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(1 - 4 of 4)
- Title
- GLUTAMATE EXCITOTOXICITY IN EPILEPSY AND ISCHEMIA.
- Creator
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Soundarapandian, Mangala Meenakshi, Lu, YouMIng, University of Central Florida
- Abstract / Description
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'Excitotoxicity' represents the excitatory amino acid mediated degeneration of neurons. Glutamate is the major excitatory neurotransmitter in the brain. Glutamate excitotoxicity has been implicated in a number of neurodegenerative disorders like Stroke, Epilepsy, Alzheimer's disease and traumatic brain injury. This neurotoxicity is summed up by the 'glutamate hypothesis' which describes the cause of neuronal cell death as an excessive release of glutamate causing over...
Show more'Excitotoxicity' represents the excitatory amino acid mediated degeneration of neurons. Glutamate is the major excitatory neurotransmitter in the brain. Glutamate excitotoxicity has been implicated in a number of neurodegenerative disorders like Stroke, Epilepsy, Alzheimer's disease and traumatic brain injury. This neurotoxicity is summed up by the 'glutamate hypothesis' which describes the cause of neuronal cell death as an excessive release of glutamate causing over excitation of the glutamate receptors and subsequent increase in influx of calcium leading to cell death. An effort to counteract this neurotoxicity has lead to the development of glutamate receptor antagonists that can effectively serve as neuroprotective agents. Nevertheless, the downside to these drugs has been the side effects observed in clinical trial patients due to their disruptive action on the physiological function of these receptors like learning and memory. This work was undertaken to identify targets that can effectively be used to treat excitotoxicity without affecting any normal physiological functions. In one approach, (chapter I) we have identified the KATP channels as an effective modulator of epileptogenesis. In another approach, (Chapter II) we show that targeting the AMPA receptor subunit GluR2 is a practical strategy for stroke therapy. KATP channels that are gated by intracellular ATP/ADP concentrations are a unique subtype of potassium channels and play an essential role in coupling intracellular metabolic events to electrical activity. Opening of KATP channels during energy deficits in the central nervous system (CNS) induces efflux of potassium ions and in turn hyperpolarizes neurons. Thus, activation of KATP channels is thought to be able to counteract excitatory insults and protect against neuronal death. Here, we show that, functional Kir6.1 channels are located at excitatory pre-synaptic terminals as a complex with type-1 Sulfonylurea receptors (SUR1) in the hippocampus. The mutant mice with deficiencies in expressing the Kir6.1 or the SUR1 gene are more vulnerable to generation of epileptic form of seizures, compared to wild-type controls. Whole-cell patch clamp recordings demonstrate that genetic deletion of the Kir6.1/SUR1 channels enhances glutamate release at CA3 synapses. Hence, expression of functional Kir6.1/SUR1 channels inhibits seizure responses and possibly acts via limiting excitatory glutamate release. In addition to epilepsy, ischemic stroke is a leading cause of death in developed countries. A critical feature of this disease is a highly selective pattern of neuronal loss; certain identifiable subsets of neurons, particularly CA1 pyramidal neurons in the hippocampus are severely damaged, whereas others remain intact. A key step in this selective neuronal injury is Ca2+/Zn2+ entry into vulnerable neurons through -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor channels, a principle subtype of glutamate receptors. AMPA receptor channels are assembled from glutamate receptor (GluR) -1, -2, -3, and -4 subunits. Circumstance data have indicated that the GluR2 subunits dictate Ca2+/Zn2+ permeability of AMPA receptor channels and gate injurious Ca2+/Zn2+ signals in vulnerable neurons. Here we show that ischemic insults induce toxic Ca2+ entry through AMPA receptors into vulnerable neurons by modification of GluR2 RNA editing. Thus, targeting of GluR2 subunit can be considered as a promising target for stroke therapy.
Show less - Date Issued
- 2007
- Identifier
- CFE0001911, ucf:47483
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0001911
- Title
- NURSING INTERVENTIONS IN THE CARE OF PATIENTS UNDERGOING INDUCED HYPOTHERMIA.
- Creator
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Zimmerman, Angela, Amidei, Christina, University of Central Florida
- Abstract / Description
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Use of induced hypothermia for the purpose of lowering intracranial pressure and preserving neuronal function has increased as research data reveals a trend of positive outcomes in patients treated with this therapy. Recently induced hypothermia following cardiac arrest due to ventricular fibrillation has been deemed successful. Current research has expanded to evaluate the effectiveness of induced hypothermia as a treatment modality for severe stroke and head trauma. In spite of its efficacy...
Show moreUse of induced hypothermia for the purpose of lowering intracranial pressure and preserving neuronal function has increased as research data reveals a trend of positive outcomes in patients treated with this therapy. Recently induced hypothermia following cardiac arrest due to ventricular fibrillation has been deemed successful. Current research has expanded to evaluate the effectiveness of induced hypothermia as a treatment modality for severe stroke and head trauma. In spite of its efficacy, complications exist with this treatment modality. The purpose of this literature review is to examine potential complications secondary to induced hypothermia and highlight the nurse's role in managing patient care. At the present, patient protocols for induced hypothermia are lacking. The success of treatment is largely dependent on the skill of the healthcare team to prevent further harm and enhance therapeutic outcomes by providing astute assessment and management of complications in patients undergoing induced hypothermia. The desired outcome of this review is to promote integration of research in the development of evidence-based protocols for induced hypothermia.
Show less - Date Issued
- 2011
- Identifier
- CFH0003836, ucf:44718
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH0003836
- Title
- Mechanisms of Alpha-Synuclein-Induced Neurodegenertaion in Parkinson's Disease and Stroke.
- Creator
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Belal, Cherine, Chan, Sic, Ebert, Steven, Self, William, Teter, Kenneth, University of Central Florida
- Abstract / Description
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Parkinson's disease (PD) is a debilitating neurodegenerative disorder affecting one million Americans. Despite its social and economic impact, the pathological cascades that lead to neuron dysfunction and degeneration in PD are poorly understood. Endoplasmic reticulum (ER) stress has been implicated as an initiator or contributing factor in neurodegenerative diseases including PD. The ER is an organelle central to protein folding and intracellular Ca2+ homeostasis. Perturbations of these...
Show moreParkinson's disease (PD) is a debilitating neurodegenerative disorder affecting one million Americans. Despite its social and economic impact, the pathological cascades that lead to neuron dysfunction and degeneration in PD are poorly understood. Endoplasmic reticulum (ER) stress has been implicated as an initiator or contributing factor in neurodegenerative diseases including PD. The ER is an organelle central to protein folding and intracellular Ca2+ homeostasis. Perturbations of these functions result in ER stress and upregulation of ER stress proteins, of which some have been implicated in counteracting ER stress-induced cell death. The mechanisms that lead to ER stress and how ER stress proteins contribute to the degenerative cascades remain unclear but their understanding is critical to devising effective therapies for PD. Both the accumulation of mutant a-synuclein (aSyn), which causes an inherited form of PD, and the inhibition of mitochondrial complex I function by PD-inducing neurotoxin lead to ER stress. The critical involvement of ER stress in experimental models of PD supports its potential relevance to PD pathogenesis and led us to test the hypothesis whether the homocysteine-inducible ER protein (Herp), an ubiquitin-like domain (UBD) containing ER-resident protein, can counteract mutant Alpha Syn- and neurotoxin- induced pathological cascades.
Show less - Date Issued
- 2011
- Identifier
- CFE0004470, ucf:49310
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0004470
- Title
- Plasticity of Central and Peripheral Nervous System: Effects of Oxygen-Glucose Deprivation (OGD), Chronic Intermittent Hypoxia (CIH) and hSOD1 Overexpression.
- Creator
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Chen, Jin, Cheng, Zixi, Naser, Saleh, Singla, Dinender, University of Central Florida
- Abstract / Description
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Transient receptor potential canonical 6 (TRPC6) channels are permeable to Na+ and Ca2+ and are widely expressed in the brain. In this study, we investigated the role of TRPC6 following ischemia/reperfusion (I/R) and oxygen-glucose deprivation (OGD). We found that TRPC6 expression was increased in wild type (WT) mice cortical neurons following I/R and in primary neurons with OGD, and that deletion of TRPC6 reduced the I/R-induced brain infarct in mice and the OGD- /neurotoxin-induced neuronal...
Show moreTransient receptor potential canonical 6 (TRPC6) channels are permeable to Na+ and Ca2+ and are widely expressed in the brain. In this study, we investigated the role of TRPC6 following ischemia/reperfusion (I/R) and oxygen-glucose deprivation (OGD). We found that TRPC6 expression was increased in wild type (WT) mice cortical neurons following I/R and in primary neurons with OGD, and that deletion of TRPC6 reduced the I/R-induced brain infarct in mice and the OGD- /neurotoxin-induced neuronal death. Using live-cell imaging to examine intracellular Ca2+ levels ([Ca2+]i), we found that OGD induced a significant higher increase in glutamate-evoked Ca2+ influx compared to untreated control and such an increase was reduced by TRPC6 deletion. Enhancement of TRPC6 expression using AdCMV-TRPC6-GFP infection in WT neurons increased [Ca2+]i in response to glutamate application compared to AdCMV-GFP control. Inhibition of N-methyl-d-aspartic acid receptor (NMDAR) with MK801 decreased TRPC6-dependent increase of [Ca2+]i, indicating that such a Ca2+ influx was NMDAR dependent. Furthermore, TRPC6-dependent Ca2+ influx was blunted by blockade of Na+ entry. Finally, OGD-enhanced Ca2+ influx was reduced, but not completely blocked, in the presence of voltage dependent Na+ channel blocker tetrodotoxin (TTX) and dl???amino?3?hydroxy?5?methyl?4?isoxazole propionic acid (AMPA) blocker CNQX. Altogether, we concluded that I/R-induced brain damage was, in part, due to upregulation of TRPC6 in cortical neurons. We postulate that overexpression of TRPC6 following I/R may induce neuronal death partially through TRPC6-dependent Na+ entry which activated NMDAR, thus leading to a damaging Ca2+ overload. These findings may provide a potential target for future intervention in stroke-induced brain damage. Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder that is associated with many cardiovascular complications, such as autonomic dysfunctions, stroke and heart failure. Chronic intermittent hypoxia (CIH) is a prominent feature of OSA. In CIH exposed rodents (a model for OSA), CIH induces the similar cardiovascular complications as seen in OSA patients. In particular, OSA impairs baroreflex control of the heart rate (HR), which is used as an independent indicator for heart failure. Since the baroreflex control arc includes the aortic depressor nerve (ADN), vagal efferent and central components, we hypothesize that CIH induces dysfunctions of all three components. Since mice can be genetically manipulated, an understanding of the effects of CIH on multiple neural components in the baroreflex arc in wild type mice may lead to a future study of treatments. In this study, we have examined the effects of CIH on baroreceptor afferent, central and vagal efferent components of the baroreflex circuitry in normal wild type C57BL/6J mice. Mice (4-5 months) were exposed to room air (RA) or CIH for 35-50 days and were then anesthetized with isoflurane, ventilated and catheterized for measurement of mean arterial blood pressure (MAP) and HR. Baroreceptor function was characterized by measuring percent changes of integrated ADN activity (Int ADNA) relative to the baseline value in response to the vasodilator sodium nitroprusside and the vasoconstrictor phenylephrine-induced changes in MAP. Data were fitted to a sigmoid logistic function curve. HR responses to electrical stimulation of the left ADN and the right vagus nerve were assessed under anesthesia. Compared with RA controls, CIH significantly increased maximum baroreceptor gain or maximum slope, maximum Int ADNA, and Int ADNA range (maximum-minimum Int ADNA). In addition, CIH maintained the maximum amplitude of the bradycardic response to vagal efferent stimulation. In contrast, CIH significantly reduced the maximum amplitude of bradycardic response to left ADN stimulation. Thus, CIH decreased central mediation of the baroreflex, but augmented the baroreceptor afferent function and maintained vagal efferent control of HR in mice. Excessive reactive oxygen species (ROS) (such as the superoxide radical) is commonly associated with cardiac autonomic dysfunctions. Though superoxide dismutase 1 (SOD1) overexpression may protect against ROS damage to the autonomic nervous system, superoxide radical reduction may change normal physiological functions. Previously, we demonstrated that human SOD1 (hSOD1) overexpression did not change baroreflex bradycardia and tachycardia, but increased aortic depressor nerve activity (ADNA) in responses to arterial pressure changes in C57B6SJL-Tg (SOD1)2 Gur/J mice. Since the barorelfex arc includes afferent, central and efferent components, the objective of this study was to determine whether hSOD1 overexpression alters the central and vagal efferent mediation of the heart rate (HR) responses. Our data indicate that SOD1 overexpression decreased HR responses to vagal efferent nerve stimulations but did not change HR responses to aortic nerve stimulation. Along with the previous study, we suggest that SOD1 overexpression preserves the normal baroreflex function but may alter the functions of aortic depressor nerve, vagal efferent and central components differently. While SOD1 overexpression likely enhanced aortic depressor nerve function and central mediation of bradycardia, it decreased vagal efferent control of HR. Currently, we are using the hSOD1 overexpressing mouse model to determine whether hSOD1 overexpression can preserve normal afferent, efferent, and central components of the baroreflex arc in the CIH model of sleep apnea.
Show less - Date Issued
- 2017
- Identifier
- CFE0006576, ucf:51334
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0006576
