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PubMed2003

Susceptibility of hippocampal neurons to mechanically induced injury.

Experimental models of traumatic cortical brain injury in rodents reveal that specific regions of the hippocampus (e.g., CA3 and hilar subfields) are severely injured despite their distance from the initial insult. Hippocampal neurons may be intrinsically more vulnerable to mechanical insult than cortical neurons due to increased NMDA receptor densities and lower energy capacities, as evidenced by increased susceptibility to ischemic insults. The selective vulnerability of hippocampal neurons was evaluated using an in vitro model of TBI in which either primary rat cortical or hippocampal neurons (E17) seeded onto silicone substrates were subjected to graded levels of mechanical stretch. Although cortical neurons exhibited significantly longer increases in stretch-induced membrane permeability, injury of hippocampal neurons resulted in larger increases in intracellular free calcium concentration [Ca(2+)](i) and cell death. [ATP](i) deficits due to stretch were apparent by 60 min after injury in cortical neurons but recovered by 24 h, whereas significant deficits in [ATP](i) were not observed in hippocampal neurons until 24 h after injury. MK801 pretreatment decreased the stretch-induced [Ca(2+)](i) transients in both hippocampal and cortical cultures, thereby negating the regional specificity. However, MK801 pretreatment did not improve hippocampal viability and paradoxically, significantly increased cell death among cortical neurons. As the hippocampus is the primary brain region responsible for the memory deficits and epileptic seizures associated with TBI, understanding why this region is selectively damaged could lead to the development of more accurate mechanical tolerances as well as effective pharmaceutical agents.

Adenosine Triphosphate↗

PubMed1993

Does neuromelanin contribute to the vulnerability of catecholaminergic neurons in monkeys intoxicated with MPTP?

The question has been raised as to whether neuromelanin, a by-product of catecholamine metabolism which accumulates during aging in primate midbrain neurons, contributes to the selective vulnerability of subgroups of dopaminergic neurons in Parkinson's disease. 1-Methyl-4-phenylpyridinium (MPP+) a metabolite of 1-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP) is toxic to dopaminergic neurons, particularly in primates, producing a motor syndrome similar to that observed in Parkinson's disease. To test whether this neurotoxin preferentially affects melanized neurons, the survival of melanized and non-melanized catecholaminergic neurons was analysed after MPTP intoxication in the midbrain of the cynomolgus monkey (Macaca fascicularis). Experiments were performed on six animals chronically treated with MPTP (two were severely disabled, four moderately affected) and two age-matched control monkeys. Two populations of neurons were examined on regularly spaced sections throughout the midbrain: catecholaminergic neurons, identified by tyrosine hydroxylase immunohistochemistry and neuromelanin-containing neurons, visualized by Masson's method. The total number of neurons of each type was estimated in the different midbrain catecholaminergic cell groups using computer assisted image analysis. In the midbrains of control animals not all catecholaminergic neurons contained neuromelanin. The percentage of melanized neurons compared to the total population of tyrosine hydroxylase-positive neurons was high in the substantia nigra pars compacta (81.5%) and in the locus coeruleus (98%), intermediate in the substantia nigra pars lateralis (70%), in the catecholaminergic cell group A8 (50%), and in the ventral tegmental area (41.5%) and almost nil in the central gray substance. In MPTP-treated monkeys, the severity of the loss of catecholaminergic neurons was variable within the different midbrain cell groups, though of similar intensity in severely and mildly disabled monkeys. A relationship was found between the loss of dopaminergic neurons in the different mesencephalic cell groups of MPTP-intoxicated animals and the percentage of melanized neurons they normally contain (r = 0.98; P = 0.04). The percentage loss of catecholaminergic neurons in the locus coeruleus, the only noradrenergic cell group studied, was lower than expected from the correlation curve obtained for dopaminergic cell groups. Altogether, these findings indicate: (i) that dopaminergic neurons are more vulnerable to MPTP-toxicity than noradrenergic neurons; and (ii) that among dopaminergic neurons, those containing neuromelanin are more susceptible, indicating a possible role of neuromelanin in MPTP-toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2004

Lack of regional selectivity during the progression of Parkinson disease: implications for pathogenesis.

BACKGROUND: Dopamine terminal loss in the putamen of patients with Parkinson disease (PD) shows a regional heterogeneity, reflecting selective vulnerability of degenerating neurons to mechanisms of cell death. HYPOTHESIS: If the same pathogenic mechanisms are responsible for the onset and progression of PD, the regional selectivity of dopamine cell loss will be the same throughout the course of the disorder. OBJECTIVE: To investigate the regional selectivity of dopamine terminal loss during the progression of PD. PARTICIPANTS: We studied 67 patients with PD and 20 healthy subjects using positron emission tomography with [(11)C](+/-)dihydrotetrabenazine (DTBZ). RESULTS: Regional values of DTBZ binding potential (calculated as maximum specific binding [B(max)] divided by the equilibrium dissociation constant K(d)) against disease duration in the putamen of PD patients were best described by a multivariate exponential model with distinct parallel asymptotic values that were significantly (P<.001) different across 4 regions of the putamen. The extent of loss of DTBZ binding potential with disease progression during the clinical stage of PD (early vs late PD) was similar between the anterior (-33%, using early PD as the baseline) and posterior (-29%) putamen. In contrast, the extent of loss of DTBZ binding potential in early PD, which reflects the cumulated loss of DTBZ binding potential from the onset of the disorder (in healthy subjects vs those with early PD), was significantly (P<.001) lower in the posterior (-58%, using healthy subjects as the baseline) than the anterior (-42%) putamen. CONCLUSION: To the extent that DTBZ positron emission tomography provides an accurate estimate of loss of dopamine neurons, our findings suggest that the mechanisms responsible for the progression of PD may not be the same as those responsible for its onset.

Aged↗

PubMed1990

Neuronal disorders: studies of animal models and human diseases.

The peripheral nervous system and the central nervous system (CNS) are comprised of assemblies of neurons that communicate via electrical and chemical signals. Different disease processes selectively affect specific populations of neurons and/or specific cell functions (i.e., "selective vulnerability" of neurons is a principal determinant of phenotypes of disease). New cellular and molecular biological approaches have begun to clarify some of the mechanisms of selective cell injury in human diseases and their animal models. Following a brief review of the normal biology of nerve cells, we use illustrations drawn from studies of experimental and human diseases to discuss the mechanisms of structural/chemical abnormalities that occur in a variety of neuronal disorders.

Animals↗

PubMed2003

Altered protein expression levels of Fas/CD95 and Fas ligand in differentially vulnerable brain areas in rats after global cerebral ischemia.

To assess the role of the apoptosis-inducing death receptor Fas/CD95 and Fas Ligand (FasL) after global cerebral ischemia, expression of these proteins was investigated in differentially, i.e. selectively vulnerable brain areas. Following experimentally induced cardiac arrest of 6 min duration, rats were resuscitated. After 3, 6, and 24 h of reperfusion, the thalamus and hippocampus of one hemisphere were analyzed for Fas/CD95 and FasL by immunoblotting and semiquantitative densitometry. Corresponding hemispheres were examined by immunohistochemistry. No significant changes in hippocampal Fas/CD95 expression were revealed in comparison to sham operated animals. In the thalamus, a significant reduction in Fas/CD95 expression was observed after 24 h of reperfusion. FasL expression in the hippocampus had declined after 3 and 6 h, as compared with control animals. In contrast, in the thalamus a significant induction of FasL expression was observed after 3 h. Immunohistochemistry revealed a predominantly neuronal expression of the two proteins. In light of the observed increased expression of FasL in the thalamus, such an induction may lead to significant activation of the Fas/CD95 signaling cascade. Our results suggest for the first time a possible role of the Fas/CD95-FasL system after global cerebral ischemia.

Animals↗

PubMed1995

Nerve conduction studies, skeletal muscle EMG, and sphincter EMG in multiple system atrophy.

Although autonomic failure, parkinsonism, and cerebellar and pyramidal signs are well documented in multiple system atrophy, much less is known about the frequency and severity of involvement of the peripheral nervous system. The frequency and nature of peripheral nerve involvement has therefore been determined in 74 patients with multiple system atrophy using nerve conduction studies and skeletal muscle EMG. These findings were compared with those on sphincter EMG. Ninety per cent of the patients had an abnormal sphincter EMG, indicating denervation and reinnervation consistent with anterior horn cell loss in Onuf's nucleus, but only 40% had either abnormal nerve conduction studies (mixed sensorimotor axonal neuropathy in 17.5%) or abnormal skeletal muscle EMG (suggesting partial denervation in 22.5%). These data indicate a remarkable selective vulnerability of the anterior horn cells of Onuf's nucleus innervating external sphincter muscles relative to those supplying skeletal muscle in patients with multiple system atrophy. If this selective pattern of involvement can be explained it may be a clue to pathogenetic mechanisms in multiple system atrophy.

Adult↗

PubMed1984

Sustained upgaze in coma.

Sustained upgaze is a rare phenomenon that is observed primarily in those patients with coma secondary to cardiac arrest or prolonged hypotension. Because of "selective vulnerability" of the brain, cardiac arrest or prolonged hypotension may produce both cerebral and cerebellar cortical damage sparing the brain stem vestibulo-ocular reflex (VOR) pathways. This selective damage may be responsible for the generation of sustained upgaze. The VORs receive their selective inhibition from the cerebellar flocculus. This inhibition is exerted on only one of the two VOR pathways converging on each extra-ocular muscle, so that total disinhibition of the VOR pathway activities will result in a tonic upward bias. The underlying neuronal mechanism of sustained upgaze appears to be due to total floccular disinhibition resulting in upward drift produced by the biased VOR and the lack of correcting saccades due to cerebral dysfunction releasing the brain stem ocular motor systems from their control.

Cerebellar Cortex↗

PubMed1994

[Cerebral ischemia and neuronal death].

The neurons in the hippocampus, striatum, and cerebral or cerebellar cortex are particularly vulnerable to a short period of ischemia. Following brief ischemic insult, neurons die after a latent period for a few days (delayed neuronal death). To account for this selective vulnerability to ischemia, glutamate-calcium hypothesis has come to be widely accepted. Glutamate, a major excitatory neurotransmitter, increases during ischemia. The hypothesis proposes that accumulated extracellular glutamate in turn triggers an increase of intracellular Ca2+ and eventually neuronal cell death. When neurons are subjected to sublethal ischemia, they express stress response and become transiently tolerant to further ischemia. These characteristics of ischemic neuronal death following brief ischemia indicate that neuronal death under such situation is not due to simple destruction of the cell. On the contrary, the fate of neurons following ischemia seems to depend on the basic cellular function which determines death or survival. This assumption is partially supported by the fact that some neurotrophic factors can save neurons following ischemic. However, the further basic mechanism of ischemic neuronal cell death is still unknown.

Animals↗

PubMed2001

Effective reduction of neuronal death by inhibiting gap junctional intercellular communication in a rodent model of global transient cerebral ischemia.

Gap junctions assemble astrocytes into syncytia, allowing exchange of metabolites, catabolites, and second-messenger molecules. Connexin43 is the predominant connexin of astrocytic gap junctions. The distribution of gap junction protein connexin43 was analyzed in different subfields of the hippocampal formation as a function of time after transient forebrain ischemia. One decisive key step in understanding why an ischemic insult gradually expands may be to establish how gap junction channels permit dying cells in the ischemic focus to communicate, in particular, with viable cells. The role of gap junctional intercellular communication in the hippocampus under ischemic conditions could be decisive for cell death propagation. We found that the vulnerable CA1/CA2 subfields have a higher density of gap junctions than the resistant CA3/CA4 areas, that changes in the distribution of connexin43 immunoreactivity may correlate with the phenomenon of selective vulnerability, and that inhibition of astrocytic gap junction permeability by octanol restricts the flow of undesirable neurotoxins that could potentially exacerbate neuronal damage. This provides a novel perspective for analysis of the pathophysiology of cerebral ischemia.

Animals↗

PubMed1979

Ischemic lesions of the hippocampus and their relation to Ammon's horn sclerosis. A neuropathological study of two cases and a comparison to the vascular anatomy.

Two adult brains with small ischemic lesions in the hippocampus, due to impairment of the supply from the posterior cerebral artery, are presented. The first case corresponds to what is described in the literature as "incisural sclerosis" and shows no difference in vulnerability between the Sommer and the Spielmeyer sector. In the second case the hippocampal lesion is due to an embolic occlusion of the posterior cerebral artery and consists of selective necrosis of the subiculum, the Sommer sector and part of the endfolium of the pyramidal layer, the Spielmeyer sector remaining noninfarcted. The postmortem angiograms of 12l hippocampi of adults, as well as full term born and premature infants, show that the h1 and h2 sectors and part of the h3 sector of the hippocampus are supplied by the same "sulcus" arteries. Although there is a selective vulnerability to ischemia in some sectors of the hippocampus, which is typical for Ammon's horn sclerosis, this cannot be explained by a difference of arterial supply or by compression of arteries during the process of birth.

Blood Vessels↗

PubMed2004

Differential expression of mGluR5 in human lumbosacral motoneurons.

Glutamatergic excitotoxicity is one of the main hypotheses to explain motoneuronal degeneration in amyotrophic lateral sclerosis (ALS). Interestingly, autonomic motoneurons remain almost unaffected, even in late stages of the disease. Since glutamate receptors may mediate neurotoxic as well as neuroprotective effects, different expression patterns may contribute to neuronal vulnerability. We and others have previously described a significantly higher expression of group I metabotropic glutamate receptors (mGluRs) in rat autonomic motoneurons compared to somatic motoneurons. Here we show a selective expression of the group I receptor mGluR5 in human parasympathetic Onuf's nucleus. These results are in accordance with previous findings in rat and strengthen the hypothesis that mGluR expression may provide a possible clue to the selective vulnerability in ALS.

Amyotrophic Lateral Sclerosis↗

PubMed1990

Ischemia induces release of glutamate in regions spared from histopathologic damage in the rat.

Excessive release of glutamate is thought to play a major role in the susceptibility of neurons to ischemia. In the present study, we evaluated whether differences in the magnitude of glutamate release resulted in some regions being vulnerable to ischemia, but others being spared from irreversible histopathologic damage. Specifically, we compared the temporal profile of ischemia-induced changes in extracellular levels of glutamate in a region selectively vulnerable to 10 minutes of transient ischemia (CA1 sector of the hippocampus) to the changes occurring in regions that, although rendered ischemic, are usually unaffected by a 10-minute insult (i.e., thalamus, cortex, and dorsolateral striatum). In an attempt to correlate the regional changes in glutamate release to the magnitude of the ischemic insult, the degree of ischemia (e.g., ATP depletion, lactate accumulation, and local cerebral blood flow reduction) and the final histopathologic outcome were also evaluated in these regions. Blood flow reduction and energy depletion were severe and uniform in all regions. However, the histopathologic outcome illustrated a different pattern. Although the CA1 sector of the hippocampus was severely damaged, all other brain regions were unaffected by the 10-minute insult. Extracellular glutamate levels, measured by microdialysis, were significantly elevated during ischemia in all four regions. These levels continued to increase during the early recirculation period and gradually returned to baseline by 30 minutes of reperfusion, with a similar temporal changes in all four brain structures. These results, taken with our previous findings, demonstrate that elevated intraischemic glutamate levels are insufficient to independently engender ischemic damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed2004

The presence of the APP(swe) mutation in mice does not increase the vulnerability of cholinergic basal forebrain neurons to neuroinflammation.

Neuroinflammation, and elevated levels of inflammatory proteins, such as tumor necrosis factor-alpha, and the deposition of beta-amyloid may interact to contribute to the pathogenesis of Alzheimer's disease. We reproduced a component of the neuroinflammatory state within the basal forebrain cholinergic system, a region that is vulnerable to degeneration in Alzheimer's disease, of transgenic Tg2576 mice that express the Swedish double mutation of the human amyloid precursor protein (APPswe). We have previously shown that basal forebrain cholinergic neurons are selectively vulnerable to the consequences of neuroinflammation. In the current study, tumor necrosis factor-alpha was infused into the basal forebrain region of APPswe and nontransgenic control mice for 20 days with the expectation that the presence of the transgene would enhance the loss of cholinergic neurons. Chronic infusion of tumor necrosis factor-alpha significantly decreased cortical choline acetyltransferase activity, reduced the number of choline acetyltransferase-immunoreactive cells and increased the number of activated astrocytes and microglia within the basal forebrain. The presence of the APPswe gene did not enhance the vulnerability of forebrain cholinergic neurons to the chronic neuroinflammation. Furthermore, combined treatment of these mice with memantine demonstrated that the neurotoxic effects of tumor necrosis factor-alpha upon cholinergic cells did not require the activation of the N-methyl-d-aspartate receptors. In contrast, we have previously shown that memantine was able to provide neuroprotection to cholinergic forebrain neurons from the consequences of exposure to the inflammogen lipopolysaccharide. These results provide insight into the mechanism by which neuroinflammation may selectively target specific neural systems during the progression of Alzheimer's disease.

Acetylcholine↗

PubMed1999

Evidence disputing the importance of excitotoxicity in hippocampal neuron death after experimental traumatic brain injury.

The hippocampus is selectively vulnerable to experimental traumatic brain injury (TBI). Beneficial effects of glutamate receptor antagonists and increased extracellular levels of glutamate have suggested that glutamate-mediated excitotoxicity may be responsible for this selective damage. In order to clarify this important issue, we applied a severe parasagittal fluid percussion injury (FPI) to strains of mice shown to be susceptible and resistant to kainic acid (KA)-induced excitotoxic hippocampal damage. Dystrophic neurons were present by 10 min after FPI in the hippocampi of both strains. Damaged hippocampal neurons were absent at 4 days and 7 days. Additionally, there was no significant difference (p = 1.00) in CA3 neuron survival between KA-susceptible and -resistant mice at 4 days. In conclusion, excitotoxicity does not significantly contribute to hippocampal neuron loss after FPI and, in contrast to classic studies of excitotoxicity in vivo, the pattern of hippocampal cell death after TBI is extremely acute.

Animals↗

PubMed1991

Neonatal striatal NADPH-diaphorase neurons are vulnerable to quisqualate and its analogue alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA).

A small population of neurons in the mammalian striatum and cerebral cortex contain NADPH-diaphorase. Recently, this class of neurons has been found in vitro to be selectively vulnerable to low concentrations of non-N-methyl-D-aspartate (NMDA) glutamate agonists. To determine if this pattern exists in vivo, we injected either quisqualate (QA) or its inotropic site analogue alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA) into the striatum of neonatal rat pups and found a dose-dependent loss of NADPH-diaphorase reactive neurons. These data suggest that the QA receptor may be present and functional at postnatal day 7 when other glutamate receptor subtypes have not yet fully developed and that QA is working through its inotropic site since AMPA causes the same dose-dependent cell death.

Animals↗

PubMed1995

Expression of beta-actin and alpha-tubulin mRNA in gerbil brain following transient ischemia and reperfusion up to 1 month.

The time course of mRNA expressions of two cytoskeletal proteins, beta-actin and alpha-tubulin, was studied by Northern blot analysis and in situ hybridization in the same gerbil brains at various periods of recirculation following 10 min of forebrain ischemia. On Northern blot analysis, beta-actin mRNA in the forebrain showed increase after 6 h and 24 h recirculation. There was wide variation in its expression 3 days postischemia (PI), and by 7 days PI it had returned to control. The alpha-tubulin mRNA in the forebrain was shown to be reduced 6 h PI in our previous study. In the present analysis of Northern blots of delayed postischemic periods, there was no significant change in its expression even though there were variations. In situ hybridization revealed a decline in the mRNA expressions of both alpha-tubulin and beta-actin in the CA1 region as early as 6-24 h PI with the reductions being prominent at 3 days PI. By 7 days PI, beta-actin was only faintly visible while alpha-tubulin was completely absent in the CA1 region. Neither RNA was detectable in CA1 1 month PI. The heat shock-70 protein was expressed by 1 h PI, and it continued to be expressed up to 24 h, returning to control by 3 days PI. These results indicate that ischemia inhibits mRNA expressions of cytoskeletal protein in the selectively vulnerable region of the brain, i.e. CA1. The time course of the reduction of the two mRNAs coincides with delayed neuronal death suggesting that the cytoskeletal proteins may play important roles in selective postischemic neuronal injury.

Actins↗

PubMed1993

Brain pHi, cerebral blood flow, and NADH fluorescence during severe incomplete global ischemia in rabbits.

BACKGROUND AND PURPOSE: The aim of this experiment was to study the serial changes in brain intracellular pH, cerebral blood flow, and the oxidation/reduction level of intramitochondrial nicotinamide adenine dinucleotide fluorescence across the cortical surface during severe incomplete global ischemia. METHODS: Reduced nicotinamide adenine dinucleotide fluorescence and brain intracellular pH using the pH-sensitive indicator umbelliferone were measured with in vivo panoramic fluorescence imaging of the cortical surface. Cerebral blood flow was measured with the clearance of both umbelliferone and xenon-133. Fifteen minutes of severe incomplete global ischemia was produced by temporary occlusion of the innominate, left carotid, and subclavian arteries in five fasted New Zealand White rabbits. RESULTS: Baseline brain intracellular pH was homogeneous over the exposed cortex, measuring 7.00 +/- 0.02, while cerebral blood flow was 48.0 +/- 2.6 ml/100 g/min. During 15 minutes of ischemia, cerebral blood flow measured 6.3 +/- 1.8 ml/100 g/min and brain pH declined to 6.61 +/- 0.02 (p < 0.005); in addition, there were acidotic foci with pH measuring 6.40 +/- 0.10. During reperfusion, there was an initial normalization of brain intracellular pH without an alkaline shift followed by a recurrent cortical acidosis of pH 6.88 +/- 0.06. There was a heterogeneous pattern of fluorescence that increased significantly following 60 minutes of reperfusion, coinciding with a postischemic hypoperfusion. The hypoperfusion was a uniform reduction in cerebral blood flow over the brain's surface, with reductions of 42.5% and 44.2% at 30 and 45 minutes, respectively. CONCLUSIONS: During incomplete global ischemia there is a heterogeneous pattern of brain intracellular pH and reduced nicotinamide adenine dinucleotide changes that do not correlate with changes in cortical blood flow. The acidotic foci that were approximately 0.2 pH units more acidotic than the surrounding cortex may be the result of continued glucose delivery under anaerobic conditions. The degree of reduced nicotinamide adenine dinucleotide fluorescence suggests that the cortex is most vulnerable to metabolic failure after 60 minutes of reperfusion following severe incomplete global ischemia. The heterogeneous pattern of brain intracellular pH and reduced nicotinamide adenine dinucleotide changes suggest that there may be a selective vulnerability of cortical tissue to an ischemic challenge.

Animals↗

PubMed1993

Differential vulnerability in the hindbrain neurons and local cerebral blood flow during bilateral vertebral occlusion in gerbils.

Differential vulnerability in the hindbrain neurons was examined immunohistochemically during hindbrain ischemia in the gerbil. Hindbrain ischemia was produced by extracranial occlusion of the bilateral vertebral arteries just before their entry into the transverse foramen of the cervical vertebra. Local cerebral blood flow was measured by quantitative autoradiographic technique after 5 min of ischemia and was reduced to less than 5 ml/100 g per min in the cerebellum, the pons, and the medulla, indicating that severe and reproducible hindbrain ischemia was induced immediately after occlusion. For immunohistochemical investigation, four gerbils each were used for each ischemic period of 5, 10, 15, and 30 min. Immunohistochemical lesions, detected by the reaction for microtubule-associated protein 2, were visible in the lateral vestibular nucleus and the cerebellar interpositus nucleus even after 5 min of ischemia. These results suggested that these areas were more vulnerable than others, although blood flow was markedly reduced in various regions of the hindbrain. In contrast, areas related to respiratory or cardiovascular control were rather resistant to ischemia. The present study suggests that selective vulnerability during hindbrain ischemia depends mainly on different metabolic characteristics inherent to various neurons in the hindbrain.

Animals↗