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Michael Tymianski

Publications and source records attributed to Michael Tymianski.

17 recordsLinked to original sources
PubMed2006

Inhibition of caspase-mediated apoptosis by peroxynitrite in traumatic brain injury.

In traumatic brain injury (TBI), neurons surviving the primary insult may succumb through poorly understood secondary mechanisms. In vitro, cortical neurons exposed to stretch injury exhibited enhanced vulnerability to NMDA, apoptotic-like DNA fragmentation, peroxynitrite (PN) formation, and cytoplasmic cytochrome c accumulation. Surprisingly, caspase-3 activity was undetectable by both immunoblotting and fluorogenic activity assays. Therefore, we hypothesized that PN directly inhibits caspases in these neurons. Consistent with this, stretch injury in cultured neurons elicited tyrosine nitration of procaspase-3, but not caspase-9 or Apaf-1, suggesting a direct interaction of PN with caspase-3. In an ex vivo system, PN inhibited the activity of caspase-3, and this inhibition was reversible with the addition of the sulfhydryl reducing agent dithiothreitol, indicating that PN inhibits caspases by cysteinyl oxidation. Moreover, in cultures, the PN donor 3-morpholinosydnonimine (SIN-1) blocked staurosporine-induced caspase-3 activation and its downstream effects including PARP-1 [poly-(ADP-ribose) polymerase-1] cleavage and phosphotidylserine inversion, suggesting that peroxynitrite can inhibit caspase-3-mediated apoptosis. To examine these mechanisms in vivo, rats were exposed to a lateral fluid percussion injury (FPI). FPI caused increased neuronal protein nitration that colocalized with TUNEL staining, indicating that PN was associated with neurodegeneration. Caspase-3 activity was inhibited in brain lysates harvested after FPI and was restored by adding dithiothreitol. Our data show that caspase-mediated apoptosis is inhibited in neurons subjected to stretch in vitro and to TBI in vivo, mostly because of cysteinyl oxidation of caspase-3 by PN. However, this is insufficient to prevent cell death, indicating that the TBI therapy may, at a minimum, require a combination of both anti-apoptotic and anti-oxidant strategies.

Animals↗
PubMed2006

A discriminative prediction model of neurological outcome for patients undergoing surgery of brain arteriovenous malformations.

BACKGROUND AND PURPOSE: To develop and validate a discriminative model for predicting neurological morbidity after brain arteriovenous malformation (bAVM) surgery. METHODS: Of 233 consecutive, prospectively enrolled patients undergoing bAVM surgery, the first 175 were used to derive, and the last 58 to validate, the prediction model. Demographic and angiographic factors were related to modified Rankin Scale scores assigned before, within 72 hours, at 7 days and at > or =1 year after surgery to seek predictors of postoperative neurological deficits (modified Rankin Scale score > or =3). These factors included nidus size, eloquence, venous drainage, diffuseness, white matter configuration, arterial perforator supply and associated aneurysms. RESULTS: Brain eloquence, diffuse nidus and deep venous drainage were significant predictors of early disabling neurological deficits (odds ratios of 4.33, 3.49 and 2.38, respectively). The rounded odds ratios form a weighted 9-point prediction model (maximum scores for eloquence+diffuseness+deep drainage=4+3+2). The score discriminated the probability of experiencing both early (first week) and permanently (at > or =1 year) disabling neurological deficits as follows: 0 to 2: 1.8%, 3 to 5: 17.4%, 6 to 7: 31.6%, >7: 52.9% for early and 0 to 2: 1.8%, 3 to 5: 4.4%, 6 to 7: 18.4%, >7: 32.4% for permanently disabling outcomes. The discrimination of the model was 0.80 with 2.8% optimism. Validation in the second patient cohort revealed good performance at risk stratification. CONCLUSIONS: Relative weights assigned to brain eloquence, diffuse nidus morphology and deep venous drainage of a bAVM provide a simple and discriminative prediction model for neurological outcome after bAVM surgery.

Adolescent↗
PubMed2006

Symptomatic non-atherosclerotic bilateral extracranial vertebral artery occlusion treated with extracranial to intracranial bypass: case report.

Posterior fossa ischemia is not a very frequent situation. It is responsible for about 25% of all ischemic strokes, and the vast majority of the cases are related to atherosclerotic stenosis of the vertebral and/or basilar arteries. Acute ischemia can also occur in the setting of vertebral artery dissection, traumatic or spontaneous. Recently, blunt trauma has been increasingly recognized as a cause for craniocervical artery injury. The management options for both traumatic and atherosclerotic lesions of the posterior fossa are still under debate. We present a case of a delayed onset of hemodynamic ischemic symptoms due to bilateral vertebral artery occlusion probably related to remote trauma to the head and neck in a 55-year-old-man treated successfully with extracranial to intracranial bypass.

Arterial Occlusive Diseases↗
PubMed2005

TRPMs and neuronal cell death.

Death of CNS neurons during acute injury occurs as a result of a complex combination of excitotoxicity, necrosis, apoptosis, oedema and inflammatory reactions. Neuroprotection via glutamate receptor blockade or antioxidant or anti-inflammatory therapy have not proven effective in the clinical treatment of brain damage due to narrow therapeutic windows, poor pharmacokinetics or blockade of the signalling essential for normal excitatory neurotransmission and neuronal survival. Recent work in neuronal biochemistry, genomics and proteomics has increased understanding of the molecular organization of the excitatory synapse and the neuronal postsynaptic density. Transient receptor potential (TRP) channels are an exciting new family of cation channels that are highly expressed in the brain. Several members can be induced by oxidative stress and oxygen free radicals, both of which play important roles in neurodegeneration. Recent work has indicated that members of the melastatin subfamily (TRPM) of TRP proteins, particularly TRPM7 and TRPM2, may play key roles in neuronal death that is activated by oxidative stress and downstream from excitotoxic signal pathways. This discovery provides an exiting new avenue for research into the pathophysiology and treatment of acute neurodegeneration.

Calcium↗
PubMed2005

TRPM7 and ischemic CNS injury.

Ischemic brain damage represents a major source of morbidity and mortality in westernized society and poses a significant financial burden on the health care system. To date, few effective therapies have been realized to treat stroke and once promising avenues such as antiexcitotoxic therapy with NMDA receptor antagonists have not proven clinically useful. Thus, we need to identify new targets for research and therapeutic intervention of the neurodegeneration caused by stroke. Transient receptor potential (TRP) channels are an exciting new family of cation channels that respond to intracellular and extracellular stimuli. Indeed, several members can be induced by oxidative stress and oxygen free radicals. We have recently demonstrated that one member, TRPM7, is an essential mediator of anoxic neuronal death that is activated by oxidative stress, in parallel to excitotoxic signal pathways. Thus, future treatment of ischemic brain injury may need to include strategies that inhibit or modulate TRPM7 activity. Further investigation of the physiology and pathophysiology of TRPM7 and other TRP family members is needed to provide both pharmacological targets and a better understanding of ischemic brain disorders.

Brain Ischemia↗
PubMed2005

Preoperative and postoperative mapping of cerebrovascular reactivity in moyamoya disease by using blood oxygen level-dependent magnetic resonance imaging.

OBJECT: The ability to map cerebrovascular reactivity (CVR) at the tissue level in patients with moyamoya disease could have considerable impact on patient management, especially in guiding surgical intervention and assessing the effectiveness of surgical revascularization. This paper introduces a new noninvasive magnetic resonance (MR) imaging-based method to map CVR. Preoperative and postoperative results are reported in three cases to demonstrate the efficacy of this technique in assessing vascular reserve at the microvascular level. METHODS: Three patients with angiographically confirmed moyamoya disease were evaluated before and after surgical revascularization. Measurements of CVR were obtained by rapidly manipulating end-tidal PCO2 between hypercapnic and hypocapnic states during MR imaging. The CVR maps were then calculated by comparing the percentage of changes in MR signal with changes in end-tidal PCO2. Presurgical CVR maps showed distinct regions of positive and negative reactivity that correlated precisely with the vascular territories supplied by severely narrowed vessels. Postsurgical reactivity maps demonstrated improvement in the two patients with positive clinical outcome and no change in the patient in whom a failed superficial temporal artery-middle cerebral artery bypass was performed. CONCLUSIONS: Magnetic imaging-based CVR mapping during rapid manipulation of end-tidal PCO2 is an exciting new method for determining the location and extent of abnormal vascular reactivity secondary to proximal large-vessel stenoses in moyamoya disease. Although the study group is small, there seems to be considerable potential for guiding preoperative decisions and monitoring efficacy of surgical revascularization.

Adult↗
PubMed2005

Analysis of cost related to clinical and angiographic outcomes of aneurysm patients enrolled in the international subarachnoid aneurysm trial in a North American setting.

OBJECTIVE: The goal of this study was to compare, in a North American setting, the cost-effectiveness of neurosurgical clipping versus endovascular coiling treatment of ruptured intracranial aneurysms. A secondary goal was to assess the clinical outcomes of patients enrolled into the International Subarachnoid Aneurysm Trial (ISAT) from the largest contributing North American center. METHODS: Of 230 patients with ruptured intracranial aneurysms, 62 were randomized into ISAT at our institution. Of these, 30 were randomized to endovascular coiling and 32 to neurosurgical clipping. For these, we evaluated the costs of treatment related to all aspects of the inpatient stay, the clinical outcomes at 2 months and at 1 year using the modified Rankin Scale, and the radiological outcomes at 6 months after Guglielmi detachable coiling. RESULTS: There were no significant differences in the total cost of treatment between the endovascular group and the neurosurgical clipping group. The benefits of apparent decrease in length of stay in the endovascular group were offset by higher procedure costs. There were no significant differences in clinical outcomes at 2 months and at 1 year. At 6 months after coiling, 15 (50%) of 30 aneurysms were completely obliterated, and 19 (63%) of 30 were angiographically stable. CONCLUSION: The high procedure costs of endovascular coiling tended to offset apparent reductions in length of stay. Long-term follow-up is indicated both for costs incurred after initial treatment and for clinical outcome in patients with incompletely obliterated aneurysms.

Aneurysm, Ruptured↗
PubMed2004

Vulnerability of central neurons to secondary insults after in vitro mechanical stretch.

Mild traumatic brain injuries are of major public health significance. Neurons in such injuries often survive the primary mechanical deformation only to succumb to subsequent insults. To study mechanisms of vulnerability of injured neurons to secondary insults, we used an in vitro model of sublethal mechanical stretch. Stretch enhanced the vulnerability of the neurons to excitotoxic insults, causing nuclear irregularities, DNA fragmentation, and death suggestive of apoptosis. However, the DNA degradation was not attributable to classical (caspase mediated) or caspase-independent apoptosis. Rather, it was associated with profound stretch-induced mitochondrial dysfunction and the overproduction of reactive oxygen species (ROS). Sublethally stretched neurons produced surprisingly high levels of ROS, but these in isolation were insufficient to kill the cells. To be lethal, the ROS also needed to combine with nitric oxide (NO) to form the highly reactive species peroxynitrite. Peroxynitrite was not produced after stretch alone and arose only after combining stretch with an insult capable of stimulating NO production, such as NMDA or an NO donor. This explained the exquisite sensitivity of sublethally stretched neurons to a secondary NMDA insult. ROS scavengers and NO synthase (NOS) inhibitors prevented cell death and DNA degradation. Moreover, inhibiting neuronal NOS activation by NMDA using peptides that perturb NMDA receptor-postsynaptic density-95 interactions also reduced protein nitration and cell death, indicating that the reactive nitrogen species produced were neuronal in origin. Our data explain the mechanism of enhanced vulnerability of sublethally injured neurons to secondary excitotoxic insults and highlight the importance of secondary mechanisms to the ultimate outcome of neurons in mild neurotrauma.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2004

Molecular mechanisms underlying specificity of excitotoxic signaling in neurons.

The central role of glutamate receptors in mediating excitotoxic neuronal death in stroke, epilepsy and trauma has been well established. Glutamate is the major excitatory amino acid transmitter within the CNS and it's signaling is mediated by a number of postsynaptic ionotropic and metabotropic receptors. Although calcium ions are considered key regulators of excitotoxicity, new evidence suggests that specific second messenger pathways rather than total Ca(2+) load, are responsible for mediating neuronal degeneration. Glutamate receptors are found localized at the synapse within electron dense structures known as the postsynaptic density (PSD). Localization at the PSD is mediated by binding of glutamate receptors to submembrane proteins such as actin and PDZ containing proteins. PDZ domains are conserved motifs that mediate protein-protein interactions and self-association. In addition to glutamate receptors PDZ-containing proteins bind a multitude of intracellular signal molecules including nitric oxide synthase. In this way PDZ proteins provide a mechanism for clustering glutamate receptors at the synapse together with their corresponding signal transduction proteins. PSD organization may thus facilitate the individual neurotoxic signal mechanisms downstream of receptors during glutamate overactivity. Evidence exists showing that inhibiting signals downstream of glutamate receptors, such as nitric oxide and PARP-1 can reduce excitotoxic insult. Furthermore we have shown that uncoupling the interaction between specific glutamate receptors from their PDZ proteins protects neurons against glutamate-mediated excitotoxicity. These findings have significant implications for the treatment of neurodegenerative diseases using therapeutics that specifically target intracellular protein-protein interactions.

Amino Acid Motifs↗
PubMed2003

A key role for TRPM7 channels in anoxic neuronal death.

Excitotoxicity in brain ischemia triggers neuronal death and neurological disability, and yet these are not prevented by antiexcitotoxic therapy (AET) in humans. Here, we show that in neurons subjected to prolonged oxygen glucose deprivation (OGD), AET unmasks a dominant death mechanism perpetuated by a Ca2+-permeable nonselective cation conductance (IOGD). IOGD was activated by reactive oxygen/nitrogen species (ROS), and permitted neuronal Ca2+ overload and further ROS production despite AET. IOGD currents corresponded to those evoked in HEK-293 cells expressing the nonselective cation conductance TRPM7. In cortical neurons, blocking IOGD or suppressing TRPM7 expression blocked TRPM7 currents, anoxic 45Ca2+ uptake, ROS production, and anoxic death. TRPM7 suppression eliminated the need for AET to rescue anoxic neurons and permitted the survival of neurons previously destined to die from prolonged anoxia. Thus, excitotoxicity is a subset of a greater overall anoxic cell death mechanism, in which TRPM7 channels play a key role.

Animals↗
PubMed2003

Novel concepts in excitotoxic neurodegeneration after stroke.

Brain injury following cerebral ischaemia (stroke) involves a complex combination of pathological processes, including excitotoxicity and inflammation leading to necrotic and apoptotic forms of cell death. At the cellular level, excitotoxicity is mediated by glutamate and its cognate receptors, resulting in increased intracellular calcium and free radical production, and eventual cell death. Recent evidence suggests that scaffolding molecules that associate with glutamate receptors at the postsynaptic density allow coupling of receptor activity to specific second messengers capable of mediating excitotoxicity. These findings have important implications in the search for effective neuroprotective therapies in treating stroke.

Animals↗
PubMed2003

Novel treatment of excitotoxicity: targeted disruption of intracellular signalling from glutamate receptors.

Glutamate signalling plays key physiological roles in excitatory neurotransmission and CNS plasticity, but also mediates excitotoxicity, the process responsible for triggering neurodegeneration through glutamate receptor overactivation. Excitotoxicity is thought to be a key neurotoxic mechanism in neurological disorders, including brain ischemia, CNS trauma and epilepsy. However, treating excitotoxicity using glutamate receptor antagonists has not proven clinically viable, necessitating more sophisticated approaches. Increasing knowledge of the composition of the postsynaptic density at glutamatergic synapses has allowed us to extend our understanding of the molecular mechanisms of excitotoxicity and to dissect out the distinct signalling pathways responsible for excitotoxic damage. Key molecules in these pathways are physically linked to the cytoplasmic face of glutamate receptors by scaffolding proteins that exhibit binding specificity for some receptors over others. This imparts specificity to physiological and pathological glutamatergic signalling. Recently, we have capitalized on this knowledge and, using targeted peptides to selectively disrupt intracellular interactions linked to glutamate receptors, have blocked excitotoxic signalling in neurones. This therapeutic approach circumvents the negative consequences of blocking glutamate receptors, and may be a practical strategy for treating neurological disorders that involve excitotoxicity.

Animals↗
PubMed2003

Enhanced vulnerability to NMDA toxicity in sublethal traumatic neuronal injury in vitro.

Traumatic brain injury causes neuronal disruption and triggers secondary events leading to additional neuronal death. To study injuries triggered by secondary events, we exposed cultured cortical neurons to sublethal mechanical stretch, thus eliminating confounding death from primary trauma. Sublethally stretched neurons maintained cell membrane integrity, viability, and electrophysiological function. However, stretching induced in the cells a heightened vulnerability to subsequent challenges with L-glutamate or NMDA. This heightened vulnerability was specifically mediated by NMDA receptors (NMDARs), as stretched neurons did not become more vulnerable to either kainate toxicity or to that induced by the Ca(2+) ionophore A23187. Stretch-enhanced vulnerability to NMDA occurred independently of endogenous glutamate release, but required Ca(2+) and Na(+) influx through NMDARs. Stretch did not affect the electrophysiological properties of NMDARs nor excitatory synaptic activity, indicating that specificity of enhanced vulnerability to NMDA involves postsynaptic mechanisms downstream from NMDARs. To test whether this specificity requires physical interactions between NMDARs and cytoskeletal elements, we perturbed actin filaments and microtubules, both of which are linked to NMDARs. This had no effect on the stretch-induced vulnerability to NMDA, suggesting that sublethal stretch does not affect cell survival through the cytoskeleton. Our data illustrate that sublethal in vitro stretch injury triggers distinct signaling pathways that lead to secondary injury, rather than causing a generalized increase in vulnerability to secondary insults.

Animals↗
PubMed2003

Peptide action in stroke therapy.

Glutamate receptor antagonists, although effective in preventing in vitro excitotoxic death, also block the glutamatergic signalling that is essential for normal excitatory neurotransmission and neuronal survival. This has contributed to the failure of clinical trials employing glutamate receptor antagonists as stroke therapeutics. However, recent years have seen an increased understanding of the molecular organisation of glutamate receptors in the neuronal postsynaptic density. This and a dissection of their associated intracellular signalling cascades has allowed the identification of distinct pathways responsible for excitotoxicity. It has become possible to uncouple toxic signalling cascades from glutamate receptors by targeting the interactions of membrane receptors with downstream proteins. Toxic signalling can be effectively uncoupled from glutamate receptors using targeted, cell-permeable peptides to disrupt specific protein-protein interactions. This approach does not block essential excitatory neurotransmission, but attenuates neurotoxic signals specifically and reduces stroke damage. This novel approach to blocking excitotoxic signalling in cerebral ischaemia may constitute a practical approach to stroke therapy.

Animals↗
PubMed2002

Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions.

N-methyl-D-aspartate receptors (NMDARs) mediate ischemic brain damage but also mediate essential neuronal excitation. To treat stroke without blocking NMDARs, we transduced neurons with peptides that disrupted the interaction of NMDARs with the postsynaptic density protein PSD-95. This procedure dissociated NMDARs from downstream neurotoxic signaling without blocking synaptic activity or calcium influx. The peptides, when applied either before or 1 hour after an insult, protected cultured neurons from excitotoxicity, reduced focal ischemic brain damage in rats, and improved their neurological function. This approach circumvents the negative consequences associated with blocking NMDARs and may constitute a practical stroke therapy.

Amino Acid Sequence↗
PubMedDate not supplied

Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity.

Excitotoxicity contributes to neuronal degeneration in many acute CNS diseases, including ischemia, trauma, and epilepsy, and may also play a role in chronic diseases, such as amyotrophic lateral sclerosis (ALS). Key mediators of excitotoxic damage are Ca ions (Ca(2+)), which under physiological conditions govern a multitude of cellular processes, including cell growth, differentiation, and synaptic activity. Consequently, homeostatic mechanisms exist to maintain a low intracellular Ca(2+) ion concentration so that Ca(2+) signals remain spatially and temporally localized. This permits multiple independent Ca-mediated signaling pathways to occur in the same cell. In excitotoxicity, excessive synaptic release of glutamate can lead to the disregulation of Ca(2+) homeostasis. Glutamate activates postsynaptic receptors, including the ionotropic N-methyl-D-aspartate (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) proprionate (AMPA), and kainate receptors. Upon their activation, these open their associated ion channel to allow the influx of Ca(2+) and Na(+) ions. Although physiological elevations in intracellular Ca(2+) are salient to normal cell functioning, the excessive influx of Ca(2+) together with any Ca(2+) release from intracellular compartments can overwhelm Ca(2+)-regulatory mechanisms and lead to cell death. Although Ca(2+) disregulation is paramount to neurodegeneration, the exact mechanism by which Ca(2+) ions actually mediate excitotoxicity is less clear. One hypothesis outlined in this review suggests that Ca(2+)-dependent neurotoxicity occurs following the activation of distinct signaling cascades downstream from key points of Ca(2+) entry at synapses, and that triggers of these cascades are physically co-localized with specific glutamate receptors. Thus, we summarize the importance of Ca(2+) regulation in mammalian neurons and the excitotoxicity hypothesis, and focus on the molecular determinants of glutamate receptor-mediated excitotoxic mechanisms.

Animals↗