bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuronal Protein Kinase Signaling Cascades and Excitotoxic Cell Death
Authors: SKAPER STEPHEN D. , FACCI LAURA , STRIJBOS PAUL J.L.M.
Published: July 2010

Abstract: Perturbation of normal survival mechanisms may play a role in a large number of disease processes. Glutamate neurotoxicity, particularly when mediated by the N‐methyl‐d‐aspartate (NMDA) subtype of glutamate receptors, has been hypothesized to underlie several types of acute brain injury, including stroke. Several neurological insults linked to excessive release of glutamate and neuronal death result in tyrosine kinase activation, including p44/42 mitogen activated protein (MAP) kinase. To further explore a role for MAP kinase activation in excitotoxicity, we used a novel tissue culture model to induce neurotoxicity. Removal of the endogenous blockade by Mg2+ of the NMDA receptor in cultured hippocampal neurons triggers a self perpetuating cycle of excitotoxicity, which has relatively slow onset, and is critically dependent on NMDA receptors and activation of voltage gated Na+ channels. These injury conditions led to a rapid phosphorylation of p44/42 that was blocked by MAP kinase kinase (MEK) inhibitors. MEK inhibition was associated with protection against synaptically mediated excitotoxicity. Interestingly, hippocampal neurons preconditioned by a sublethal exposure to Mg2+‐free conditions were rendered resistant to injury induced by a subsequently longer exposure to this insult; the preconditioning effect was MAP kinase dependent. The MAP kinase signaling pathway can also promote polypeptide growth factor mediated neuronal survival. MAP kinase regulated pathways may act to promote survival or death, depending upon the cellular context in which they are activated.
Adenosine Extracellular Brain Concentrations and Role of A2AReceptors in Ischemia
Authors: PEDATA FELICITA , CORSI CLAUDIA , MELANI ALESSIA , BORDONI FRANCESCA , LATINI SERENA
Published: July 2010

Abstract:Various experimental approaches have been used to determine the concentration of adenosine in extracellular brain fluid. The cortical cup technique or the microdialysis technique, when adenosine concentrations are evaluated 24 hours after implantation of the microdialysis probe, are able to measure adenosine in the nM range under normoxic conditions and in the μM range under ischemia.In vitroestimation of adenosine show that it can reach 30 μM at the receptor level during ischemia, a concentration able to stimulate all adenosine receptor subtypes so far identified. Although the protective role of A1receptors in ischemia seems consistent, the protective role of A2Areceptors appears to be controversial. Both A2Aagonists and antagonists have been shown to be neuroprotective in variousin vivoischemia models. Although A2Aagonists may be protective, mainly through peripherally mediated effects, A2Aantagonists may be protective through local brain mediated effects. It is possible that A2Areceptors are tonically activated following a prolonged increase of adenosine concentration, such as occurs during ischemia. A2Areceptor activation desensitizes A1receptors and reduces A1mediated effects. Under these conditions A2Areceptor antagonists may be protective by potentiating all the neuroprotective A1mediated effects, including decreased neurotoxicity due to reduced ischemia induced glutamate outflow.
Neuroprotective Role of Neurophysiological Monitoring During Endovascular Procedures in the Spinal Cord
Authors: SALA FRANCESCO , NIIMI YASUNARI , BERENSTEIN ALEX , DELETIS VEDRAN
Published: July 2010

Abstract: The endovascular treatment of spinal vascular malformations places the spinal cord at risk for ischemia. When these procedures are performed using general anesthesia, the neurophysiological monitoring methods currently available provide the only means by which to assess the functional integrity of sensory and motor pathways. Neurophysiological monitoring allows a warning for the neuroradiologist of impending irreversible neurological damage so that action may be taken for the prompt restoration of adequate spinal cord perfusion. Muscle motor evoked potentials (mMEPs) better reflect spinal cord perfusion in the anterior spinal artery territory than do somatosensory evoked potentials (SEPs), although their use during spinal endovascular procedures remains anecdotal in the literature. In the study reported here we assessed: (1) the feasibility of intraoperative neurophysiological monitoring, (2) the role of provocative tests with Amytal and Xylocaine, and (3) the specific but complementary role played by SEPs and mMEPs, during endovascular embolization of spinal vascular malformations and tumors. The results suggest that: (1) neurophysiological monitoring is feasible during most endovascular procedures in the spine and spinal cord under general anesthesia, (2) provocative tests enhance the safety of the procedure, (3) mMEPs are more feasible than SEPs and more sensitive than SEPs to provocative tests. We strongly suggest the use of multimodal neurophysiological monitoring and provocative tests during the endovascular treatment of spinal and spinal cord vascular lesions.
The Action of Acetyl‐l‐Carnitine on the Neurotoxicity Evoked by Amyloid Fragments and Peroxide on Primary Rat Cortical Neurones
Authors: VIRMANI M.A. , CASO V. , SPADONI A. , ROSSI S. , RUSSO F. , GAETANI F.
Published: July 2010

Abstract: The amyloid β‐peptides have been implicated in the excitotoxic mechanism of neuronal injury in the pathogenesis of Alzheimer's disease. In this paper we examine the effect of different amyloid fragments (β A1–40, A1–28, and A25–35), as well as potential neuroprotective compounds on rat cortical neuron viability. Exposure of neurones to β A25–35 or A1–40 at concentrations as low as 1 μg/ml inhibited, significantly, the MTT response and this level of inhibition was similar after 24‐h or three‐day exposure. Furthermore, the level of inhibition was not affected by the presence or absence of 5% horse serum in the medium. Preexposure (10 min) of neurones to ALC at concentrations of 0.1, 1, 5, and 10 mM attenuated the inhibition of the MTT response caused by β A25–35 (50 μg/ml) in serum free medium for 24 h. The treatment of cells with vitamin E (100 μM), catalase (4 mg/ml), NGF (0.1 and 10 ng/ml), or cycloheximide (0.1 μg/ml) significantly restored the MTT response that was inhibited by β A25–35. The mechanism for the protective actions of these compounds against β A25–35 toxicity is not clear but may involve free radical scavenger action and preservation of energy production, although other mechanisms, especially for ALC, such as a direct effect on A‐β interaction with charged anionic phospholipids and/or stabilizing action on membranes, are also possible.
Post‐Stroke Dementia
Authors: ZHAO XILONG , YEH JAY Z. , NARAHASHI TOSHIO
Published: July 2010

Abstract: Nefiracetam is a new pyrrolidone nootropic drug that is being developed for clinical use in the treatment of post‐stroke vascular‐type and Alzheimer's‐type dementia. Among a few neuroreceptors that have been identified as potential targets of nootropics, neuronal nicotinic acetylcholine receptors (nnAChRs) are deemed the most important since they are related to learning, memory, and Alzheimer's disease dementia. We have recently found potent stimulating action of nefiracetam on nnAChRs. Rat cortical neurons in long‐term primary culture expressed nnAChRs. Whole‐cell patch clamp experiments revealed two types of currents induced by ACh, α‐bungarotoxin (α‐BuTX)‐sensitive, rapidly desensitizing, α7‐type currents and α‐BuTX‐insensitive, slowly desensitizing, α4β2‐type currents. Although α7‐type currents were only weakly inhibited by nefiracetam, α4β2‐type currents were potently and efficaciously potentiated by nefiracetam. Nefiracetam at 0.1 nM reversibly potentiated ACh‐induced currents to 200–300% of control. Very high concentrations (about 10 μM) also potentiated these currents, but to a lesser extent, indicative of the bell‐shaped dose‐response relationship known to occur for nefiracetam, even in animal behavior experiments. Three specific inhibitors of each of PKA and PKC did not prevent nefiracetam from potentiating ACh‐induced currents, indicating that these protein kinases are not involved in nefiracetam action. Pretreatment with pertussis toxin did not alter nefiracetam potentiation, indicating Gi/Go proteins are not involved. Pretreatment with cholera toxin did abolish nefiracetam potentiation. Thus, nefiracetam potentiation is mediated via Gs proteins. In conclusion, nefiracetam stimulates α4β2‐type nnAChRs via Gs proteins at nanomolar concentrations. The potentiation of α4β2‐type nnAChRs is thought to be at least partially responsible for cognitive enhancing action.
Neuroprotective and Cognition‐Enhancing Properties of MK‐801 Flexible Analogs
Authors: BACHURIN SERGEY , TKACHENKO SERGEY , BASKIN IGOR , LERMONTOVA NADEGDA , MUKHINA TATYANA , PETROVA LYUDMILA , USTINOV ANATOLIY , PROSHIN ALEXEY , GRIGORIEV VLADIMIR , LUKOYANOV NIKOLAY , PALYULIN VLADIMIR , ZEFIROV NIKOLAY
Published: July 2010

Abstract:Neuroprotective and biobehavioral properties of a series of novel open chain MK‐801 analogs, as well as their structure‐activity relationships have been investigated. Three groups of compounds were synthesized: monobenzylamino, benzhydrylamino, and dibenzylamino (DBA) analogs of MK‐801. It was revealed that DBA analogs exhibit pronounced glutamate‐induced calcium uptake blocking properties and anti‐NMDA activity. The hit compound of DBA series, NT‐1505, was investigated for its ability to improve cognition functions in animal model of Alzheimer's disease type dementia, simulated by treating animals with cholinotoxin AF64A. The results from an active avoidance test and a Morris water maze test showed that experimental animals, treated additionally with NT‐1505, exhibited much better learning ability and memory than the control group (AF64A treated) and close to that of the vehicle group of animals (treated with physiological solution). Study of NT‐1505 influence on locomotor activity revealed that it is characterized by a spectrum of behavioral activity radically different from that of MK‐801, and in contrast to the latter one does not produce any psychotomimetic side effects in the therapeutically significant dose interval. The computed docking of MK‐801 and its flexible analogs on the NMDA receptor elucidated the crucial role of the hydrogen bond formed between these compounds and the asparagine residue for magnesium binding in the NMDA receptor. It was suggested that strong hydrophobic interaction between MK‐801 and the hydrophobic pocket in the NMDA receptor‐channel complex determines much higher irreversibility of this adduct compared to the intermediates formed between this site and Mg ions or flexible DBA derivatives, which might explain the absence of PCP‐like side effects of the latter compounds.
Synaptic Deprivation and Age‐Related Vulnerability to Hypoxic‐Ischemic Neuronal Injury
Authors: MARINI ANN M. , CHOI JOHN , LABUTTA ROBERT
Published: July 2010

Abstract: Advanced age is associated with physiological changes, such as cerebral autoregulation dysfunction, atrial fibrillation, reduced cerebral blood flow, elevated blood pressure, and other changes. Stroke‐related dementia is associated with brain loss principally due to strokes, and neuropathological examination of the brains of old people shows a direct correlation between the extent of brain loss and dementia. However, the exact mechanism of the age related vulnerability to hypoxic‐ischemic neuronal injury remains unknown. The majority of synapses in the brain use excitatory amino acids as their neurotransmitter. Glutamate, a major endogenous excitatory amino acid required for normal physiological excitation, is also involved in the pathophysiology of hypoxic‐ischemic neuronal injury. The N‐methyl‐d‐aspartate (NMDA) glutamate receptor subtype plays a major role in mediating hypoxic‐ischemic neuronal injury. NMDA receptors also mediate adaptive responses important for synaptic plasticity. This report explores the possible role of synaptic activity as a protective mechanism against neuronal cell death. Specifically, the role of NMDA receptors in neuronal plasticity by upregulating a survival pathway is discussed. Loss of a neuronal population that uses glutamate as its neurotransmitter leads to a loss of activity on the postsynaptic neurons or synaptic deprivation. Deprivation of excitatory amino acids on the postsynaptic neurons results in the failure of activity‐dependent induced intrinsic survival pathways induced by NMDA receptors. The loss of neuroprotective intrinsic survival pathways increases the vulnerability of these neurons to more hypoxic‐ischemic neuronal damage. Since cerebral infarction is also age related, this hypothesis provides a plausible explanation of how we become more vulnerable to hypoxic‐ischemic neuronal injury as a function of age.
Non‐Pharmacologic (Physiologic) Neuroprotection in the Treatment of Brain Ischemia
Authors: AUER ROLAND N.
Published: July 2010

Abstract: Clinical trials for ischemic stroke have been characterized by a disappointing series of negative results, using a panoply of pharmacologic agents. This paper emphasizes five physiologic measures that can be taken to mitigate ischemic brain damage. These are (1) hypothermia, (2) insulin, (3) arterial hyperoxemia, (4) blood pressure control and (5) magnesium. Hypothermia is protective in both focal and global ischemia, even postischemically protecting against selective neuronal necrosis and infarction. The total equation for protection includes the (i) postischemic delay, (ii) depth, and (iii) duration of hypothermia. Insulin operates by lowering glucose levels to the normal range in focal ischemia. It is possible that very low glucose levels are detrimental in focal ischemia with paradoxical augmentation of the infarct size, and that spreading depression plays a role in this. Controlled arterial hyperoxemia seems effective experimentally in reducing infarct size, operating mechanistically by either a direct effect of oxygen, or vasoconstriction causing shunting of blood into the infarct, or both. Blood pressure is a critical determinant of infarct size, and raising blood pressure improves collateral blood flow and reduces stroke size. To be used clinically, however, hemorrhage must be ruled out. The most dramatic clinical effects of blood pressure are seen in aneurysm patients with vasospasm, where minor increases in blood pressure reverse temporary hemiparesis by reducing ischemia. Magnesium is likely the safest NMDA antagonist, with a long history of safe administration to pregnant women with eclampsia. There is potential interaction with insulin, in that magnesium causes hyperglycemia, which requires insulin to counteract it. Magnesium and insulin together have been shown effective in experimental brain ischemia. In the absence of safe and effective pharmacologic neuroprotection agents, clinical trials should be designed and launched to test these physiologic measures, singly and in combination, to reduce brain damage after ischemia.
On the Relationship Between Plasma Concentrations of Drugs and Outcome of Stroke Studies in Laboratory Animals
Authors: CURRY STEPHEN H.
Published: July 2010

Abstract:In assessing plasma concentrations of drugs in relation to neuroprotective effect, emphasis should be placed on measured or calculated concentrations during the window of opportunity for effect, rather than at the end of the experiment. Unbound (plasma free) concentrations should be especially considered as should brain penetration to the stroked area. Problem‐solving exercises should includepost hocassessment of dosing residues and proof of exposure. The shape of the graph of response versus concentration in plasma is very steep, giving the impression of an all‐or‐none effect. Although higher doses lead to greater effects, attempts to statistically correlate plasma level and infarct size are likely to be unsuccessful. There is strong evidence that the pharmacokinetic properties of drugs are affected by the physiological consequences of ischemia.
Gene Therapy for Treatment of Cerebral Ischemia Using Defective Herpes Simplex Viral Vectors
Authors: YENARI MIDORI A. , DUMAS THEODORE C. , SAPOLSKY ROBERT M. , STEINBERG GARY K.
Published: July 2010

Abstract: Significant advances have been made over the past few years concerning the cellular and molecular events underlying neuron death. Recently, it is becoming increasingly clear that some of genes induced during cerebral ischemia may actually serve to rescue the cell from death. However, the injured cell may not be capable of expressing protein at high enough levels to be protective. One of the most exciting arenas of such interventions is the use of viral vectors to deliver potentially neuroprotective genes at high levels. Neurotropic herpes simplex viral (HSV) strains are an obvious choice for gene therapy to the brain, and we have used bipromoter vectors that are capable of transferring various genes to neurons. Using this system in experimental models of stroke, cardiac arrest, and excitotoxicity, we have found that it is possible to enhance neuron survival against such cerebral insults by overexpressing genes that target various facets of injury. These include energy restoration by the glucose transporter (GLUT‐1), buffering calcium excess by calbindin, preventing protein malfolding or aggregation by stress proteins and inhibiting apoptotic death by BCL‐2. We show that in some cases, gene therapy is also effective after the onset of injury, and also address whether successful gene therapy necessarily spares function. Although gene therapy is limited to the few hundred cells the vector is capable of transfecting, we consider the possibility of such gene therapy becoming relevant to clinical neurology in the future.
Delayed Multidose Treatment with Nicotinamide Extends the Degree and Duration of Neuroprotection by Reducing Infarction and Improving Behavioral Scores up to Two Weeks Following Transient Focal Cerebral Ischemia in Wistar Rats
Authors: MAYNARD KENNETH I. , AYOUB ISSAM A. , SHEN CHIUNG‐CHYI
Published: July 2010

Abstract: A single, delayed dose of nicotinamide (NAm) was shown to be protective against focal cerebral ischemia in rats, but the protection was limited to three to seven days following stroke. The investigation reported here was conducted to examine if the use of multiple doses of NAm, administered after the onset of focal cerebral ischemia, would extend the duration of neuroprotection compared with a single dose treatment regimen. Male Wistar rats were subjected to transient focal cerebral ischemia by occluding the right middle cerebral artery (MCAo) for two hours. Following MCAo, motor and sensory behavioral tests were performed daily and the cerebral infarct volumes were measured at two weeks after sacrifice. Each animal was placed into one of four groups that received either normal saline alone (Group S), one (Group A), two (Group B), or three (Group C) doses of NAm (500 mg/kg). Each animal, therefore, received three treatments over two weeks, with the first dose administered intravenously two hours after the onset of MCAo. Single and multiple doses of NAm reduced the infarction (p < 0.01) and improved (p < 0.05) the neurologic sensory and motor behavior when compared with the saline‐treated animals up to two weeks after stroke. Moreover, animals that received multiple doses of NAm recuperated full motor function not different from normal, preoperative motor behavior. Delayed treatment with NAm given as multiple doses, therefore, further enhances the extent and duration of neuroprotection by significantly reducing cerebral infarct volumes, improving neurologic behavioral scores, and confers a complete motor recovery up to two weeks from the onset of focal cerebral ischemia in Wistar rats.
Cell Death in Spinal Cord Injury (SCI) Requires de Novo Protein Synthesis
Authors: RAY SWAPAN K. , MATZELLE DENISE D. , WILFORD GLORIA G. , HOGAN EDWARD L. , BANIK NAREN L.
Published: July 2010

Abstract: Degradation of cytoskeletal proteins by calpain, a Ca2+‐dependent cysteine protease, may promote neuronal apoptosis in the lesion and surrounding areas following spinal cord injury (SCI). Clinically relevant moderate (40 g‐cm force) SCI in rats was induced at T12 by a standardized weight‐drop method. Internucleosomal DNA fragmentation or apoptosis in the lesion was inhibited by 24‐h treatment of SCI rats with cycloheximide (1 mg/kg), indicating a requirement for de novo protein synthesis in this process. To prove an involvement of calpain activity in mediation of apoptosis in SCI, we treated SCI rats with a cell‐permeable calpain inhibitor E‐64‐d (1 mg/kg). Following 24‐h treatment, a 5‐cm‐long spinal cord section centered at the lesion was collected, and divided equally into five segments (1 cm each) to determine calpain activity, as shown by degradation of the 68‐kD neurofilament protein (NFP), and apoptosis as indicated by internucleosomal DNA fragmentation. Neurodegeneration propagated from the site of injury to neighboring rostral and caudal regions. Both calpain activity and apoptosis were readily detectable in the lesion, and moderately so in neighboring areas of untreated SCI rats, whereas these were almost undetectable in E‐64‐d‐treated SCI rats, and absent in sham animals. Results indicate that apoptosis in the SCI lesion and penumbra is prominently associated with calpain activity and is inhibited by the calpain inhibitor E‐64‐d providing neuroprotective benefit.
The Anti‐Parkinson Drug Rasagiline and Its Cholinesterase Inhibitor Derivatives Exert Neuroprotection Unrelated to MAO Inhibition in Cell Culture andin Vivo
Authors: YOUDIM MOUSSA B.H. , WADIA A. , TATTON W. , WEINSTOCK MARTA
Published: July 2010

Abstract:The antiapoptotic and neuroprotective activity of irreversible monoamine oxidase (MAO) B inhibitor, rasagiline [r(+)‐N‐propargyl‐1‐aminioindan], itsS‐isomer (TVP1022) and TV 3219, a novel anti‐Alzheimer cholinesterase‐MAO inhibitor drug derived from rasagiline were examined in PC12 cells cultures andin vivo. We found that these drugs have potent antiapoptotic and neuroprotective activities in response to serum and NGF withdrawal in partially neuronally differentiated PC12 cells and prevent the fall in mitochondrial membrane potential, the first step in cell death. Closed head injury studies in mice have shown that both rasagiline and TVP1022 are neuroprotective. All these compounds possess a propargyl moiety, which normally is responsible for irreversible inactivation of MAO, as is seen with rasagiline. However, neither TVP1022 nor TV3219 are MAO inhibitors, both share the antiapoptotic and neuroprotective actions of rasagiline, indicating that MAO inhibition is not a prerequisite for neuroprotection and that the propargyl moiety exhibits intrinsic neuroprotective pharmacological activity that requires identification.
Degenerins
Authors: TAVERNARAKIS NEKTARIOS , DRISCOLL MONICA
Published: July 2010

Abstract: Mechanosensory signaling, believed to be mediated by mechanically gated ion channels, constitutes the basis for the senses of touch and hearing, and contributes fundamentally to the development and homeostasis of all organisms. Despite this profound importance in biology, little is known of the molecular identities or functional requirements of mechanically gated ion channels. Genetic analyses of touch sensation and locomotion in Caenorhabditis elegans have implicated a new class of ion channels, the degenerins (DEG) in nematode mechanotransduction. Related fly and vertebrate proteins, the epithelial sodium channel (ENaC) family, have been implicated in several important processes, including transduction of mechanical stimuli, pain sensation, gametogenesis, sodium reabsorption, and blood pressure regulation. Still‐to‐be‐discovered DEG/ENaC proteins may compose the core of the elusive human mechanotransducer.
Cardiac Sympathetic Afferent Activation Provoked by Myocardial Ischemia and Reperfusion
Authors: LONGHURST JOHN C. , TJEN‐A‐LOOI STEPHANIE C. , FU LIANG‐WU
Published: July 2010

Abstract:Cardiac sympathetic afferents are known to reflexly activate the cardiovascular system, leading to increases in blood pressure, heart rate, and myocardial contractile function. During myocardial ischemia, these sensory nerves also transmit the sensation of pain (angina pectoris) and cause tachyarrhythmias. The authors' laboratory has been interested in defining the mechanisms of activation of this neural system during ischemia and reperfusion. During these periods, reactive oxygen species, particularly hydroxyl radicals, are produced from the breakdown of purine metabolites and lead to stimulation of sympathetic (and vagal) ventricular chemosensitive nerve endings. For example, stimulation with hydrogen peroxide leads to a small reflex increase in blood pressure from the predominant sympathetic afferent activation that is reduced by simultaneous activation of cardiac vagal afferents (known to exert predominantly depressor reflexes). Central integration of these two opposing reflexes likely occurs at several regions of the brain stem, including the nucleus tractus solitarii, where neural occlusion occurs during simultaneous cardiac sympathetic and vagal‐afferent stimulation. Activation of platelets also appears to play a role during myocardial ischemia, leading to local release of serotonin (5HT), which, through a 5HT3mechanism, stimulates sympathetic afferents. Finally, regional changes in pH from lactic acid (but not hypercapnia), stimulate ventricular afferents and may activate kallikrein to increase bradykinin (BK), which, in turn, breaks down arachidonic acid to form prostaglandins. Prostaglandins sensitize cardiac sympathetic afferents to BK. Thus, stimulation of cardiac sympathetic afferents during ischemia and reperfusion and the resulting reflex events form a multifactorial process resulting from activation of a number of chemical pathways in the myocardium.
Toward an Understanding of the Molecules that Sense Myocardial Ischemia
Authors: BENSON CHRISTOPHER J. , SUTHERLAND STEPHANI P.
Published: July 2010

Abstract: Cardiac afferent neurons are activated in the setting of myocardial ischemia and mediate the sensation of angina. However, the precise stimuli and receptive molecules responsible are not completely understood. To further investigate the molecular components involved, cardiac afferents were isolated in dissociated culture and patch‐clamp experiments were performed on these cells. It was found that acidic pH evoked large inward currents in almost all cardiac sympathetic afferents. By comparison, the responses to other potential chemical mediators were inconsistent and much smaller. The biophysical properties of the acid‐evoked currents in cardiac afferents match the acid‐sensing ion channel 3 (ASIC3).
Cellular Mechanisms of Baroreceptor Integration at the Nucleus Tractus Solitarius
Authors: ANDRESEN MICHAEL C. , DOYLE MARK W. , JIN YOUNG‐HO , BAILEY TIMOTHY W.
Published: July 2010

Abstract:The autonomic nervous system makes important contributions to the homeostatic regulation of the heart and blood vessels through arterial baroreflexes, and yet our understanding of the central nervous system mechanisms is limited. The sensory synapse of baroreceptors in the nucleus tractus solitarius (NTS) is unique because its participation is obligatory in the baroreflex. Here we describe experiments targeting this synapse to provide greater understanding of the cellular mechanisms at the earliest stages of the baroreflex. Our approach utilizes electrophysiology, pharmacology, and anatomical tracers to identify and evaluate key elements of the sensory information processing in NTS.
Neurotransmission of the Cardiovascular Reflexes in the Nucleus Tractus Solitarii of Awake Rats
Authors: MACHADO BENEDITO H.
Published: July 2010

Abstract:Chemoreflex activation with potassium cyanide (i.v.) produces pressor and bradycardic responses in awake rats. Microinjection of AP‐5, a selective NMDA receptor antagonist, into the nucleus tractus solitarii (NTS) produced a dose‐dependent blockade of the bradycardic response; while microinjection of DNQX, a selective non‐NMDA receptor antagonist, or kynurenic acid, a nonselective ionotropic receptor antagonist, produced only a partial reduction in the pressor response, indicating that the bradycardic component of the chemoreflex is mediated by NMDA receptors and that the sympathoexcitatory component may involve neurotransmitters other than excitatory amino acids. With respect to the baroreflex, we verified that the gain of baroreflex bradycardia in response to phenyleprine (Phe) infusion was significantly reduced in a dose‐dependent manner by microinjection of AP‐5 into the NTS, indicating that the parasympathetic component of the baroreflex is mediated mainly by NMDA receptors. However, in a series of experiments involving the electrical stimulation of the aortic depressor nerve (ADN) we observed that the maximal bradycardic response was almost blocked by the combination of microinjection of NMDA and non‐NMDA receptor antagonists into the NTS, while the depressor response was only partially reduced. These data indicate that the bradycardic response produced by the activation of the baroreflex with Phe is mediated by mechanisms differing from those in response to the electrical stimulation of the ADN because phenylephrine also activates carotid and aortic baroreceptors, while unilateral electrical stimulation of the ADN involves only one specific set of baroreceptor afferents. These data also indicate that the sympatho inhibitory component of this response may involve neurotransmitters other than l‐glutamate. We discuss the possibility that two different afferent systems of arterial baroreceptors are involved in the modulation of parasympathoexcitation and sympathoinhibition: one activated within the normal range of pulsatile arterial pressure (on a pulse‐to‐pulse basis) and the other acting under circumstances of challenge to the pulsatile arterial pressure above the normal range.
Exercise and Sensory Integration
Authors: POTTS JEFFREY T.
Published: July 2010

Abstract:Since NTS neurons receive synaptic input from many sensory modalities, it is crucial to understand the neuronal mechanisms involved in synaptic processing. We have proposed that GABA‐containing neurons in the NTS are the primary target for somatic afferent fibers activated by skeletal muscle contraction. In our model, local inhibition of baroreceptor signaling is necessary to counteract the increase in baroreceptor input such that NTS output is normalized and baroreflex sensitivity is maintained during exercise. This GABAergic mechanism, in conjunction with sympathoexcitation evoked by somatic afferents, preserves reflex sensitivity and resets the baroreflex, respectively. Unfortunately, there is insufficient data to date to support or refute the proposed role for GABA on baroreflex function during exercise. However, we feel that this model will be useful in formulating future experiments to explore these synaptic interactions.
Regulation of Sympathetic Tone and Arterial Pressure by the Rostral Ventrolateral Medulla after Depletion of C1 Cells in Rats
Authors: GUYENET P. G. , SCHREIHOFER A. M. , STORNETTA R. L.
Published: July 2010

Abstract:This review describes experiments designed to determine the role of bulbospinal (BS) C1 cells in regulating the sympathetic outflow and blood pressure. This goal was achieved by analyzing the physiological consequences of destroying BS C1 cells. These cells were destroyed by suicide transport of an anti‐dopamine‐beta‐hydroxylase antibody conjugated to saporin (anti‐DβH‐SAP). Two to 3 weeks after spinal cord injection (T2‐T6), the toxin destroyed 75–85% of BS C1 and C3 cells along with >95% of BS noradrenergic neurons (A5, A6, A7). The toxin spared BS noncatecholaminergic cells. Under anesthesia, toxin‐treated rats had a normal blood pressure and an apparently normal sympathetic nerve discharge (SNA, splanchnic), and intravenous clonidine caused a normal degree of sympathoinhibition. Inhibition of rostral ventrolateral medulla (RVLM) neurons by bilateral injection of muscimol caused the same hypotension and sympathoinhibition as in control rats. The baroreflex range was 41% attenuated by the toxin, but the MAP50was unchanged. Sympathoexcitatory responses to stimulation of peripheral chemoreceptors with cyanide or to electrical stimulation of RVLM were severely depressed (60% to 80%) in toxin‐treated rats. Rats in which A5 neurons were selectively destroyed had no deficit in the parameters tested. Unit recordings of BS RVLM neurons indicated that the toxin destroyed most barosensitive C1 neurons, but spared noncatecholaminergic lightly myelinated BS cells. In summary, the integrity of C1 neurons is not essential for the generation of SNA and the maintenance of BP under resting conditions, perhaps because these functions are performed primarily by noncatecholaminergic BS neurons. However, the deficits caused by treatment with anti‐DβH‐SAP indicate that BS C1 neurons play a crucial role in several sympathoexcitatory responses mediated by the RVLM.
Integrative Sympathetic Baroreflex Regulation of Arterial Pressure
Authors: SUNAGAWA KENJI , SATO TAKAYUKI , KAWADA TORU
Published: July 2010

Abstract: The baroreflex system is the most important negative feedback control system functioning physiologically to attenuate the effects of rapid perturbation in arterial pressure. However, the complexity of the system resulting from the closed‐feedback loop, nonlinearity, and system memory makes detailed quantitative characterization of the baroreflex system difficult. To overcome such limitations, we proposed a framework to decompose the baroreflex loop into two major arcs, that is, the mechanoneural arc and neuromechanical arc. Steady state analysis indicated that such decomposition allowed us to analytically determine the operating point by equilibrating two respective function curves. Dynamic analysis suggested that the mechanoneural arc accelerated the slow mechanical response of the neuromechanical arc. The acceleration mechanism in the mechanoneural arc optimized arterial pressure regulation in achieving both stability and quickness. Establishment of such an integrative framework allowed the development of an artificial feedback control system able to regulate sympathetic vasomotor tone.
Renal Arterial Pressure Variability
Authors: NAFZ B. , PERSSON P. B.
Published: July 2010

Abstract: It is becoming generally appreciated that blood pressure (BP) fluctuations can have major pathophysiological importance in hypertensives. Nonetheless, little is known regarding the influence of short‐term changes in BP on kidney function, a crucial control element for long‐term BP regulation. This overview summarizes first efforts to unravel the importance of BP dynamics on renal function. It seems that the kidney is not only an important control element in the BP regulation network; the renal vascular bed may also be very susceptible to BP oscillations, which can occur, for example, from baroreflex malfunction.
Rhythmicities in Sympathetic Discharge: A Signal of Cardiorespiratory Integration in Developing Animals
Authors: HUNDLEY BRUCE W. , SICA ANTHONY L. , GOOTMAN PHYLLIS M.
Published: July 2010

Abstract:We have been pursuing various avenues of investigation to elucidate the postnatal maturation of neural regulation of cardiovascular and respiratory integration. In this paper we present our results from a systematic analysis of age‐related modulations of sympathetic (SYMP) activity with respect to experimental alterations in baroreceptor afferent inputs. The three age groups of piglets were chosen based on different responses to a complex stimulus, i.e., the Valsalva maneuver. Postnatal maturation of SYMP activity was examined by spectral analysis of SYMP discharge using cross‐power, full and partial coherence. Three general oscillations were observed in spontaneous SYMP discharges in the 0–30 Hz range. We divided that range into five frequency bands (0–2, 2–6, 6–12, 12–20, 20–30 Hz), which included periodicities in phase with both central respiratory activity and the cardiac cycle. Spectral analyses of SYMP activity after either baroreceptor activation (phenylephrine) or deactivation (nitroprusside) revealed that respiratory modulation was age‐related across all frequencies while baroreceptor modulation was usually age‐related within three of the five frequency bands. These results lead to questions concerning the possible role of the autonomic nervous system and/or central interactions between the respiratory and SYMP rhythm generators in the etiology of sudden infant death syndrome (SIDS).
Reversible Resistance to Apoptosis in Cutaneous T Cell Lymphoma
Authors: MEECH SANDRA J. , EDELSON RICHARD , WALSH PATRICK , NORRIS DAVID A. , DUKE RICHARD C.
Published: July 2010

Abstract: Mycosis fungoides and its leukemic variant, Sézary syndrome, represent the most common forms of cutaneous T cell lymphomas (CTCL). These disorders are clonal neoplasms characterized by the progressive accumulation of cells that resemble activated/memory CD4+ T cells. Unlike their normal counterparts, these malignant lymphocytes have prolonged life spans and are resistant to dying following treatment with most chemotherapeutic agents. This suggests that CTCL undergo abnormal programmed cell death; however, data regarding apoptotic defects in CTCL are limited. Regulation of apoptosis in lymphocytes that regularly undergo clonal expansion is necessarily complex and will be reviewed here. Clonally expanded lymphocytes rely primarily on Fas‐mediated pathways to initiate apoptosis. Factors leading to the resistance of apoptosis in CTCL and new therapeutic approaches for reversing this resistance will be discussed, including the important role that the Fas death pathway may play in the pathogenesis and treatment of CTCL.
Progression of Lymphomatoid Papulosis to Systemic Lymphoma Is Associated with Escape from Growth Inhibition by Transforming Growth Factor‐β and CD30 Ligand
Authors: KADIN MARSHALL E. , LEVI EDI , KEMPF WERNER
Published: July 2010

Abstract: Our objective is to understand the mechanism of progression of lymphomatoid papulosis (LyP) to CD30+ systemic lymphoma. LyP lesions appear in recurrent crops that regress, only to reappear at a later date in the same or different locations. About 10% of patients develop systemic lymphoma. Because transforming growth factor‐beta (TGF‐β) and CD30 ligand inhibit the growth of normal lymphocytes and can be detected in regressing lesions of LyP, we tested the effect of these cytokines on cell lines clonally derived from LyP in the progression to systemic lymphoma. TGF‐β failed to inhibit the growth of lymphoma cells from advanced disease due to mutations of the TGF‐β receptor complex that prevented binding of the ligand to tumor cells. A CD30 ligand agonist antibody caused proliferation of tumor cells from one patient and had no effect on tumor cells of another. In contrast, a Fas agonist antibody caused significant growth inhibition of all cell lines. The results suggest that progression of LyP to lymphoma is associated with escape of lymphoma cells from growth regulation by TGF‐β and CD30 ligand.
The Role of Human T Cell Lymphotropic Virus Type I Tax in the Development of Cutaneous T Cell Lymphoma
Authors: ZUCKER‐FRANKLIN DOROTHEA
Published: July 2010

Abstract:Although it has been well established that the human T cell lymphotropic virus type I (HTLV‐I) causes adult T cell leukemia/lymphoma (ATLL) in regions of the world where this virus is endemic, its role in the pathogenesis of cutaneous T cell lymphoma (CTCL) in the Western world has been less well established. Most patients with CTCL are negative for antibodies to the structural proteins of HTLV‐I, and thus a causative role for this virus is usually dismissed. However, the Tax sequence of HTLV‐I has been found in the peripheral blood mononuclear cells of practically all patients with CTCL. Such patients express Tax mRNA and have antibodies to p40Tax, the protein encoded by this sequence. Sequence analysis of a 159‐bp region of Tax extracted from CTCL cells proved to be homologous with the same region prepared from a cell line infected with prototypic HTLV‐I. Byin situPCR, Tax has been demonstrated in the lymphocytes infiltrating the skin as well as in the keratinocytes of such patients. Apart from the pathophysiologic and clinical interest of these studies, these observations may have therapeutic implications.In vitro, the proliferation of HTLV‐I‐transformed cells can be inhibited by antisense to HTLV‐I Tax. Since Tax has not been identified in the normal human genome, antisense to Tax deserves serious consideration as a treatment modality for patients whose cells have been demonstrated to harbor Tax.
Extracorporeal Photochemoimmunotherapy in Cutaneous T Cell Lymphomas
Authors: KNOBLER ROBERT , GIRARDI MICHAEL
Published: July 2010

Abstract: Extracorporeal photochemotherapy (ECP), or photopheresis, is a widely used treatment for cutaneous T cell lymphoma (CTCL) and other T cell‐mediated disorders, having been administered in more than 150 centers worldwide more than 200,000 times. Consistent with the theme of this conference—that is, highlighting the potentially most productive investigative avenues for unraveling the mysteries of CTCL in the next decade—ECP has been futuristic since its inception in the early 1980s. In 1988, the treatment was the first FDA‐approved selective immunotherapy for any type of cancer. Yet, the mechanism by which it could suppress a clone of CTCL cells or inactivate multiple autoreactive T cell clones in graft‐versus‐host disease (GVHD) or allograft rejection remained obscure until quite recently. In fact, the scientific principles necessary to begin to comprehend the basis of ECP's efficacy were not available when the treatment was first introduced in 1982. In the intervening years, necessary detailed knowledge of the structure and function of the clonotypic T cell receptors, of class I major histocompatibility complex (MHC) presentation of tumor antigens, of CTCL tumor‐specific antigens, of dendritic antigen presenting cell (DC) biology, and of 8‐methoxypsoralen immunopharmacology has been attained. Although much remains to be learned, we now appreciate that ECP simultaneously and efficiently induces both apoptosis of disease‐causing T cells and conversion of monocytes to functional DCs. By processing and presenting the unique antigenic determinants of pathogenic T cell clones, the DCs can either initiate a clinically relevant anti‐CTCL cytotoxic response or suppress the activity of autoreactive T cell clones. This paper will review clinical trials of ECP in CTCL and evolving scientific understanding of ECP's mechanism in the context of exciting future directions.
Percutaneous Peptide Immunization via Corneum Barrier‐disrupted Murine Skin for Experimental Tumor Immunoprophylaxis
Authors: TAKIGAWA MASAHIRO , TOKURA YOSHIKI , HASHIZUME HIDEO , YAGI HIROAKI , SEO NAOHIRO
Published: July 2010

Abstract: Percutaneous peptide immunization is a method in which tumor‐specific cytotoxic T lymphocytes (CTL) are primed in the lymph nodes and spleen following application of tumor peptides to corneum barrier‐disrupted murine skin. Immunized mice are protected against subsequent challenge with corresponding tumors and suppress the growth of established tumors. CTL expansion after peptide application seems to be mediated by epidermal Langerhans' cells. In the human, disruption of permeability barrier by tape stripping also induces activation of epidermal Langerhans' cells. Thus, percutaneous peptide immunization provides a simple and noninvasive means of inducing potent antitumor immunity that may be exploited for cancer immunotherapy in the human.
Role of Gene Regulation during Vestibular Compensation
Authors: BALABAN CAREY D.
Published: July 2010

Abstract:Identification of the role of gene regulation in vestibular compensation is one aspect of a larger issue: the identification of molecular bases for plasticity in multiple vestibulo‐ocular, vestibulo‐spinal, vestibulo‐collic, and vestibulo‐autonomic responses. To achieve this goal, it is incumbent on investigators to examine molecular events within the contexts of the single neuron, the location of the neuron in pathways, and the timing of the molecular events relative to behavioral compensation. Hence, the goal of identifying molecular bases for a particular compensatory response (e.g., the disappearance of spontaneous nystagmus in the light or the disappearance of static head tilt) requires careful attention to the time course of physiologic compensation and the location of the effects within central pathways that have the potential to affect the responses. The effects of impeding these site‐specific and time‐specific changes can then be tested to determine their role in the compensatory process. A consideration of the recent literature on molecular events related to the resolution of spontaneous nystagmus in the light indicates that a meaningful approach to these issues requires a broadening of our conceptual approach. Specifically, one must consider the roles of transcriptional, translational, and posttranslational events on the turnover of critical signaling substrates for vestibular compensation.
Monoclonal L‐Citrulline Immunostaining Reveals Nitric Oxide‐Producing Vestibular Neurons
Authors: HOLSTEIN GAY R. , FRIEDRICH VICTOR L. , MARTINELLI GIORGIO P.
Published: July 2010

Abstract: Nitric oxide is an unstable free radical that serves as a novel messenger molecule in the central nervous system (CNS). In order to understand the interplay between classic and novel chemical communication systems in vestibular pathways, the staining obtained using a monoclonal antibody directed against L‐citrulline was compared with the labeling observed using more traditional markers for the presence of nitric oxide. Brainstem tissue from adult rats was processed for immunocytochemistry employing a monoclonal antibody directed against L‐citrulline, a polyclonal antiserum against neuronal nitric oxide synthase, and/or NADPH‐diaphorase histochemistry. Our findings demonstrate that L‐citrulline can be fixed in situ by vascular perfusion, and can be visualized in fixed CNS tissue sections by immunocytochemistry. Further, the same vestibular regions and cell types are labeled by NADPH‐diaphorase histochemistry, by the neuronal nitric oxide synthase antiserum, and by our anti‐L‐citrulline antibody. Clusters of L‐citrulline‐immunoreactive neurons are present in subregions of the vestibular nuclei, including the caudal portion of the inferior vestibular nucleus, the magnocellular portion of the medial vestibular nucleus, and the large cells in the ventral tier of the lateral vestibular nucleus. NADPH‐diaphorase histochemical staining of these neurons clearly demonstrated their multipolar, fusiform and globular somata and long varicose dendritic processes. These results provide support for the suggestion that nitric oxide serves key roles in both vestibulo‐autonomic and vestibulo‐spinal pathways.