Michael Norenberg - Academia.edu (original) (raw)

Papers by Michael Norenberg

Journal of Neurochemistry, 2008

Astrocyte swelling and brain edema are major neuropathological findings in the acute form of hepa... more Astrocyte swelling and brain edema are major neuropathological findings in the acute form of hepatic encephalopathy (fulminant hepatic failure), and substantial evidence supports the view that elevated brain ammonia level is an important etiological factor in this condition. Although the mechanism by which ammonia brings about astrocyte swelling remains to be determined, oxidative/nitrosative stress and mitogen-activated protein kinases (MAPKs) have been considered as important elements in this process. One factor known to be activated by both oxidative stress and MAPKs is nuclear factor jB (NFjB), a transcription factor that activates many genes, including inducible nitric oxide synthase (iNOS). As the product of iNOS, nitric oxide (NO), is known to cause astrocyte swelling, we examined the potential involvement of NFjB in ammoniainduced astrocyte swelling. Western blot analysis of cultured astrocytes showed a significant increase in NFjB nuclear translocation (a measure of NFjB activation) from 12 h to 2 days after treatment with NH 4 Cl (5 mM). Cultures treated with anti-oxidants, including superoxide dismutase, catalase, and vitamin E as well as the MAPKs inhibitors, SB239063 (an inhibitor of p38-MAPK) and SP600125 (an inhibitor of c-Jun N-terminal kinase), significantly diminished NFjB activation by ammonia, supporting a role of oxidative stress and MAPKs in NFjB activation. The activation of NFjB was associated with increased iNOS protein expression and NO generation, and these changes were blocked by BAY 11-7082, an inhibitor of NFjB. Additionally, ammonia-induced astrocyte swelling was inhibited by the NFjB inhibitors, BAY 11-7082 and SN-50, thereby implicating NFjB in the mechanism of astrocyte swelling. Our studies indicate that cultured astrocytes exposed to ammonia display NFjB activation, which is likely to be a consequence of oxidative stress and activation of MAPKs. NFjB activation appears to contribute to the mechanism of ammonia-induced astrocyte swelling, apparently through its up-regulation of iNOS protein expression and the subsequent generation of NO.

Archives of Neurology, 1974

A subacute experimental model of he-patic encephalopathy was created in the rat by constructing a... more A subacute experimental model of he-patic encephalopathy was created in the rat by constructing a portacaval shunt with subsequent gavage feeding of a cat-ionic ammonium exchange resin. The clinical course was characterized by fluc-tuating levels of consciousness, ...

Brain Research, 1994

Exposure of primary cultured astrocytes for 3 days to 1 /~M of either dopamme, serotonm or norepm... more Exposure of primary cultured astrocytes for 3 days to 1 /~M of either dopamme, serotonm or norepmephrine resulted in upregulatlon (25-34% increase In Bma x) of the peripheral-type benzodlazeplne receptors (PBRs) labeled with [~H]Ro5-4864. A similar treatment with y-aminobutyric acid [GABA] caused a 2-fold increase m the affimty (K d) ol [3H]Ro5-4864. The monoamlnes tested and GABA had no effect on the binding parameters of [3H]PK 11195, another selectwe PBR hgand. The present study indicates that Ro5-4864 binding sites are susceptible to regulation by specific neurotransm~tters and provides further ewdence for the distinction between Ro5-4864 and PK 11195 binding sites of the PBRs m cultured astrocytes.

Neurochemical Research, 2005

Ammonia is a neurotoxin that is implicated in the CNS dysfunction associated with hepatic encepha... more Ammonia is a neurotoxin that is implicated in the CNS dysfunction associated with hepatic encephalopathy, urea cycle disorders, Reye's syndrome and other neurological conditions. While in vivo studies suggest that astrocytes are the principal target of ammonia toxicity, recent in vitro investigations suggest that neurons may also be directly affected by ammonia. To further examine the issue of neural cell sensitivity to ammonia, pure rat cortical neuronal cultures, as well as co-cultures of neurons and astrocytes, were exposed to 5 mM NH 4 Cl for 48 h. Cultures were examined for morphological changes by light microscopy, measures of cell death, free radical production and changes in the mitochondrial inner membrane potential. Ammonia caused extensive degenerative changes in pure cultured neurons, while such neuronal changes were minor in the co-cultures. Similarly, processes of pure cultured neurons displayed a significant loss of the mitochondrial inner membrane potential, as compared to neurons in co-cultures. Cell death (LDH release) in ammonia-treated neuronal cultures was twice as great as untreated controls, while in co-cultures ammonia did not significantly increase cell death. Free radical production at 3 min was increased (69%, P<0.05) in pure neuronal cultures but not in co-cultures. The neuroprotective effects observed in co-cultures may have been mediated by the astrocyte's ability to scavenge free radicals, by their detoxification of ammonia and/or by their neurotrophic actions. The neuroprotective action of astrocytes may explain the failure to detect significant pathological changes in neurons in ammonia toxicity in vivo.

Journal of Radiology Case Reports, 2011

Primary neoplasms of the petrous apex are rare and include eosinophilic granuloma, chondroma, cho... more Primary neoplasms of the petrous apex are rare and include eosinophilic granuloma, chondroma, chondrosarcoma, chordoma, and schwannoma. We report just the second published case of an intraosseous schwannoma of the petrous apex and are the first to describe the entity using magnetic resonance imaging. By studying the computed tomography and magnetic resonance imaging features of this rare tumor, it is possible to suggest the diagnosis preoperatively.

Scientific American, 1989

Journal of Spinal Disorders, 1991

Trends in Pharmacological Sciences, 2006

Science, 1980

The activities of cyclic nucleotide phosphohydrolase, an enzyme marker for oligodendrocytes, and ... more The activities of cyclic nucleotide phosphohydrolase, an enzyme marker for oligodendrocytes, and glutamine synthetase, an enzyme marker for astrocytes, were studied at early (21 to 26) and late (82 to 88) cell passages. The activity of cyclic nucleotide phosphohydrolase was markedly high and that of glutamine synthetase was low in the early passages, but this relation was reversed in the late passages. These findings suggest a "transdifferentiation" of C6 glial cells with passage in culture.

Neuroscience Letters, 2006

Exposure to manganese in an industrial or clinical setting can lead to manganism, a neurological ... more Exposure to manganese in an industrial or clinical setting can lead to manganism, a neurological disorder with similarities to Parkinson's disease. Although the pathogenetic basis of this disorder is unclear, studies indicate this metal is highly accumulated in astrocytes, suggesting an involvement of these glial cells. To investigate this issue, we have used a recently characterized, sub-acute model of manganese neurotoxicity. Treatment of rats with manganese (II) chloride (50 mg/kg body weight, i.p.) once daily for 1 or 4 days led to increases in manganese levels of up to 232, 523, and 427% in the cerebral cortex, globus pallidus, and cerebellum, respectively, by instrumental neutron activation analysis. These changes were accompanied by development of pathological changes in glial morphology identified as Alzheimer type II astrocytosis in both cortical and sub-cortical structures. Co-treatment with either the antioxidant N-acetylcysteine or the manganese chelator 1,2-cyclohexylenedinitrilotetraacetic acid completely blocked this pathology, indicating the cellular transformation may be mediated by oxidative stress associated with the presence of this metal. These findings represent, to our knowledge, the first report of early induction of this pathological hallmark of manganese neurotoxicity, an event previously considered a consequence of chronic exposure to manganese in primates and in human cases of manganism. Our results also indicate that use of this rodent model may provide a novel opportunity to examine the nature and role of the Alzheimer type II astrocyte in the pathophysiology of this disorder as well as in other disease processes in which cerebral accumulation of manganese occurs.

Neurology, 1989

We describe seven men with a neurologic disease clinically indistinguishable from multiple sclero... more We describe seven men with a neurologic disease clinically indistinguishable from multiple sclerosis occurring in association with seropositivity for the human immunodeficiency virus, type 1 (HIV-1). Histopathology of the CNS obtained in three patients (2 by brain biopsy, 1 at autopsy) was consistent with MS. The neurologic symptoms preceded the onset of clinically evident immunosuppression in all patients. In three men, HIV-1 seropositivity was demonstrated concomitantly or within 3 months of the onset of their neurologic disease. In the others, features of MS preceded the demonstration of HIV-1 seropositivity by 41 months, 59 months, 11 years, and 18 years, respectively. Despite the superimposition of varying degrees of cellular immunodeficiency associated with HIV-1 infection, six of these men continued to experience relapsing neurologic symptoms.

Neurochemical Research, 1994

Uptake of myo-inositol by astrocytes in hypertonic medium (440 mosm/kg H2O) was increased near 3-... more Uptake of myo-inositol by astrocytes in hypertonic medium (440 mosm/kg H2O) was increased near 3-fold after incubation for 24 hours, which continued for 72 hours, as compared with the uptake by cells cultured in isotonic medium (38 nmoles/mg protein). myo-Inositol uptake by astrocytes cultured in hypotonic medium (180 mosm/kg H2O) for periods up to 72 hours was reduced by 74% to 8 to 10 nmoles/mg protein. Astrocytes incubated in either hypotonic or hypertonic medium for 24 hours and then placed in isotonic medium reversed the initial down- or up-regulation of uptake. Activation of chronic RVD and RVI correlates with regulation of myo-inositol uptake. A 30 to 40 mosm/kg H2O deviation from physiological osmolality can influence myo-inositol homeostasis. The intracellular content of myo-inositol in astrocytes in isotonic medium was 25.6 +/- 1.3 micrograms/mg protein (28 mM). This level of myo-inositol is sufficient for this compound to function as an osmoregulator in primary astrocytes and it is likely to contribute to the maintenance of brain volume.

Journal of the American College of Surgeons, 2007

There are few reproducible models of blast injury, so it is difficult to evaluate new or existing... more There are few reproducible models of blast injury, so it is difficult to evaluate new or existing therapies. We developed a clinically relevant polytrauma model to test the hypothesis that cerebrovascular resuscitation is optimized when intravenous fluid is restricted. Anesthetized swine (42+/-5 kg, n=35) received blasts to the head and bilateral chests with captive bolt guns, followed by hypoventilation (4 breaths/min; FiO(2)=0.21). After 30 minutes, resuscitation was divided into phases to simulate typical prehospital, emergency room, and ICU care. For 30 to 45 minutes, group 1, the control group (n=5), received 1L of normal saline (NS). For 45 to 120 minutes, additional NS was titrated to mean arterial pressure (MAP) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 60 mmHg. After 120 minutes, mannitol (1g/kg) and phenylephrine were administered to manage cerebral perfusion pressure (CPP) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 70 mmHg, plus additional NS was given to maintain central venous pressure (CVP) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 12 mmHg. In group 2 (n=5), MAP and CPP targets were the same, but the CVP target was&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;8 mmHg. Group 3 (n=5) received 1 L of NS followed only by CPP management. Group 4 (n=5) received Hextend (Abbott Laboratories), instead of NS, to the same MAP and CPP targets as group 2. Polytrauma caused 13 deaths in the 35 animals. In survivors, at 30 minutes, MAP was 60 to 65 mmHg, heart rate was &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;100 beats/min, PaO(2) was &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 50 mmHg, and lactate was&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;5 mmol/L. In two experiments, no fluid or pressor was administered; the tachycardia and hypotension persisted. The first liter of intravenous fluid partially corrected these variables, and also partially corrected mixed venous O(2), gastric and portal venous O(2), cardiac output, renal blood flow, and urine output. Additional NS (total of 36+/-1 mL/kg/h and 17+/-6 mL/kg/h, in groups 1 and 2, respectively) correlated with increased intracranial pressure to 38+/-4 mmHg (group 1) and 26+/-4 mmHg (group 2) versus 22+/-4 mmHg in group 3 (who received 5+/-1 mL/kg/h). CPP was maintained only after mannitol and phenylephrine. By 5 hours, brain tissue PO(2) was&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;20 mmHg in groups 1 and 2, but only 6+/-1 mmHg in group 3. In contrast, minimal Hextend (6+/-3 mL/kg/h) was needed; the corrections in MAP and CPP were immediate and sustained, intracranial pressure was lower (14+/-2 mmHg), and brain tissue PO(2) was&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 20 mmHg. Neuropathologic changes were consistent with traumatic brain injury, but there were no statistically significant differences between groups. After polytrauma and resuscitation to standard MAP and CPP targets with mannitol and pressor therapy, we concluded that intracranial hypertension was attenuated and brain oxygenation was maintained with intravenous fluid restriction; cerebrovascular resuscitation was optimized with Hextend versus NS; and longer term studies are needed to determine neuropathologic consequences.

Journal of Neurotrauma, 2000

Schwannosis (aberrant proliferation of Schwann cells and nerve fibers) has been reported followin... more Schwannosis (aberrant proliferation of Schwann cells and nerve fibers) has been reported following spinal cord injury (SCI). In this study, we examined the incidence of schwannosis following human SCI, and investigated its relationship to gliosis. We found evidence of schwannosis in 32 out of 65 cases (48%) of human SCI that survived 24 h to 24 years after injury; this incidence rose to 82% in those patients who survived for more than 4 months. Schwannosis was not observed in cases that survived less than 4 months after injury. In affected cases, it was generally noted in areas that had low immunoreactivity for glial fibrillary acidic protein (GFAP), suggesting that reduced gliosis might have contributed to the aberrant proliferation of Schwann cells following SCI. Since chondroitin sulfate proteoglycan (CSPG) has been proposed to play a role in Schwann cell/glial interaction, we performed immunohistochemical staining for CSPG to investigate its potential relationship with schwannosis. CSPG in the injured cord was generally associated with the blood vessel walls, but was also sometimes noted in reactive astrocytes. In SCI with schwannosis, CSPG staining was more prominent and confined largely to the extracellular matrix and basal lamina of proliferating Schwann cells. Our study suggests that Schwann cells, which may have been displaced from spinal roots and introduced into the injured cord through a break in the pial surface, are capable of proliferating and producing CSPG, particularly in the setting of reduced gliosis. Since CSPG has been associated with inhibition of neurite outgrowth, its increased production by aberrant Schwann cells may impair spinal cord regeneration after injury.

Journal of Neurotrauma, 2003

Cardiovascular dysfunction is common after cervical spinal cord injury (SCI) in humans. At least ... more Cardiovascular dysfunction is common after cervical spinal cord injury (SCI) in humans. At least three spinal cord elements involved in cardiovascular control have been identified: descending vasomotor pathways (DVPs), sympathetic preganglionic neurons, and spinal afferents. However, little is known about the localization of the DVPs within the human spinal cord, which limits our understanding of the mechanisms of cardiovascular dysfunction after SCI. This study was undertaken to examine the association of cardiovascular abnormalities after SCI in humans with the severity of degeneration and axonal loss within the DVPs. A detailed chart review and histopathological examination of postmortem spinal cord tissue was conducted in individuals with cervical SCI (n = 7) and control individuals with an intact central nervous system (n = 5). Individuals with SCI were divided into group 1 (severe cardiovascular abnormalities) and group 2 (no/minor cardiovascular disturbances). The area of degeneration and the number of preserved axons within different areas of the spinal cord were quantitated using EMPIX imaging software. Two areas of possible localization of DVPs were investigated: area I, within the dorsal aspects of the lateral funiculus; and area II, within the white matter adjacent to the dorsolateral aspect of the lateral horn. Comparison of the extent of axonal degeneration in both SCI groups demonstrated that individuals in group 1 had more extensive axonal degeneration than those in group 2. The number of intact axons within areas I and II in individuals from group 1 was significantly lower than those from group 2 or control cases (p = 0.029; p = 0.028). The most dramatic axonal loss was observed within area I in individuals with cardiovascular dysfunction. We conclude that loss and degeneration of DVPs, which are localized within the dorsolateral aspects of the human spinal cord, contributes to abnormal cardiovascular control after SCI. This information adds to our knowledge of pathobiology of cardiovascular dysfunction after human SCI and may ultimately suggest novel therapeutic strategies as regenerative and reparative approaches become translated to the clinic.

Journal of Neuropathology and Experimental Neurology, 1984

Journal of Neurochemistry, 2011

Brain Research, 1979

The distribution of glutamine synthetase was determined in rat brain by ultrastructural immunocyt... more The distribution of glutamine synthetase was determined in rat brain by ultrastructural immunocytochemistry. Except for trace amounts in a rare indeterminate glial cell, all the reaction product was located in astrocytes. Specifically, none was observed in neurons, synaptic endings, oligodendrocytes, microglial cells, pericytes, endothelial cells and other mesenchymal vascular elements. The results of this study clearly indicate that the astrocyte forms the compartment in brain concerned with glutamine synthesis, thereby assigning a key role to the astrocyte in the metabolism of ammonia and the putative neurotransmitters, glutamic acid and gamma-aminobutyric acid. The localization of glutamine synthetase in astrocytes additionally provides a valuable marker for a number of neurobiological studies.