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Biomedical subjects

B J Snider

Publications and source records attributed to B J Snider.

11 recordsLinked to original sources
PubMed2001

Cycloheximide reduces infarct volume when administered up to 6 h after mild focal ischemia in rats.

We have previously described a rodent model of brief (30 min) middle cerebral artery occlusion followed by reperfusion, in which infarction develops gradually, reaching completion more than 3 days after ischemia, accompanied by morphological, biochemical, and pharmacological evidence of apoptosis. In the present study, we tested the hypotheses that delayed administration of a protein synthesis inhibitor would be effective in reducing tissue injury in this slowly evolving ischemic infarction, and that efficacy of this treatment would wane with more prolonged ischemia. Focal cerebral ischemia was induced in Long-Evans rats by occlusion of the right middle cerebral artery. Infarction volume was analyzed using triphenyl tetrazolium chloride staining, and morphology was studied using hematoxylin and eosin stained sections. Following 30 min middle cerebral artery occlusion and reperfusion, the core ischemic region exhibited vacuolization in the neuropil by 36 h after ischemia, and infarction reached full size by 7 days after ischemia. Cycloheximide reduced infarct volume when given up to 6 h after ischemia. If the duration of ischemic insult was increased to 90 min, the therapeutic window for delayed cycloheximide was only 30 min. In permanent middle cerebral artery occlusion, cycloheximide was ineffective even when given prior to ischemia onset. After mild, but not severe, ischemic insults, cerebral infarction develops slowly and may be treatable with protein synthesis inhibitors, even when treatment is delayed for up to 6 h after the onset of ischemia.

Animals↗
PubMed2001

Extracellular apparent diffusion in rat brain.

The apparent diffusion coefficients (ADCs) of a series of markers concentrated in the extracellular space of normal rat brain were measured to evaluate, by inference, the ADC of water in the extracellular space. The markers (mannitol, phenylphosphonate, and polyethylene glycols) are defined as "compartment selective" because tissue culture experiments demonstrate some leakage into the intracellular space, making them less "compartment specific" than commonly believed. These primarily extracellular markers have ADCs similar to those of intracellular metabolites of comparable hydrodynamic radius, suggesting that water ADC values in the intra- and extracellular spaces are similar. If this is the case, then it is unlikely that a net shift of water from the extra- to the intracellular space contributes significantly to the reduction in water ADC detected following brain injury. Rather, this reduction is more likely due primarily to a reduction of the ADC of intracellular water associated with injury.

Analysis of Variance↗
PubMed2000

Nitric oxide reduces Ca(2+) and Zn(2+) influx through voltage-gated Ca(2+) channels and reduces Zn(2+) neurotoxicity.

The translocation of synaptic Zn(2+) from nerve terminals into selectively vulnerable neurons may contribute to the death of these neurons after global ischemia. We hypothesized that cellular Zn(2+) overload might be lethal for reasons similar to cellular Ca(2+) overload and tested the hypothesis that Zn(2+) neurotoxicity might be mediated by the activation of nitric oxide synthase. Although Zn(2+) (30-300microM) altered nitric oxide synthase activity in cerebellar extracts in solution, it did not affect nitric oxide synthase activity in cultured murine neocortical neurons. Cultured neurons exposed to 300-500microM Zn(2+) for 5min under depolarizing conditions developed widespread degeneration over the next 24h that was unaffected by the concurrent addition of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine. Furthermore, Zn(2+) neurotoxicity was attenuated when nitric oxide synthase activity in the cultures was induced by exposure to cytokines, exogenous nitric oxide was added or nitric oxide production was pharmacologically enhanced. The unexpected protective effect of nitric oxide against Zn(2+) toxicity may be explained, at least in part, by reduction of toxic Zn(2+) entry. Exposure to nitric oxide donors reduced Ba(2+) current through high-voltage activated calcium channels, as well as K(+)-stimulated neuronal uptake of 45Ca(2+) or 65Zn(2+). The oxidizing agents thimerosal and 2,2'-dithiodipyridine also reduced K(+)-stimulated cellular 45Ca(2+) uptake, while akylation of thiols by pretreatment with N-ethylmaleimide blocked the reduction of 45Ca(2+) uptake by a nitric oxide donor.The results suggest that Zn(2+)-induced neuronal death is not mediated by the activation of nitric oxide synthase; rather, available nitric oxide may attenuate Zn(2+) neurotoxicity by reducing Zn(2+) entry through voltage-gated Ca(2+) channels, perhaps by oxidizing key thiol groups.

Animals↗
PubMed1999

Apoptosis and necrosis in cerebrovascular disease.

Neuronal death following ischemic insults has been thought to reflect necrosis. However, recent evidence from several labs suggests that programmed cell death, leading to apoptosis, might additionally contribute to this death. We have used both in vitro and in vivo models to study the role of apoptosis in ischemic cell death. Some features of apoptosis (TUNEL staining, internucleosomal DNA fragmentation, sensitivity to cycloheximide) were observed following transient focal ischemia in rats. Brief transient focal ischemia was followed by delayed infarction more than 3 days later; this delayed infarction was sensitive to cycloheximide. A cycloheximide-sensitive component of neuronal cell death was also observed in cultured murine neocortical neurons deprived of oxygen-glucose in the presence of glutamate receptor antagonists. This presumed ischemic apoptosis was attenuated by caspase inhibitors, or by homozygous deletion of the bax gene. Neurons may undergo both apoptosis and necrosis after ischemic insults, and thus it may be therapeutically desirable to block both processes.

Animals↗
PubMed1998

Conditioning heat stress reduces excitotoxic and apoptotic components of oxygen-glucose deprivation-induced neuronal death in vitro.

We investigated the effects of sublethal heat stress in murine cortical cell cultures exposed to combined oxygen and glucose deprivation. Pretreatment with sublethal heat stress mildly attenuated the widespread neuronal death induced a day later by 30-60 min of oxygen-glucose deprivation. Heat stress also blunted the increase in extracellular glutamate concentrations induced by the oxygen-glucose deprivation, as well as the neuronal death and 45Ca2+ uptake induced by exogenous addition of NMDA, although no reduction was seen in neuronal death caused by exogenous kainate or in NMDA-induced whole-cell currents. However, arguing against the idea that the neuroprotective effect of heat stress against neuronal death was exclusively due to reduction of excitotoxicity was the finding that heat stress also reduced the neuronal apoptosis induced by oxygen-glucose deprivation in the presence of glutamate antagonists. This antiapoptotic effect was specific in that heat stress did not reduce neuronal vulnerability to staurosporine-induced apoptosis. Whereas heat stress transiently suppressed protein synthesis, achieving comparable protein synthesis inhibition with cycloheximide did not reproduce the neuroprotective effects of heat stress. These studies suggest that a conditioning heat stress is able to attenuate both the excitotoxic and the apoptotic components of oxygen-glucose deprivation-induced neuronal death in vitro, by mechanisms independent of protein synthesis reduction.

Animals↗
PubMed1996

Heat stress reduces glutamate toxicity in cultured neurons without hsp70 expression.

Consistent with known cytoprotective effects, mild heat stress reduced the vulnerability of cultured cortical neurons to glutamate-induced cell death. However, this neuroprotective effect occurred without expression of the inducible heat stress protein, hsp70, as detected by immunocytochemistry, immunoblotting, or metabolic labeling. Present data suggest that the anti-excitotoxic effect of mild heat stress is mediated outside of the traditional hsp70 mechanism.

Animals↗
PubMed1984

The interactions of hydrazine derivatives with rat-hepatic cytochrome P-450.

The ability of different classes of hydrazine derivatives to modify cytochrome P-450 function during turnover as judged by loss of absorbance at 416 nm, loss of CO-reactive cytochrome P-450, or destruction of haem has been studied. Addition of monosubstituted hydrazines to rat-liver microsomes caused considerable loss of CO-reactive cytochrome P-450 and haem destruction; monosubstituted hydrazides caused mainly loss of CO-reactive cytochrome P-450, most likely due to abortive complex formation. Metabolism of 1,1-disubstituted hydrazines by microsomal cytochrome P-450 resulted in loss of CO-reactive cytochrome P-450 only, with no haem destruction. The 1,2-disubstituted hydrazines and hydrazides, procarbazine and iproniazid, acted similarly to the monosubstituted hydrazines, while 1,2-dimethylhydrazine elicited no response, either in observable spectral changes or loss of CO-reactive cytochrome P-450. Synthetic diazene intermediates of phenylhydrazine and N-aminopiperidine reacted rapidly with microsomal cytochrome P-450 to form a spectral intermediate resembling the putative iron porphyrin-diazenyl complex. The decomposition of certain iron porphyrin-diazenyl derivatives apparently leads to destruction of the porphyrin prosthetic group, most likely due to haem alkylation.

Animals↗
PubMed1983

Inhibition of lipid peroxidation in spinal cord homogenates by various drugs.

The extent and kinetic profiles of lipid peroxidation induced with Fe2+-ascorbic acid in a homogenate of spinal cord from greyhound dogs were ascertained by measurement of the formation of malondialdehyde (MDA) and chemiluminescence in the presence of four drugs. Changes in MDA and chemiluminescence were correlated as a function of the activator or inhibitors. The kinetic profiles of chemiluminescence which were observed for 25 min after addition of the activator and individual inhibitors were similar regardless of the type of inhibitor studied. The most effective inhibition was by disulfiram which was approximately 11 and 33 times more effective than two other inhibitors, propyl gallate and promethazine, respectively, and 11,000 times more effective than D-alpha-tocopherol.

Animals↗
PubMed1982

Normalization of cerebellar RNA synthesis and mRNA levels after treatment of graft versus host disease.

We have previously shown that neonatal rats with graft versus host disease (GVHD) (1) synthesize significantly less cerebellar RNA, (2) have RNA that is less translationally active, and (3) have changes in the relative abundance of certain mRNAs, including the induction of one coding for protein r that is present neither in control cerebellum nor in other brain regions at any age. Here we report on the ability of the cerebellum to recover from GVHD-induced changes in the synthesis of total RNA and in the relative levels of specific mRNAs. In order to halt the disease, 11-day-old diseased Fischer animals were injected with hyperimmune alloantiserum daily for 3 days. Cytoplasmic RNAs were isolated from the cerebella of 14-day-old serum-treated animals, their diseased littermates that were not treated with serum, and littermate controls. Comparison, by two-dimensional gel analysis, of the in vitro synthesized mRNA translation products showed that most GVHD-induced alterations in the levels of specific mRNAs were not present in serum-treated animals. In particular, protein r was not synthesized by cerebellar RNAs isolated from serum-treated animals. These results show that the adverse effects of this disease are reversible at the molecular level.

Animals↗
PubMedDate not supplied

Brain non-adenylated mRNAs.

Most eukaryotic messenger RNA (mRNA) species contain a 3'-poly(A) tract. The histone mRNAs are a notable exception although a subclass of histone-encoding mRNAs is polyadenylated. A class of mRNAs lacking a poly(A) tail would be expected to be less stable than poly(A)+ mRNAs and might, like the histones, have a half-life that varied in response to changes in the intracellular milieu. Brain mRNA exhibits an unusually high degree of sequence complexity; studies published ten years ago suggested that a large component of this complexity might be present in a poly(A)- mRNA population that was expressed postnatally. The question of the existence of a complex class of poly(A)- brain mRNAs is particularly tantalizing in light of the heterogeneity of brain cells and the possibility that the stability of these poly(A)- mRNAs might vary with changes in synaptic function, changing hormonal stimulation or with other modulations of neuronal function. The mRNA complexity analyses, although intriguing, did not prove the existence of the complex class of poly(A)- brain mRNAs. The observed mRNA complexity could have resulted from a variety of artifacts, discussed in more detail below. Several attempts have been made to clone members of this class of mRNA. This search for specific poly(A)- brain mRNAs has met with only limited success. Changes in mRNA polyadenylation state do occur in brain in response to specific physiologic stimuli; however, both the role of polyadenylation and de-adenylation in specific neuronal activities and the existence and significance of poly(A)- mRNAs in brain remain unclear.

Animals↗