|
| ||
|
|
||
Cell Loss (cell + loss)
Kinds of Cell Loss Selected AbstractsAntioxidant Pretreatment Does Not Ameliorate Alcohol-Induced Purkinje Cell Loss in the Developing Rat CerebellumALCOHOLISM, Issue 7 2005Jedidiah J. Grisel Background: Recent research has suggested that oxidative stress is a potential mechanism for alcohol-induced injury and that supplementation with antioxidants can ameliorate alcohol-induced damage. In this study, two known antioxidants, melatonin and U83836E, were assessed for their effectiveness in blocking the expected alcohol-induced cerebellar Purkinje cell loss in neonatal rat pups. Methods: Sprague-Dawley rat pups were artificially reared from postnatal days (PDs) 4,9 and were exposed to either alcohol or antioxidants (melatonin or U83836E) individually or in combination. A normal control group (raised by rat dams) was included in this study. On PD 9, the brain from each pup was removed and weighed, and the cerebellar vermis was processed for stereological cell counting. Results: Alcohol exposure during the brain growth spurt produced microencephaly, in addition to significant decreases in the number and density of Purkinje cells in lobule I and the volume of lobule I. The antioxidants did not reduce any of the adverse effects observed from alcohol exposure, and they did not decrease the Purkinje cell number when administered alone. Furthermore, antioxidants did not change the only blood alcohol concentration measured on PD 6. Conclusions: The results confirmed alcohol-induced microencephaly and cerebellar Purkinje cell loss from neonatal alcohol exposure, and they showed that neither antioxidant could attenuate these adverse effects on the developing brain. The inability of antioxidants to reduce Purkinje cell loss from neonatal alcohol exposure suggests the existence of alternative mechanisms for developmental alcohol-induced Purkinje cell loss. [source] Developmental toxicity of indium: Embryotoxicity and teratogenicity in experimental animalsCONGENITAL ANOMALIES, Issue 4 2008Mikio Nakajima ABSTRACT Indium, a precious metal classified in group 13 (IIIB) in the periodic table, has been used increasingly in the semiconductor industry. Because indium is a rare metal, technology for indium recycling from transparent conducting films for liquid crystal displays is desired, and its safety evaluation is becoming increasingly necessary. The developmental toxicity of indium in experimental animals was summarized. The intravenous or oral administration of indium to pregnant animals causes growth inhibition and the death of embryos in hamsters, rats, and mice. The intravenous administration of indium to pregnant animals causes embryonic or fetal malformation, mainly involving digit and tail deformities, in hamsters and rats. The oral administration of indium also induces fetal malformation in rats and rabbits, but requires higher doses. No teratogenicity has been observed in mice. Caudal hypoplasia, probably due to excessive cell loss by increased apoptosis in the tailbud, in the early postimplantation stage was considered to account for indium-induced tail malformation as a possible pathogenetic mechanism. Findings from in vitro experiments indicated that the embryotoxicity of indium could have direct effects on the conceptuses. Toxicokinetic studies showed that the embryonic exposure concentration was more critical than the exposure time regarding the embryotoxicity of indium. It is considered from these findings that the risk of the developmental toxicity of indium in humans is low, unless an accidentally high level of exposure or unknown toxic interaction occurs because of possible human exposure routes and levels (i.e. oral, very low-level exposure). [source] Ataxic mutant mice with defects in Ca2+ channel ,1A subunit gene: morphological and functional abnormalities in cerebellar cortical neuronsCONGENITAL ANOMALIES, Issue 2 2000Kazuhiko Sawada ABSTRACT This review summarizes recent studies in the morphological and functional abnormalities of cerebella in three ataxic mutant mice, i.e. tottering mouse, leaner mouse, and rolling mouse Nagoya (RMN). These mutants carry mutations in the Ca2+ channel ,1A subunit gene, and become useful models for human neurological diseases such as episodic ataxia type-2, familial hemiplegic migraine, and spinocerebellar ataxia type-6. All three mutants exhibited altered morphology of the Purkinje cells, ectopic synaptic contacts between granule cell axons (parallel fibers) and Purkinje cell dendritic spines and abnormal expression of tyrosine hydroxylase in Purkinje cells. In leaner mice, Purkinje cell loss was observed in alternating sagittal compartments of the cerebellar cortex corresponding to the Zebrin II-negative zones. The mutated Ca2+ channel ,1A subunit was highly expressed in granule and Purkinje cells, and the P-type Ca2+ currents in Purkinje cells were selectively reduced in the mutant mice. Therefore, we concluded that altered Ca2+ currents through the mutated Ca2+ channel ,1A subunit might be involved in the functional and morphological abnormalities in granule and Purkinje cells, and might result in expressions of behavioral phenotypes including ataxia. Increased levels of corticotropin-releasing factor and cholecystokinin in some climbing and mossy fibers were observed in RMN. These neuropeptides modulated the excitability of granule and Purkinje cells, indicating the possible expression of ataxic symptoms. [source] Effects of early seizures on later behavior and epileptogenicityDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2004Gregory L. Holmes Abstract Both clinical and laboratory studies demonstrate that seizures early in life can result in permanent behavioral abnormalities and enhance epileptogenicity. Understanding the critical periods of vulnerability of the developing nervous system to seizure-induced changes may provide insights into parallel or divergent processes in the development of autism. In experimental rodent models, the consequences of seizures are dependent on age, etiology, seizure duration, and frequency. Recurring seizures in immature rats result in long-term adverse effects on learning and memory. These behavioral changes are paralleled by changes in brain connectivity, changes in excitatory neurotransmitter receptor distribution, and decreased neurogenesis. These changes occur in the absence of cell loss. Although impaired cognitive function and brain changes have been well-documented following early-onset seizures, the mechanisms of seizure-induced dysfunction remain unclear. MRDD Research Reviews 2004;10:101,105. © 2004 Wiley-Liss, Inc. [source] Binge-like ethanol exposure during the early postnatal period impairs eyeblink conditioning at short and long CS,US intervals in ratsDEVELOPMENTAL PSYCHOBIOLOGY, Issue 6 2007Tuan D. Tran Abstract Binge-like ethanol exposure on postnatal days (PD) 4,9 in rodents causes cerebellar cell loss and impaired acquisition of conditioned responses (CRs) during "short-delay" eyeblink classical conditioning (ECC), using optimal (280,350 ms) interstimulus intervals (ISIs). We extended those earlier findings by comparing acquisition of delay ECC under two different ISIs. From PD 4 to 9, rats were intubated with either 5.25 g/kg of ethanol (2/day), sham intubated, or were not intubated. They were then trained either as periadolescents (about PD 35) or as adults (>PD 90) with either the optimal short-delay (280-ms) ISI, a long-delay (880-ms) ISI, or explicitly unpaired CS and US presentations. Neonatal binge ethanol treatment significantly impaired acquisition of conditioning at both ages regardless of ISI, and deficits in the acquisition and expression of CRs were comparable across ISIs. These deficits are consistent with the previously documented ethanol-induced damage to the cerebellar,brainstem circuit essential for Pavlovian ECC. © 2007 Wiley Periodicals, Inc. Dev Psychobiol 49: 589-605, 2007. [source] The effect of prenatal hypoxia on brain development: short- and long-term consequences demonstrated in rodent modelsDEVELOPMENTAL SCIENCE, Issue 4 2006Hava Golan Hypoxia (H) and hypoxia-ischemia (HI) are major causes of foetal brain damage with long-lasting behavioral implications. The effect of hypoxia has been widely studied in human and a variety of animal models. In the present review, we summarize the latest studies testing the behavioral outcomes following prenatal hypoxia/hypoxia-ischemia in rodent models. Delayed development of sensory and motor reflexes during the first postnatal month of rodent life was observed by various groups. Impairment of motor function, learning and memory was evident in the adult animals. Activation of the signaling leading to cell death was detected as early as three hours following H/HI. An increase in the counts of apoptotic cells appeared approximately three days after the insult and peaked about seven days later. Around 14,20 days following the H/HI, the amount of cell death observed in the tissue returned to its basal levels and cell loss was apparent in the brain tissue. The study of the molecular mechanism leading to brain damage in animal models following prenatal hypoxia adds valuable insight to our knowledge of the central events that account for the morphological and functional outcomes. This understanding provides the starting point for the development and improvement of efficient treatment and intervention strategies. [source] Is the Cell Death in Mesial Temporal Sclerosis Apoptotic?EPILEPSIA, Issue 6 2003Hilmi Uysal Summary: Purpose: Mesial temporal sclerosis (MTS) is characterized by neuronal loss in the hippocampus. Studies on experimental models and patients with intractable epilepsy suggest that apoptosis may be involved in neuronal death induced by recurrent seizures. Methods: We searched evidence for apoptotic cell death in temporal lobes resected from drug-resistant epilepsy patients with MTS by using the terminal deoxynucleotidyl transferase (TdT) and digoxigenin-11-dUTP (TUNEL) method and immunohistochemistry for Bcl-2, Bax, and caspase-cleaved actin fragment, fractin. The temporal lobe specimens were obtained from 15 patients (six women and nine men; mean age, 29 ± 8 years). Results: Unlike that in normal adult brain, we observed Bcl-2 immunoreactivity in some of the remaining neurons dispersed throughout the hippocampus proper as well as in most of the reactive astroglia. Bax immunopositivity was increased in almost all neurons. Fractin immunostaining, an indicator of caspase activity, was detected in ,10% of these neurons. Des pite increased Bax expression and activation of caspases, we could not find evidence for DNA fragmentation by TUNEL staining. We also could not detect typical apoptotic changes in nuclear morphology by Hoechst-33258 or hematoxylin counterstaining. Conclusions: These data suggest that either apoptosis is not involved in cell loss in MTS, or a very slow rate of cell demise may have precluded detecting TUNEL-positive neurons dying through apoptosis. Increased Bax expression and activation of caspases support the latter possibility. [source] Correlation of Hippocampal Glucose Oxidation Capacity and Interictal FDG-PET in Temporal Lobe EpilepsyEPILEPSIA, Issue 2 2003Stefan Vielhaber Summary: ,Purpose: Interictal [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) demonstrates temporal hypometabolism in the epileptogenic zone of 60,90% of patients with temporal lobe epilepsy. The pathophysiology of this finding is still unknown. Several studies failed to show a correlation between hippocampal FDG-PET hypometabolism and neuronal cell loss. Because FDG is metabolized by hexokinase bound to the outer mitochondrial membrane, we correlated the glucose-oxidation capacity of hippocampal subfields obtained after surgical resection with the corresponding hippocampal presurgical FDG-PET activity. Methods: In 16 patients with electrophysiologically confirmed temporal lobe epilepsy, we used high-resolution respirometry to determine the basal and maximal glucose-oxidation rates in 400-,m-thick hippocampal subfields obtained after dissection of human hippocampal slices into the CA1 and CA3 pyramidal subfields and the dentate gyrus. Results: We observed a correlation of the FDG-PET activity with the maximal glucose-oxidation rate of the CA3 pyramidal subfields (rp = 0.7, p = 0.003) but not for the regions CA1 and dentate gyrus. In accordance with previous studies, no correlation of the FDG-PET to the neuronal cell density of CA1, CA3, and dentate gyrus was found. Conclusions: The interictal hippocampal FDG-PET hypometabolism in patients with temporal lobe epilepsy is correlated to the glucose-oxidation capacity of the CA3 hippocampal subfield as result of impaired oxidative metabolism. [source] Pentylenetetrazol-induced Recurrent Seizures in Rat Pups: Time Course on Spatial Learning and Long-term EffectsEPILEPSIA, Issue 6 2002Li-Tung Huang Summary: ,Purpose: Recurrent seizures in infants are associated with a high incidence of neurocognitive deficits. Animal models have suggested that the immature brain is less vulnerable to seizure-induced injury than is that in adult animals. We studied the effects of recurrent neonatal seizures on cognitive tasks performed when the animals were in adolescence and adulthood. Methods: Seizures were induced by intraperitoneal injection of pentylenetetrazol (PTZ) for 5 consecutive days, starting from postnatal day 10 (P10). At P35 and P60, rats were tested for spatial memory by using the Morris water maze task. In adulthood, motor performance was examined by the Rotarod test, and activity level was assessed by the open field test. Seizure threshold was examined by inhalant flurothyl. To assess presence or absence of spontaneous seizures, rats were video recorded for 4 h/day for 10 consecutive days for the detection of spontaneous seizures. Finally, brains were examined for histologic evidence of injury with cresyl violet stain and Timm staining in the supragranular zone and CA3 pyramidal cell layers of the hippocampus. Results: PTZ-treated rats showed significant spatial deficits in the Morris water maze at both P35 and P60. There were no differences in seizure threshold, motor balance, or activity level during the open field test. Spontaneous seizures were not recorded in any rat. The cresyl violet stain showed no cell loss in either the control or experimental rats. PTZ-treated rats exhibited more Timm staining in the CA3 subfield. However, the control and experimental rats showed similar Timm staining within the supragranular zone. Conclusions: Our findings indicate that recurrent PTZ-induced seizures result in long-term cognitive deficits and morphologic changes in the developing brain. Furthermore, these cognitive deficits could be detected during pubescence. [source] Co-expression of C-terminal truncated alpha-synuclein enhances full-length alpha-synuclein-induced pathologyEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2010Ayse Ulusoy Abstract Lewy bodies, which are a pathological hallmark of Parkinson's disease, contain insoluble polymers of alpha-synuclein (,syn). Among the different modifications that can promote the formation of toxic ,syn species, C-terminal truncation is among the most abundant alterations in patients with Parkinson's disease. In vitro, C-terminal truncated ,syn aggregates faster and sub-stoichiometric amounts of C-terminal truncated ,syn promote aggregation of the full-length ,syn (,synFL) and induce neuronal toxicity. To address in vivo the putative stimulation of ,syn-induced pathology by the presence of truncated ,syn, we used recombinant adeno-associated virus to express either ,synFL or a C-terminal truncated ,syn (1-110) in rats. We adjusted the recombinant adeno-associated virus vector concentrations so that either protein alone led to only mild to moderate axonal pathology in the terminals of nigrostriatal dopamine neurons without frank cell loss. When these two forms of ,syn were co-expressed at these pre-determined levels, it resulted in a more aggressive pathology in fiber terminals as well as dopaminergic cell loss in the substantia nigra. Using an antibody that did not detect the C-terminal truncated ,syn (1-110) but only ,synFL, we demonstrated that the co-expressed truncated protein promoted the progressive accumulation of ,synFL and formation of larger pathological accumulations. Moreover, in the co-expression group, three of the eight animals showed apomorphine-induced turning, suggesting prominent post-synaptic alterations due to impairments in the dopamine release, whereas the mild pathology induced by either form alone did not cause motor abnormalities. Taken together these data suggest that C-terminal truncated ,syn can interact with and exacerbate the formation of pathological accumulations containing ,synFL in vivo. [source] Disruption of dopamine homeostasis underlies selective neurodegeneration mediated by ,-synucleinEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2007Soon S. Park Abstract A key challenge in Parkinson's disease research is to understand mechanisms underlying selective degeneration of dopaminergic neurons mediated by genetic factors such as ,-synuclein (,-Syn). The present study examined whether dopamine (DA)-dependent oxidative stress underlies ,-Syn-mediated neurodegeneration using Drosophila primary neuronal cultures. Green fluorescent protein (GFP) was used to identify live dopaminergic neurons in primary cultures prepared on a marked photoetched coverslip, which allowed us to repeatedly access preidentified dopaminergic neurons at different time points in a non-invasive manner. This live tracking of GFP-marked dopaminergic neurons revealed age-dependent neurodegeneration mediated by a mutant human ,-Syn (A30P). Degeneration was rescued when ,-Syn neuronal cultures were incubated with 1 mm glutathione from Day 3 after culturing. Furthermore, depletion of cytoplasmic DA by 100 µm,-methyl- p -tyrosine completely rescued the early stage of ,-Syn-mediated dopaminergic cell loss, demonstrating that DA plays a major role in oxidative stress-dependent neurodegeneration mediated by ,-Syn. In contrast, overexpression of a Drosophila tyrosine hydroxylase gene (dTH1) alone caused DA neurodegeneration by enhanced DA synthesis in the cytoplasm. Age-dependent dopaminergic cell loss was comparable in ,-Syn vs dTH1-overexpressed neuronal cultures, indicating that increased DA levels in the cytoplasm is a critical change downstream of mutant ,-Syn function. Finally, overexpression of a Drosophila vesicular monoamine transporter rescued ,-Syn-mediated neurodegeneration through enhanced sequestration of cytoplasmic DA into synaptic vesicles, further indicating that a main cause of selective neurodegeneration is ,-Syn-induced disruption of DA homeostasis. All of these results demonstrate that elevated cytoplasmic DA is a main factor underlying the early stage of ,-Syn-mediated neurodegeneration. [source] Glial cell loss, proliferation and replacement in the contused murine spinal cordEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2007Judith M. Lytle Abstract Studies in the rat have shown that contusive spinal cord injury (SCI) results in devastating pathology, including significant loss of mature oligodendrocytes and astrocytes even in spared white matter. Subsequently, there is increased proliferation of endogenous NG2+ cells, postulated to contribute to replacement of mature glia chronically, which is important for functional recovery. Studies of mechanisms that stimulate endogenous progenitor cells would be facilitated by using mouse models with naturally occurring and genetically engineered mutations. To determine whether the murine response is similar to that in the rat, we performed contusive SCI on adult female C57Bl/6 mice at the T8,9 level. Animals received bromodeoxyuridine injections in the first week following injury and were killed at 1, 3, 4, 7 or 28 days postinjury (DPI). The overall loss of macroglia and the temporal,spatial response of NG2+ cells after SCI in the (C57Bl/6) mouse was very similar to that in the (Sprague,Dawley) rat. By 24 h after SCI nearly half of the macroglia in spared ventral white matter had been lost. Cell proliferation was increased at 1,7 DPI, peaking at 3,4 DPI. Dividing cells included NG2+ cells and Cd11b+ macrophages and microglia. Furthermore, cells dividing in the first week expressed markers of mature glia at 28 DPI. The similarities in endogenous progenitor cell response to SCI in the mouse and rat suggest that this is a fundamental injury response, and that transgenic mouse models may be used to further probe how this cellular response to SCI might be enhanced to improve recovery after SCI. [source] Proliferative responses to growth factors decline rapidly during postnatal maturation of mammalian hair cell epitheliaEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2007Rende Gu Abstract Millions of lives are affected by hearing and balance deficits that arise as a consequence of sensory hair cell loss. Those deficits affect mammals permanently, but hearing and balance recover in nonmammals after epithelial supporting cells divide and produce replacement hair cells. Hair cells are not effectively replaced in mammals, but balance epithelia cultured from the ears of rodents and adult humans can respond to hair cell loss with low levels of supporting cell proliferation. We have sought to stimulate vestibular proliferation; and we report here that treatment with glial growth factor 2 (rhGGF2) yields a 20-fold increase in cell proliferation within sheets of pure utricular hair cell epithelium explanted from adult rats into long-term culture. In epithelia from neonates, substantially greater proliferation responses are evoked by rhGGF2 alone, insulin alone and to a lesser degree by serum even during short-term cultures, but all these responses progressively decline during the first 2 weeks of postnatal maturation. Thus, sheets of utricular epithelium from newborn rats average >,40% labelling when cultured for 72 h with bromo-deoxyuridine (BrdU) and either rhGGF2 or insulin. Those from 5- and 6-day-olds average 8,15%, 12-day-olds average <,1% and after 72 h there is little or no labelling in epithelia from 27- and 35-day-olds. These cells are the mammalian counterparts of the progenitors that produce replacement hair cells in nonmammals, so the postnatal quiescence described here is likely to be responsible for at least part of the mammalian ear's unique vulnerability to permanent sensory deficits. [source] Hippocampal vulnerability following traumatic brain injury: a potential role for neurotrophin-4/5 in pyramidal cell neuroprotectionEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2006N. C. Royo Abstract Traumatic brain injury (TBI) causes selective hippocampal cell death, which is believed to be associated with cognitive impairment observed both in clinical and experimental settings. Although neurotrophin administration has been tested as a strategy to prevent cell death following TBI, the potential neuroprotective role of neurotrophin-4/5 (NT-4/5) in TBI remains unknown. We hypothesized that NT-4/5 would offer neuroprotection for selectively vulnerable hippocampal neurons following TBI. Measurements of NT-4/5 in rats subjected to lateral fluid percussion (LFP) TBI revealed two,threefold increases in the injured cortex and hippocampus in the acute period (1,3 days) following brain injury. Subsequently, the response of NT-4/5 knockout (NT-4/5,/,) mice to controlled-cortical impact TBI was investigated. NT-4/5,/, mice were more susceptible to selective pyramidal cell loss in Ahmon's corn (CA) subfields of the hippocampus following TBI, and showed impaired motor recovery when compared with their brain-injured wild-type controls (NT-4/5wt). Additionally, we show that acute, prolonged administration of recombinant NT-4/5 (5 µg/kg/day) prevented up to 50% of the hippocampal CA pyramidal cell death following LFP TBI in rats. These results suggest that post-traumatic increases in endogenous NT-4/5 may be part of an adaptive neuroprotective response in the injured brain, and that administration of this neurotrophic factor may be useful as a therapeutic strategy following TBI. [source] Deficits in the mid-brain raphe nuclei and striatum of the AS/AGU rat, a protein kinase C-, mutantEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2005M. Al-Fayez Abstract The AS/AGU rat carries a recessive mutation (agu) in the gene coding for the gamma isoform of protein kinase C. The rat is characterized by disordered locomotion and progressive dysfunction of the nigrostriatal dopaminergic (DA) system. This dysfunction begins with a failure to release DA within the striatum and culminates in cell loss within the substantia nigra pars compacta. The present study examines another midbrain aminergic system with input to the basal ganglia, the serotonergic (5-HT) raphe,striatal system originating in the dorsal raphe nucleus. By 3 months after birth, there is a very substantial reduction in the extracellular levels of 5-HT in the dorsal caudate-putamen of the mutants compared with controls (c. 70%). This is accompanied by a proportional increase in the levels of the 5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA). At a later age, there are reductions in whole tissue 5-HT (and increases in 5-HIAA) in both the striatum and the region containing the dorsal raphe nucleus, as well as numbers of 5-HT-immunoreactive cells in the dorsal raphe nucleus. The median raphe appears to be unaffected. The results are seen in terms of an initial dysfunction in transmitter release leading to cell death, perhaps through the formation of free radicals or neurotoxins. [source] 7-Hydroxylated epiandrosterone (7-OH-EPIA) reduces ischaemia-induced neuronal damage both in vivo and in vitroEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2003Ashley K. Pringle Abstract Recent evidence suggests that steroids such as oestradiol reduce ischaemia-induced neurodegeneration in both in vitro and in vivo models. A cytochrome P450 enzyme termed cyp7b that 7-hydroxylates many steroids is expressed at high levels in brain, although the role of 7-hydroxylated steroids is unknown. We have tested the hypothesis that the steroid-mediated neuroprotection is dependent on the formation of 7-hydroxy metabolites. Organotypic hippocampal slice cultures were prepared from Wistar rat pups and maintained in vitro for 14 days. Cultures were then exposed to 3 h hypoxia and neuronal damage assessed 24 h later using propidium iodide fluorescence as a marker of cell damage. Neurodegeneration occurred primarily in the CA1 pyramidal cell layer. The steroids oestradiol, dehydroepiandrosterone and epiandrosterone (EPIA) were devoid of neuroprotective efficacy when present at 100 nm pre-, during and post-hypoxia. The 7-hydroxy metabolites of EPIA, 7,-OH-EPIA and 7,-OH-EPIA significantly reduced neurotoxicity at 100 nm and 10 nm. 7,-OH-EPIA was also neuroprotective in two in vivo rat models of cerebral ischaemia: 0.1 mg/kg 7,-OH-EPIA significantly reduced hippocampal cell loss in a model of global forebrain ischaemia, whereas 0.03 mg/kg was neuroprotective in a model of focal ischaemia even when administration was delayed until 6 h after the onset of ischaemia. Taken together, these data demonstrate that 7-hydroxylation of steroids confers neuroprotective efficacy, and that 7,-OH-epiandrosterone represents a novel class of neuroprotective compounds with potential for use in acute neurodegenerative diseases. [source] Morphological alterations in the amygdala and hippocampus of mice during ageingEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2002Oliver Von Bohlen und Halbach Abstract Declines in memory function and behavioural dysfunction accompany normal ageing in mammals. However, the cellular and morphological basis of this decline remains largely unknown. It was assumed for a long time that cell losses in the hippocampus accompany ageing. However, recent stereological studies have questioned this finding. In addition, the effect of ageing is largely unknown in another key structure of the memory system, the amygdala. In the present study, we have estimated neuronal density and total neuronal numbers as well as density of fragments of degenerated axons in different hippocampal subfields and amygdaloid nuclei. Comparisons were made among aged (21,26 months old) mice and normal adult littermates (8 months old). No significant volume loss occurs in the hippocampus of aged mice. Small but insignificant reductions in total neuronal numbers were found in the hippocampus and in the amygdaloid nuclei. In contrast to the mild effects of ageing upon neuronal numbers, fragments of degenerated axons were increased in both hippocampus and amygdala of aged mice. These data suggest that ageing does not induce prominent cell loss in the hippocampus or amygdala, but leads to degeneration of axons that innervate these forebrain structures. Thus, mechanisms underlying age-related dysfunction depend on parameters other than neuronal numbers, at least in the hippocampal formation and the amygdala. [source] Glial-derived arginine, the nitric oxide precursor, protects neurons from NMDA-induced excitotoxicityEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2001Gilbert Grima Abstract Excitotoxic neuronal cell death is characterized by an overactivation of glutamate receptors, in particular of the NMDA subtype, and the stimulation of the neuronal nitric oxide synthase (nNOS), which catalyses the formation of nitric oxide (NO) from l -arginine (L-Arg). At low L-Arg concentrations, nNOS generates NO and superoxide (O2,,), favouring the production of the toxin peroxynitrite (ONOO,). Here we report that NMDA application for five minutes in the absence of added L-Arg induces neuronal cell death, and that the presence of L-Arg during NMDA application prevents cell loss by blocking O2,, and ONOO, formation and by inhibiting mitochondrial depolarization. Because L-Arg is transferred from glial cells to neurons upon activation of glial glutamate receptors, we hypothesized that glial cells play an important modulator role in excitotoxicity by releasing L-Arg. Indeed, as we further show, glial-derived L-Arg inhibits NMDA-induced toxic radical formation, mitochondrial dysfunction and cell death. Glial cells thus may protect neurons from excitotoxicity by supplying L-Arg. This potential neuroprotective mechanism may lead to an alternative approach for the treatment of neurodegenerative diseases involving excitotoxic processes, such as ischemia. [source] Cholinergic and noncholinergic septal neurons modulate strategy selection in spatial learningEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2001Jonathan F. X. Cahill Abstract Rats solving a simple spatial discrimination task in a plus maze initially employ a place-learning strategy, then switch to a motor response strategy. The hippocampus is required for the use of a place-learning strategy in this task. Rats with 192 IgG-saporin lesions of the medial septum/vertical limb of the diagonal band (MS/VDB), that selectively removed cholinergic neurons projecting to the hippocampus, were significantly facilitated in acquisition of the spatial discrimination, and switched from place to response strategies just as control rats did. Rats with ibotenic acid lesions of the MS/VDB, that produced cell loss in the MS/VDB but little damage to cholinergic neurons, were significantly impaired in acquiring the spatial discrimination and did not reliably employ either a place or response strategy at any point in training. This suggests that the MS/VDB modulates hippocampal involvement in place learning, but that cholinergic MS/VDB neurons are neither necessary nor sufficient for using a place strategy to solve a spatial discrimination. [source] Mice transgenic for exon 1 of the Huntington's disease gene display reduced striatal sensitivity to neurotoxicity induced by dopamine and 6-hydroxydopamineEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2001Ĺsa Petersén Abstract Huntington's disease is an autosomal dominant hereditary neurodegenerative disorder characterized by severe striatal cell loss. Dopamine (DA) has been suggested to play a role in the pathogenesis of the disease. We have previously reported that transgenic mice expressing exon 1 of the human Huntington gene (R6 lines) are resistant to quinolinic acid-induced striatal toxicity. In this study we show that with increasing age, R6/1 and R6/2 mice develop partial resistance to DA- and 6-hydroxydopamine-mediated toxicity in the striatum. Using electron microscopy, we found that the resistance is localized to the cell bodies and not to the neuropil. The reduction of dopamine and cAMP regulated phosphoprotein of a molecular weight of 32 kDa (DARPP-32) in R6/2 mice does not provide the resistance, as DA-induced striatal lesions are not reduced in size in DARPP-32 knockout mice. Neither DA receptor antagonists nor a N -methyl- d -aspartate (NMDA) receptor blocker reduce the size of DA-induced striatal lesions, suggesting that DA toxicity is not dependent upon DA- or NMDA receptor-mediated pathways. Moreover, superoxide dismutase-1 overexpression, monoamine oxidase inhibition and the treatment with the free radical scavenging spin-trap agent phenyl-butyl-tert-nitrone (PBN) also did not block DA toxicity. Levels of the antioxidant molecules, glutathione and ascorbate were not increased in R6/1 mice. Because damage to striatal neurons following intrastriatal injection of 6-hydroxydopamine was also reduced in R6 mice, a yet-to-be identified antioxidant mechanism may provide neuroprotection in these animals. We conclude that striatal neurons of R6 mice develop resistance to DA-induced toxicity with age. [source] Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductancesEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2000Stefan Hinterkeuser Abstract Functional properties of astrocytes were investigated with the patch-clamp technique in acute hippocampal brain slices obtained from surgical specimens of patients suffering from pharmaco-resistant temporal lobe epilepsy (TLE). In patients with significant neuronal cell loss, i.e. Ammon's horn sclerosis, the glial current patterns resembled properties characteristic of immature astrocytes in the murine or rat hippocampus. Depolarizing voltage steps activated delayed rectifier and transient K+ currents as well as tetrodotoxin-sensitive Na+ currents in all astrocytes analysed in the sclerotic human tissue. Hyperpolarizing voltages elicited inward rectifier currents that inactivated at membrane potentials negative to -130 mV. Comparative recordings were performed in astrocytes from patients with lesion-associated TLE that lacked significant histopathological hippocampal alterations. These cells displayed stronger inward rectification. To obtain a quantitative measure, current densities were calculated and the ratio of inward to outward K+ conductances was determined. Both values were significantly smaller in astrocytes from the sclerotic group compared with lesion-associated TLE. During normal development of rodent brain, astroglial inward rectification gradually increases. It thus appears reasonable to suggest that astrocytes in human sclerotic tissue return to an immature current pattern. Reduced astroglial inward rectification in conjunction with seizure-induced shrinkage of the extracellular space may lead to impaired spatial K+ buffering. This will result in stronger and prolonged depolarization of glial cells and neurons in response to activity-dependent K+ release, and may thus contribute to seizure generation in this particular condition of human TLE. [source] Phylogenetic analysis of developmental and postnatal mouse cell lineagesEVOLUTION AND DEVELOPMENT, Issue 1 2010Stephen J. Salipante SUMMARY Fate maps depict how cells relate together through past lineage relationships, and are useful tools for studying developmental and somatic processes. However, with existing technologies, it has not been possible to generate detailed fate maps of complex organisms such as the mouse. We and others have therefore proposed a novel approach, "phylogenetic fate mapping," where patterns of somatic mutation carried by the individual cells of an animal are used to retrospectively deduce lineage relationships through phylogenetic inference. Here, we have cataloged genomic polymorphisms at 324 mutation-prone polyguanine tracts for nearly 300 cells isolated from a single mouse, and have explored the cells' lineage relationships both phylogenetically and through a network-based approach. We present a model of mouse embryogenesis, where an early period of substantial cell mixing is followed by more coherent growth of clones later. We find that cells from certain tissues have greater numbers of close relatives in other specific tissues than expected from chance, suggesting that those populations arise from a similar pool of ancestral lineages. Finally, we have investigated the dynamics of cell turnover (the frequency of cell loss and replacement) in postnatal tissues. This work offers a longitudinal study of developmental lineages, from conception to adulthood, and provides insight into basic questions of mouse embryology as well as the somatic processes that occur after birth. [source] ApoE allelic variability influences pupil response to cholinergic challenge and cognitive impairmentGENES, BRAIN AND BEHAVIOR, Issue 3 2007L.F.M. Scinto Exaggerated pupil response to dilute tropicamide has been suggested as an early biological marker for Alzheimer's disease. The current study links apolipoprotein E (ApoE) allelic variability to the magnitude of pupil response in a sample of community-dwelling elderly without a diagnosis of Alzheimer's disease or dementia. Possession of an ,4 allele influences both the likelihood of exhibiting an exaggerated pupil response above a predetermined cut-off (13% above baseline diameter) and the absolute overall magnitude of the response. Allelic variability was also shown to correlate with cognitive impairments in memory and attention. The data in this study further elucidate the nature of the biological bond between an exaggerated pupil response and the pathology of Alzheimer's disease. ApoE allelic variability is probably linked to pupil response through its influence on tau hyperphosphorylation. The early Alzheimer's pathology seen in the Edinger,Westphal area of cranial nerve III, a major centre for pupil control, is primarily tau-based with significant cell loss in this nucleus leading to central denervation hypersensitivity even in elderly who are clinically silent but who have early pathology. [source] Increased expression of GluR2-flip in the hippocampus of the Wistar audiogenic rat strain after acute and kindled seizuresHIPPOCAMPUS, Issue 1 2010Daniel Leite Góes Gitaí Abstract The Wistar Audiogenic Rat (WAR) is an epileptic-prone strain developed by genetic selection from a Wistar progenitor based on the pattern of behavioral response to sound stimulation. Chronic acoustic stimulation protocols of WARs (audiogenic kindling) generate limbic epileptogenesis, confirmed by ictal semiology, amygdale, and hippocampal EEG, accompanied by hippocampal and amygdala cell loss, as well as neurogenesis in the dentate gyrus (DG). In an effort to identify genes involved in molecular mechanisms underlying epileptic process, we used suppression-subtractive hybridization to construct normalized cDNA library enriched for transcripts expressed in the hippocampus of WARs. The most represented gene among the 133 clones sequenced was the ionotropic glutamate receptor subunit II (GluR2), a member of the ,-amino-3-hydroxy-5-methyl-4-isoxazoleopropionic acid (AMPA) receptor. Although semiquantitative RT-PCR analysis shows that the hippocampal levels of the GluR2 subunits do not differ between naďve WARs and their Wistar counterparts, we observed that the expression of the transcript encoding the splice-variant GluR2-flip is increased in the hippocampus of WARs submitted to both acute and kindled audiogenic seizures. Moreover, using in situ hybridization, we verified upregulation of GluR2-flip mainly in the CA1 region, among the hippocampal subfields of audiogenic kindled WARs. Our findings on differential upregulation of GluR2-flip isoform in the hippocampus of WARs displaying audiogenic seizures is original and agree with and extend previous immunohistochemical for GluR2 data obtained in the Chinese P77PMC audiogenic rat strain, reinforcing the association of limbic AMPA alterations with epileptic seizures. © 2009 Wiley-Liss, Inc. [source] Hippocampal neuron and glial cell numbers in Parkinson's disease,A stereological study,HIPPOCAMPUS, Issue 10 2006F.C. Joelving Abstract Hippocampal atrophy and neuron loss are early and reproducible findings in Alzheimer's disease, and recent magnetic resonance imaging studies indicate that hippocampal atrophy may also be present in Parkinson's disease (PD). To determine whether or not cell loss occurs in PD, we estimated the total neuron and glial cell numbers as well as the total volume unilaterally in the hippocampi of eight demented PD patients and eight control subjects. Cell numbers were estimated in the neuron-containing layers of CA1, CA2-(3), CA4, the dentate gyrus, and subiculum using the optical-fractionator technique. The Cavalieri method was used to estimate the volume of the total hippocampus and its subregions. We did not find significant differences in cell numbers or volumes in PD brains when compared with control subjects. Our results thus indicate that hippocampal atrophy and cell loss are not necessarily involved in the memory impairment and dementia observed in PD. © 2006 Wiley-Liss, Inc. [source] MRI-based evaluation of locus and extent of neurotoxic lesions in monkeys ,HIPPOCAMPUS, Issue 4 2001e Málková Abstract To minimize the variability in the extent of lesions made by injections of the excitotoxin ibotenic acid in rhesus monkeys, we developed and validated an MRI-based method to determine the efficacy of the injections soon after surgery. T2-weighted MR images were obtained 6,11 days after surgery from 17 brain hemispheres of monkeys that had received bilateral lesions of either the hippocampal formation (HF), perirhinal cortex, or parahippocampal cortex. The extent of lesion estimated from the hypersignal that appeared in and outside of the targeted area on these MR images was compared with the extent of damage assessed histologically after survival periods ranging from 120,370 days. Highly significant correlations (r values between 0.85,0.99) were found between these two measures for several regions in the medial temporal lobe. Based on this finding, lack of hypersignal in the targeted area of some Ss was followed by successful reinjection of the neurotoxin to create more complete cell loss prior to the postoperative phase of the study. We also assessed the relationship between a postoperative reduction in HF volume, measured from T1-weighted MR images, and the extent of damage determined histologically in 14 hemispheres of monkeys with bilateral excitotoxic HF lesions. The HF volume decreases sharply after surgery until 40,50 days postoperatively, after which there is only a minor further decrease. Based on this finding, we obtained T1-weighted MR images at least 44 days but in most cases close to 1 year after surgery. A highly significant positive correlation (r = 0.95, P < 0.001) was found between neuronal damage and volume reduction, with nearly complete neuronal damage (96,99%) corresponding to a volume reduction of 68,79%. These MRI-based methods thus provide an accurate in vivo evaluation of the locus and extent of neurotoxic lesions. Application of these methods can ensure that each animal in the experiment is used effectively. Hippocampus 2001;11:361,370. Published 2001 Wiley-Liss, Inc. [source] Clinically reported heterozygous mutations in the PINK1 kinase domain exert a gene dosage effect,HUMAN MUTATION, Issue 11 2009Eng-King Tan Abstract Mutations in the gene encoding phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) have been associated with the loss of dopaminergic neurons characteristic of familial and sporadic Parkinson disease. We developed an in vitro system of stable human dopaminergic neuronal cell lines coexpressing an equivalent copy of normal and mutant PINK1 to simulate "heterozygous" and "homozygous" states in patients. Mutants in the N-terminus, C-terminus, and kinase domain were generated and cloned into a two-gene mammalian expression vector to generate stable mammalian expression cell lines producing an equivalent copy number of wild-type/mutant PINK1. The cell lines were subjected to oxidative stress and the rate of apoptosis and change in mitochondrial membrane potential (,,m) were assessed. Cell lines expressing kinase and C-terminus mutants exhibited a greater rate of apoptosis and decrease in ,,m, and increased time-dependent cell loss when subjected to oxidative stress compared to the wild-type. Cell lines expressing two copies of kinase mutants exhibited a greater apoptosis rate and ,,m decrease than those expressing one copy of the mutant. In time-dependent experiments, there was a significant difference between "homozygous," "heterozygous," and wild-type cell lines, with decreasing cell survival in cell lines expressing mutant copies of PINK1 compared to the wild-type. We provided the first experimental evidence that clinically reported PINK1 heterozygous mutations exert a gene dosage effect, suggesting that haploinsufficiency of PINK1 is the most likely mechanism that increased the susceptibility to dopaminergic cellular loss. Hum Mutat 30:1551,1557, 2009. © 2009 Wiley-Liss, Inc. [source] Photoperiod-induced apoptosis in the male genital tract epithelia of the golden hamsterINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 2 2007Rosa Carballada Summary The aim of this study was to identify some details of the changes induced by a short-day light regime (8:16 light:dark) on the male genital tract and accessory sex glands of the golden hamster Mesocricetus auratus. We principally examined the presence of apoptotic cells in the epithelium from different regions of the epididymis, seminal vesicles, prostate and coagulating gland. We detected an increase in the percentage of apoptotic cells in situ using the TUNEL technique in animals that were maintained for 6, 8 or 12 weeks in a short photoperiod. That those cells were indeed undergoing apoptosis was confirmed by the immunodetection of the active fragment of caspase-3. The apoptotic indices in the different tissues analysed were low, but were maintained for weeks, suggesting cell loss at a steady rate. We tried to correlate these changes with the testosterone levels in serum as well as with the oxidative stress in the tissue. On the other hand, the increase in size and number of lipofuscin granules indicated the possibility that a parallel increase in oxidative stress occurred in the tissues. The normalization in the number of apoptotic cells and lipofuscin granules in animals treated with testosterone suggests that both phenomena might be related to changes in the hormone levels. [source] The effects of correlated arrivals at a server with credit-based traffic policingINTERNATIONAL JOURNAL OF COMMUNICATION SYSTEMS, Issue 4 2001K. Mitchell Abstract In this paper we observe the steady state and transient behaviour of correlated cell arrivals into a server with credit-based traffic policing. We derive expressions for the lag- k correlations of the departure process from the traffic policing mechanism, and observe how dependencies in the departure stream affect cell loss at the server. The results illustrate the impact of the second-order statistics and the higher moments of the cell arrival processes on the traffic policing mechanism performance. Copyright © 2001 John Wiley & Sons, Ltd. [source] Reducing cell loss in banyan based ATM switching fabricsINTERNATIONAL JOURNAL OF COMMUNICATION SYSTEMS, Issue 1 2001M. Al-Mouhamed Abstract In this paper, we propose a new technique for reducing cell loss in multi-banyan-based ATM switching fabrics. We propose a switch architecture that uses incremental path reservation based on previously established connections. Path reservation is carried out sequentially within each banyan but multiple banyan planes can be concurrently reserved. We use a conflict resolution approach according to which banyans make concurrent reservation offers of conflict-free paths to head of the line cells waiting in input buffers. A reservation offer from a given banyan is allocated to the cell whose source-to-destination path uses the largest number of partially allocated switching elements which are shared with previously reserved paths. Paths are incrementally clustered within each banyan. This approach leaves the largest number of free switching elements for subsequent reservations which has the effect of reducing the potential of future conflicts and improves throughput. We present a pipelined switch architecture based on the above concept of path-clustering which we call path-clustering banyan switching fabric (PCBSF). An efficient hardware that implements PCBSF is presented together with its theoretical basis. The performance and robustness of PCBSF are evaluated under simulated uniform traffic and ATM traffic. We also compare the cell loss rate of PCBSF to that of other pipelined banyan switches by varying the switch size, input buffer size, and traffic pattern. Copyright © 2001 John Wiley & Sons, Ltd. [source] | |||||||||||||||||||||||||||||||