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PubMedDate not supplied

The release and uptake of excitatory amino acids in rat brain: effect of aging and oxidative stress.

The excitatory amino acids (EAAs) L-aspartate and L-glutamate constitute the major neurotransmitters in the mammalian brain. This study established the influence of aging and oxidative stress on the release and uptake of EAAs. The high affinity uptake of D-[3H]aspartate in synaptosomal fractions of the neostriatum, hippocampus, and neocortex was not significantly different in Fisher 344/Norwegian Brown hybrid rats aged 3, 12, 24, and 37 months. Similarly, the K(+)-evoked efflux of endogenous aspartate and glutamate from neocortical minislices was also unaffected by age. To examine the possibility that EAA nerve terminals become more vulnerable to oxidative stress with age, the influence of an inhibitor of the electron transport chain (sodium cyanide) on EAA uptake and release was determined. Although cyanide inhibited D-[3H]aspartate uptake and potentiated the potassium-evoked efflux of aspartate and glutamate in a Ca(2+)-independent fashion, neither of these changes were influenced by age. Thus, the functional integrity of EAA nerve terminals and their vulnerability to oxidative stress are both preserved in normal aging. The potency of cyanide to inhibit D-[3H]aspartate uptake did, however, display regional variability: hippocampus > neocortex > neostriatum (IC50 = 1.2 +/- 0.2 mM, 1.9 +/- 0.1 mM and 2.7 +/- 0.2 mM, respectively), suggesting that EAA nerve terminals in the hippocampus may be selectively vulnerable to oxidative stress.

Aging↗

PubMed1984

Kainate-glutamate interactions in rat cerebellar slices.

The effects of L-glutamate on the potency of kainate for stimulating guanosine 3',5'-cyclic monophosphate (cyclic GMP) accumulation and for killing neurones in incubated slices of immature (8-day) and adult rat cerebellum were investigated. L-glutamate did not potentiate the cyclic GMP responses to kainate in either the adult or the immature tissue (in contrast to a recent report), nor did it alter the pharmacological characteristics of this postsynaptic action of kainate in the immature cerebellum. Slices incubated for 2 h in the presence of L-glutamate displayed pronounced glial swelling and neuronal damage. These effects were concentration-dependent and neurones in the immature cerebellum proved to be about 10 times more susceptible than in the adult. None of the neuronal cell types appeared to be selectively vulnerable to the toxicity of glutamate. At the lower concentrations tested (300 microM in the immature tissue, 3 mM in the adult), neurotoxicity was largely restricted to regions near the cut edges of the slices, indicating that very effective mechanisms limit the diffusion of glutamate within the cerebellum. Kainate caused selective necrosis of Purkinje cells and inhibitory interneurones in slices of adult cerebellum at concentrations between 5 and 20 microM; 30 microM kainate, however, also affected granule cells. The neurotoxic potency of kainate towards all neuronal cell types was significantly lower in the immature cerebellum and was not enhanced by including glutamate in the incubation medium. Similarly, glutamate did not potentiate the neurotoxicity of kainate towards Purkinje cells and inhibitory interneurones or or towards granule cells in adult slices. It is concluded that the availability of glutamate is unlikely to be a factor which limits the neurotoxicity of kainate either in the immature or in the adult cerebellum. The increase in the neurotoxic potency of kainate with cerebellar maturation can be ascribed, more readily, to be developmentally-related appearance of kainate receptors.

Aging↗

PubMed1999

Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal.

Features that distinguish tumor vasculatures from normal blood vessels are sought to enable the destruction of preformed tumor vessels. We show that blood vessels in both a xenografted tumor and primary human tumors contain a sizable fraction of immature blood vessels that have not yet recruited periendothelial cells. These immature vessels are selectively obliterated as a consequence of vascular endothelial growth factor (VEGF) withdrawal. In a xenografted glioma, the selective vulnerability of immature vessels to VEGF loss was demonstrated by downregulating VEGF transgene expression using a tetracycline-regulated expression system. In human prostate cancer, the constitutive production of VEGF by the glandular epithelium was suppressed as a consequence of androgen-ablation therapy. VEGF loss led, in turn, to selective apoptosis of endothelial cells in vessels devoid of periendothelial cells. These results suggest that the unique dependence on VEGF of blood vessels lacking periendothelial cells can be exploited to reduce an existing tumor vasculature.

Androgens↗

PubMed1984

Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain.

In rats ischemia of the forebrain induced by a 30-minute occlusion of the carotid artery, followed by 120 minutes of arterial reperfusion, produced ischemic lesions of selectively vulnerable pyramidal cells in both hippocampi. Focal microinfusion into the dorsal hippocampus of 2-amino-7-phosphonoheptanoic acid, an antagonist of excitation at the N-methyl-D-aspartate-preferring receptor, before ischemia was induced protected against the development of ischemic damage. It is proposed that excitatory neurotransmission plays an important role in selective neuronal loss due to cerebral ischemia.

2-Amino-5-phosphonovalerate↗

PubMed1996

Neuronal lesions and behavioral modifications in rat following cerebral ischemia and reperfusion.

Neurons of the mammalian CNS differ in their vulnerability to various disease processes and other insults, particularly in their response to total anoxia/ischemia. In this study we have tested the histological and behavioral modifications induced by experimental conditions of partial cerebral ischemia in the rats. The specific morphological and histological alterations, observed in our experimental conditions of reversible partial cerebral ischemia, confirm the selective vulnerability of certain neuronal populations to ischemic injury and are also evidenced by behavioral modifications which may mirror the functional impairment observed in humans after a transitory ischemic attack.

Animals↗

PubMed2006

Vulnerability of cortical neurons to Alzheimer's and Parkinson's diseases.

Alzheimer's disease (AD) and sporadic Parkinson's disease (PD) are the most frequently occurring degenerative illnesses of the human nervous system. Both involve multiple neuronal systems, but only a few types of nerve cells are prone to develop the disease-associated intraneuronal alterations. In AD affected neurons produce neurofibrillary tangles and neuropil threads, while in PD they develop Lewy bodies and Lewy neurites. In both illnesses select types of projection cells that generate long, unmyelinated or sparsely myelinated axons are particularly susceptible. This kind of selective vulnerability induces a distinctive lesional pattern which evolves slowly over time and remains remarkably consistent across cases. In the present review, lesions developing in the cerebral cortex are described against the backdrop of the internal organisation and interconnectivities linking involved cortical areas and subcortical nuclei. In AD, six and in PD, three stages can be distinguished, reflecting the predictable manner in which the proteinaceous intraneuronal inclusions spread through the cerebral cortex. In AD stages I-II and in PD stage 4, the pathological process makes inroads into the anteromedial temporal mesocortex, entorhinal allocortex, and Ammon's horn; thereafter, in AD stages III-IV and in PD stage 5, it proceeds into the adjoining high order association areas of the basal temporal neocortex. In AD stages V-VI and in PD stage 6, the damage affects additional neocortical association areas including first order association areas and eventually extends into the primary areas of the neocortex. The gradually evolving lesional pattern in AD and PD mirrors the ground plan of the cerebral cortex. The highest densities of lesions occur in the anterior mesocortical transitional zone between allo- and neocortex. From there, the involvement diminishes by degrees and extends into both the hippocampal formation and the neocortex. The severity of the neocortical lesions decreases in inverse proportion to the trajectories of increasing cortical differentiation and hierarchical refinement.

Aged↗

PubMed1995

Regional alterations of thiamine phosphate esters and of thiamine diphosphate-dependent enzymes in relation to function in experimental Wernicke's encephalopathy.

Thiamine phosphate esters (thiamine monophosphate-TMP; thiamine diphosphate-TDP and thiamine triphosphate-TTP) were measured as their thiochrome derivatives by High Performance Liquid Chromatography in the brains of pyrithiamine-treated rats at various stages during the development of thiamine deficiency encephalopathy. Severe encephalopathy was accompanied by significant reductions of all three thiamine phosphate esters in brain. Neurological symptoms of thiamine deficiency appeared when brain levels of TMP and TDP fell below 15% of normal values. Activities of the TDP-dependent enzyme alpha-ketoglutarate dehydrogenase were more severely reduced in thalamus compared to cerebral cortex, a less vulnerable brain structure. On the other hand, reductions of TTP, the non-cofactor form of thiamine, occurred to a greater extent in cerebral cortex than thalamus. Early reductions of TDP-dependent enzymes and the ensuing metabolic pertubations such as lactic acidosis impaired brain energy metabolism, and NMDA-receptor mediated excitotoxicity offer rational explanations for the selective vulnerability of brain structures such as thalamus to the deleterious effects of thiamine deficiency.

Animals↗

PubMed1993

Casein kinase II activity in the postischemic rat brain increases in brain regions resistant to ischemia and decreases in vulnerable areas.

Casein kinase II (CKII) is a protein kinase acting in the intracellular cascade of reactions activated by growth factor receptors, and that has a profound influence on cell proliferation and survival. In this investigation, we studied the changes in the activity and levels of CKII in the rat brain exposed to 10, 15 and 20 min of transient forebrain ischemia followed by variable periods of reperfusion. The cytosolic CKII activity decreased during reperfusion by approximately 30 and approximately 50% in the selectively vulnerable areas, striatum and the CA1 region of the hippocampus, respectively. In the resistant CA3 region of hippocampus and neocortex, the activity increased by approximately 20 and approximately 60%, respectively. The postischemic changes in CKII activity were dependent on the duration of the ischemic insult. The levels of CKII did not change after ischemia, suggesting that the enzyme is modulated by covalent modification or is interacting with an endogenous inhibitor/activator. Treatment of the cytosolic fraction from cortex of rats exposed to ischemia and 1 h of reperfusion with agarose-bound phosphatase decreased the activity of CKII to control levels, suggesting that CKII activation after ischemia involves a phosphorylation of the enzyme. The correlation between postischemic CKII activity and neuronal survival implies that preservation or activation of CKII activity may be important for neuronal survival after cerebral ischemia.

Alkaline Phosphatase↗

PubMed2000

Traumatic brain injury alters the molecular fingerprint of TUNEL-positive cortical neurons In vivo: A single-cell analysis.

The cerebral cortex is selectively vulnerable to cell death after traumatic brain injury (TBI). We hypothesized that the ratio of mRNAs encoding proteins important for cell survival and/or cell death is altered in individual damaged neurons after injury that may contribute to the cell's fate. To investigate this possibility, we used amplified antisense mRNA (aRNA) amplification to examine the relative abundance of 31 selected candidate mRNAs in individual cortical neurons with fragmented DNA at 12 or 24 hr after lateral fluid percussion brain injury in anesthetized rats. Only pyramidal neurons characterized by nuclear terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end labeling (TUNEL) reactivity with little cytoplasmic staining were analyzed. For controls, non-TUNEL-positive neurons from the cortex of sham-injured animals were obtained and subjected to aRNA amplification. At 12 hr after injury, injured neurons exhibited a decrease in the relative abundance of specific mRNAs including those encoding for endogenous neuroprotective proteins. By 24 hr after injury, many of the mRNAs altered at 12 hr after injury had returned to baseline (sham-injured) levels except for increases in caspase-2 and bax mRNAs. These data suggest that TBI induces a temporal and selective alteration in the gene expression profiles or "molecular fingerprints" of TUNEL-positive neurons in the cerebral cortex. These patterns of gene expression may provide information about the molecular basis of cell death in this region after TBI and may suggest multiple avenues for therapeutic intervention.

Animals↗

PubMed2006

Targeting the alpha 7 nicotinic acetylcholine receptor to reduce amyloid accumulation in Alzheimer's disease pyramidal neurons.

Although there is still no known effective preventative treatment or cure for Alzheimer's disease (AD), the development of new drugs that target pathological features that appear early in the course of this disease and alleviate some of the early cognitive and memory symptoms is a laudable goal that may be one step closer. To date, the acetylcholinesterase inhibitors have been the most widely used AD drugs and have been somewhat successful in slowing loss of cognition. In the last few years, a number of studies have demonstrated that amyloid beta (1-42) (Abeta42), the predominant Abeta peptide species in amyloid plaques, first accumulates in vulnerable neurons prior to plaque formation. Recently, we have shown that many (if not most) amyloid plaques in the entorhinal cortex of AD brains are actually the lysis remnants of degenerated, Abeta42-overburdened neurons. Furthermore, the most vulnerable neurons appear to be those that abundantly express the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), and internalization of Abeta42 appears to be facilitated by the high-affinity binding of Abeta42 to the alpha7nAChR on neuronal cell surfaces, followed by endocytosis of the resulting complex and its accumulation within the lysosomal compartment. This mechanism provides a reasonable explanation for the selective vulnerability of cholinergic and cholinoceptive neurons in AD brains and for the fact that Abeta42 is the dominant Abeta peptide species in both intraneuronal accumulations and amyloid plaques. In view of the pathophysiological consequences of Abeta42 binding to alpha7nAChR on neuronal surfaces that stem from excessive intraneuronal Abeta42 accumulation, the alpha7nAChR could be an important therapeutic target for treatment of AD. In addition, it further emphasizes the potential merits of new and effective therapeutic strategies pointed towards the goal of lowering of Abeta42 levels in the blood and cerebrospinal fluid as well as blocking Abeta42 in the blood from penetrating the blood-brain barrier and entering into the brain parenchyma.

Alzheimer Disease↗

PubMed1993

The role of signal transduction in the delayed necrosis of the hippocampal CA1 pyramidal cells following transient ischemia.

A short period of cerebral ischemia leads to necrosis of the hippocampal CA1 pyramidal cells. Until recently no mechanisms contributing to this selective vulnerability were known. During the last decade an increasing amount of research has been concentrated on identifying signs of disturbed signal transduction in these neurons after ischemia. The present thesis is a review of these studies with some emphasis on my own contributions to the field. Gerbil and rat models of transient global ischemia are the most frequently employed. In order to produce the selective necrosis the main arteries to the brain are occluded for 5-20 minutes. In the rat it is often also necessary to lower the blood pressure. It takes 2-7 days of recirculation before the CA1 pyramidal cells become necrotic. The studies show that the necrosis can be attenuated or aggravated by drugs acting as inhibitors or enhancers of signal transduction--also if administered shortly after ischemia. The necrosis can be similarly influenced by lesions of excitatory or inhibitory afferent neurons. The protective effect of the lesion however, can be due to the lesion-induced decrease in metabolism. During ischemia there is an increase in the extracellular concentration of several excitatory and inhibitory neurotransmitters as well as in intracellular second messengers. Some of the latter also show an increase during recirculation. In vitro autoradiographic studies of receptor proteins show either unchanged or diffusely distributed downregulation of the ligand binding to the various extra- and intracellular receptor proteins following ischemia and early recirculation. A second decrease is seen in the CA1 at the time of and probably secondary to the necrosis. The IP3 receptor decrease appears during the first minutes of recirculation and lasts for up to 14 days. The protective lesion of the excitatory afferents from CA3 also leads to a decrease in IP3 binding. The changes in receptor regulation are not accompanied by increased postischemic electrophysiological activity in the CA1. In vivo autoradiographic mapping of the regional cerebral metabolic rate of glucose show increased metabolism in the CA1 during the first hour of recirculation compared to the rest of the brain were it is depressed. This relative hypermetabolism is not seen if the CA1 has been deprived of its primary source of excitatory afferents. A later secondary increase seen in the more or less necrotic CA1 pyramidal cell layer is probably due to macrophage activity. In situ hybridization and immunohistochemical studies on the expression of c-fos mRNA and protein respectively has been used to depict neurons with increased activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2026

Single-cell transcriptomic atlas of Alzheimer's disease middle temporal gyrus reveals region, cell type, and sex specificity of gene expression with novel genetic risk for MERTK in female.

BackgroundAlzheimer's disease (AD), the most common age-related neurodegenerative disease, is closely associated with both amyloid-β plaque and neuroinflammation. Two thirds of AD patients are female, and they have a higher disease risk; women with AD have more extensive brain histological changes than men along with more severe cognitive symptoms and neurodegeneration.ObjectiveThis study aimed to determine how sex difference induces structural brain changes and molecular cell vulnerabilities in AD, with a focus on identifying sex-specific transcriptional alterations and genetic risk factors.MethodsWe performed single nucleus RNA sequencing on postmortem brains from individuals with AD and age- and sex-matched controls, focusing on the middle temporal gyrus, a cortical brain region strongly affected by the disease, and integrated single nucleus RNA sequencing results with genome-wide association study (GWAS) data using cell type-specific enrichment and generalized gene-set analysis approaches. The analysis pipeline is provided with threshold information.ResultsWe identified a selectively vulnerable subpopulation of layer 2/3 excitatory neurons that were RORB-negative and CDH9-expressing in both males and females. Disease-associated, but sex-independent, reactive astrocyte signatures were also present. In clear contrast, the microglia signatures of AD brains differed between males and females. Integrating single cell transcriptomic data with results from GWAS, we identified MERTK genetic variation as a candidate novel risk factor for AD selectively in females.ConclusionsTaken together, our single cell atlas of middle temporal gyrus revealed a unique cellular-level view of sex-specific transcriptional changes in AD, illuminating GWAS identification of sex-specific AD genes. These data serve as a rich resource for interrogation of the molecular and cellular basis of AD.

Alzheimer's disease↗

PubMed2002

Gene expression profiles of cholinergic nucleus basalis neurons in Alzheimer's disease.

Cholinergic neurons of the nucleus basalis (NB) are selectively vulnerable in Alzheimer's disease (AD), yet the molecular mechanisms associated with their dysfunction remain unknown. We used single cell RNA amplification and custom array technology to examine the expression of functional classes of mRNAs found in anterior NB neurons from normal aged and AD subjects. mRNAs encoding neurotrophin receptors, synaptic proteins, protein phosphatases, and amyloid-related proteins were evaluated. We found that trkB and trkC mRNAs were selectively down-regulated in NB neurons, whereas p75NTR mRNA levels remained stable in end stage AD. TrkA mRNA was reduced by approximately 28%, but did not reach statistical significance. There was a down-regulation of synaptophysin, synaptotagmin, and protein phosphatases PP1alpha and PP1beta mRNAs in AD. In contrast, we found a selective up-regulation of cathepsin D mRNA in NB neurons in AD brain. Thus, anterior NB neurons undergo selective alterations in gene expression in AD. These results may provide clues to the molecular pathogenesis of NB neuronal degeneration during AD.

Aged↗

PubMed2001

High abundance of GluR1 mRNA and reduced Q/R editing of GluR2 mRNA in individual NADPH-diaphorase neurons.

Striatal and cortical neurons containing NADPH-diaphorase [NADPH-d(+)] are highly vulnerable to excitotoxicity that is induced by activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)- or kainate-sensitive glutamate receptors. This has been attributed to Ca2+ entry through AMPA/kainate receptors in NADPH-d(+) neurons. In this study, we applied single cell RT-PCR technique to test the hypothesis that differences in levels and processing of the GluR2 subunit would contribute to the selective vulnerability of NADPH-d(+) neurons to AMPA. The nested PCR specific for GluR1-GluR4 showed that rat striatal NADPH-d(+) neurons expressed twice as much GluR1 mRNA as NADPH-d(-) neurons did. The percentage of RNA editing at the Q/R site of GluR2 was 46% in NADPH-d(+) neurons and 92% in NADPH-d(-) neurons. These results suggest that the unedited expression of GluR2 and the reduced ratio of GluR2/GluR1 render NADPH-d(+) neurons highly sensitive to Ca2+-mediated AMPA neurotoxicity. In support of this, most NADPH-d(+) neurons exposed to 100 microM AMPA showed Co2+ uptake and survived AMPA challenge only in the absence of extracellular Ca2+.

Animals↗

PubMed1988

Evidence for dual serotonergic projections to neocortex: axons from the dorsal and median raphe nuclei are differentially vulnerable to the neurotoxin p-chloroamphetamine (PCA).

Previous studies have shown that there are morphologically dissimilar serotonergic (5-HT) axon types in rat cerebral cortex which are differentially sensitive to the neurotoxic effects of certain psychotropic drugs: methylenedioxyamphetamines (MDA and MDMA) and p-chloroamphetamine (PCA) cause degeneration of fine 5-HT axon terminals in cortex, while sparing beaded axons. Moreover, a recent anterograde transport study suggests that fine and beaded 5-HT axons arise from the dorsal raphe (DR) and median raphe (MR) nuclei, respectively. These data led us to propose that the DR projection to neocortex is selectively vulnerable to the neurotoxic effects of PCA, while the MR projection is resistant; this hypothesis was tested in the present study by comparing retrograde axonal transport of the fluorescent tracer Fluoro-Gold in PCA-treated and control rats. Using this method, only axons that survive PCA treatment can take up and transport the injected label back to the cell bodies of origin, thus allowing us to determine which raphe-cortical projections remain intact after PCA. The results show that PCA administration produces a loss of fine 5-HT axon terminals in neocortex and a concomitant reduction in the number of retrogradely labeled neurons in the DR (77% decrease), when compared to controls. In contrast, beaded 5-HT axon terminals are spared and the number of labeled neurons in the MR remains unchanged after PCA. These results demonstrate that DR and MR projections to cortex are differentially vulnerable to PCA: fine axon terminals arise from neurons in the DR and are highly sensitive to the neurotoxic effects, whereas beaded axons from the MR are resistant. We therefore propose that there are two anatomically and functionally separate 5-HT projections to cortex having different (1) nuclei of origin, (2) axon morphology, (3) regional distributions, and (4) pharmacological properties. Since the mood-altering substances MDA, MDMA, and PCA act specifically upon 5-HT axon terminals from the dorsal raphe nucleus, DR neurons may be preferentially involved in the control of affective state.

Amphetamines↗

PubMed1994

Cortical neurones with Ca2+ permeable AMPA/kainate channels display distinct receptor immunoreactivity and are GABAergic.

A minority subset of cortical neurones exhibit kainate-activated Co2+ uptake, a marker for AMPA/kainate receptor gated Ca2+-permeable channels. Consistent with enhanced Ca2+ influx through these channels, Co2+-positive neurones are unusually vulnerable to death induced by exposure to either AMPA or kainate. Here we show that Co2+-positive cortical neurones express a distinctive profile of AMPA receptor subunits as determined by immunostaining. Co2+-positive neurones were much less likely to express GluR2/GluR3, and much more likely to express GluR1 or GluR4, than the general cortical neuronal population. Thus expression of AMPA receptors lacking the GluR2 subunit may explain the Co2+ staining, and selective vulnerability to kainate exhibited by Co2+-positive cells. Almost all GABAergic neurones, identified by immunostaining for glutamic acid decarboxylase, were Co2+-positive. The widespread presence of Ca2+-permeable AMPA/kainate receptor-gated channels on cortical GABAergic neurones may have important implications for the fate of cortical inhibition in disease states associated with the excitotoxic overstimulation of glutamate receptors.

Animals↗

PubMed2002

Parvalbumin-containing interneurons in rat hippocampus have an AMPA receptor profile suggestive of vulnerability to excitotoxicity.

alpha-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate excitatory neurotransmission in the central nervous system, and contain combinations of four subunits (GluR1-4). We developed a GluR3-specific monoclonal antibody and quantified the cellular distribution of GluR3 in rat hippocampus. GluR3 immunoreactivity was detected in all pyramidal neurons and most interneurons. In addition, we found a subset of parvalbumin (PV)-containing interneurons in the hippocampus and neocortex that was notable for its intense GluR3 immunoreactivity and lack of GluR2 immunoreactivity. Such an expression pattern of AMPA receptor subunits is likely to make these interneurons selectively vulnerable to excitotoxicity.

Animals↗

PubMed1986

Differential responsiveness of proximal tubule segments to metabolic inhibitors in the isolated perfused rat kidney.

Rat kidneys were perfused for 90 minutes with cyanide, rotenone, antimycin, 2-deoxyglucose, or combinations of rotenone or antimycin with 2-deoxyglucose in oxygenated Krebs-albumin medium. Following perfusion, proximal tubule injury was evaluated by light microscopy. The types of lesions seen were similar to those previously reported after hypoxic perfusion and included brush border clubbing/mitochondrial swelling in S1 and S2 and cytoplasmic edema or cell fragmentation in S3. This finding supports the contention that these lesions represent characteristic responses of these segment types and that the S3 response differs from that in S1 and S2. S1 appeared most vulnerable to low dose cyanide or inhibition of mitochondrial electron transport (rotenone, antimycin). Inhibition of glycolysis (2-deoxyglucose) only produced injury in S2 tubules. With high dose cyanide or a combination of 2-deoxyglucose with either rotenone or antimycin, there was diffuse proximal tubule damage. Thus S3 appeared more resistant than the convoluted tubular segments to both inhibition of glycolysis and to inhibition of mitochondrial electron transport. This finding stands in contrast to the selective vulnerability of the S3 segment in ischemic renal injury.

Animals↗