in the central nervous system (CNS) of the pond snail Lymnaea stagnalis, which can acquire classical and operant conditioning. Immunoblotting of CE showed that the anti-CE antibody prepared from squid can detect Lymnaea CE. In the cerebral ganglia, CE-like immunoreactivity was exhibited in two pairs of cell clusters that receive taste signals from the superior or median lip nerves. In both pedal ganglia, CE-like immunoreactivity was detected in 1-4 cell of the PeA clusters, which are involved in the withdrawal response. Our results therefore showed that CE is involved in the feeding and withdrawal neural networks, suggesting that CE may function in associative learning of feeding and withdrawal behavior in L. stagnalis.
We recently established adrenal medullary cell line tsAM5D, immortalized with a temperature-sensitive mutant of the oncogene simian virus 40 large T-antigen. When cultured with basic fibroblast growth factor (bFGF) and ciliary neurotrophic factor (CNTF), tsAM5D cells proliferated at the permissive temperature (33 degreesC) for the expression of the oncogene and differentiated into neuron-like cells at the nonpermissive temperature (39 degreesC). In the present study, we investigated the gene expression of several neurotrophic factors associated with the neuronal differentiation induced by the temperature shift. Using real-time RT-PCR analysis on bFGF and CNTF-treated cells, we found up-regulated expression of mRNAs for bFGF, leukemia inhibitory factor, transforming growth factor (TGF)-beta2, persephin, acidic fibroblast growth factor, neurotrophin-3, preproenkephalin, and TGF-beta1 and down-regulated expression of the mRNAs for interleukin-6, neurturin, and CNTF. No apparent differences were observed in the mRNA level of insulin-like growth factor-2, TGF-beta3, and neurotrophin-4/5. These results suggest that the regulated expression of neurotrophic factor genes play an important role in the neuronal differentiation of tsAM5D cells.
In the present study, we have calculated the total neuronal number and volume of the tuberomammillary nucleus and of each of its subgroups E1, E2 and E3 in the Wistar rat. This estimation was done using stereological methods that can produce accurate quantifications. Neuronal number was estimated by applying the optical fractionator and the total volume of the nucleus by Cavalieri's method. Simultaneously, we quantified the argyrophilic nucleolar organizer regions (Ag-NORS) of the neurons from these subgroups. The number and area of the Ag-NORs stained with the silver nitrate technique, reflect the protein synthesis activity of these neurons.Our results show that the tuberomammillary nucleus has a unilateral total neuronal number of 2,460 neurons and a unilateral volume of 0.08756 mm(3). We also find statistically significant differences on a morphological level among the different subgroups of the tuberomammillary nucleus. Hence, E2 has the largest number of neurons followed by E3 whereas E1 is the subgroup with the smallest neuronal density. There were no significant differences in the functional parameters: area of neuronal nucleus and mean area and number of Ag-NOR, among the groups.
