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Nina J Solenski

Publications and source records attributed to Nina J Solenski.

8 recordsLinked to original sources
PubMed2006

Nitric oxide impairs mitochondrial movement in cortical neurons during hypoxia.

Cortical nitric oxide (NO) production increases during hypoxia/ischemia in the immature brain and is associated with both neurotoxicity and mitochondrial dysfunction. Mitochondrial redistribution within the cell is critical to normal neuronal function, however, the effects of hypoxia on mitochondrial dynamics are not known. This study tested the hypothesis that hypoxia impairs mitochondrial movement via NO-mediated pathways. Fluorescently labeled mitochondria were studied using time-lapse digital video microscopy in cultured cortical neurons exposed either to hypoxia/re-oxygenation or to diethyleneamine/nitric oxide adduct, DETA-NO (100-500 microm). Two NO synthase inhibitors, were used to determine NO specificity. Mitochondrial mean velocity, the percentage of movement (i.e. the time spent moving) and mitochondrial morphology were analyzed. Exposure to hypoxia reduced mitochondrial movement to 10.4 +/- 1.3% at 0 h and 7.4 +/- 1.7% at 1 h of re-oxygenation, versus 25.6 +/- 1.4% in controls (p < 0.05). Mean mitochondrial velocity (microm s(-1)) decreased from 0.374 +/- 0.01 in controls to 0.146 +/- 0.01 at 0 h and 0.177 +/- 0.02 at 1 h of re-oxygenation (p < 0.001). Exposure to DETA-NO resulted in a significant decrease in mean mitochondrial velocity at all tested time points. Treatment with NG-nitro-L-arginine methyl ester (L-NAME) prevented the hypoxia-induced decrease in mitochondrial movement at 0 h (30.1 +/- 1.6%) and at 1 h (26.1 +/- 9%) of re-oxygenation. Exposure to either hypoxia/re-oxygenation or NO also resulted in the rapid decrease in mitochondrial size. Both hypoxia and NO exposure result in impaired mitochondrial movement and morphology in cultured cortical neurons. As the effect of hypoxia on mitochondrial movement and morphology can be partially prevented by a nitric oxide synthase (NOS) inhibitor, these data suggest that an NO-mediated pathway is at least partially involved.

Animals↗
PubMed2005

Mechanisms of ischemic neuroprotection by acetyl-L-carnitine.

Acetyl-L-carnitine is a naturally occurring substance that, when administered at supraphysiologic concentrations, is neuroprotective in several animal models of global and focal cerebral ischemia. Three primary mechanisms of action are supported by neurochemical outcome measures performed with these models and with in vitro models of acute neuronal cell death. The metabolic hypothesis is based on the oxidative metabolism of the acetyl component of acetyl-L-carnitine and is a simple explanation for the reduction in postischemic brain lactate levels and elevation of ATP seen with drug administration. The antioxidant mechanism is supported by reduction of oxidative stress markers, for example, protein oxidation, in both brain tissue and cerebrospinal fluid. The relatively uncharacterized mechanism of inhibiting excitotoxicity could be extremely important in both acute brain injury and chronic neurodegenerative disorders. New experiments performed with primary cultures of rat cortical neurons indicate that the presence of acetyl-L-carnitine significantly inhibits both acute and delayed cell death following exposure to NMDA, an excitotoxic glutamate antagonist. Finally, several other mechanisms of action are possible, including a neurotrophic effect of acetyl-L-carnitine and inhibition of mitochondrial permeability transition. While the multiple potential mechanisms of neuroprotection by acetyl-L-carnitine limit an accurate designation of the most important mode of action, they are compatible with the concept that several brain injury pathways must be inhibited to optimize therapeutic efficacy.

Acetylcarnitine↗
PubMed2004

Transient ischemic attacks: Part I. Diagnosis and evaluation.

Transient ischemic attack is no longer considered a benign event but, rather, a critical harbinger of impending stroke. Failure to quickly recognize and evaluate this warning sign could mean missing an opportunity to prevent permanent disability or death. The 90-day risk of stroke after a transient ischemic attack has been estimated to be approximately 10 percent, with one half of strokes occurring within the first two days of the attack. The 90-day stroke risk is even higher when a transient ischemic attack results from internal carotid artery stenosis. Most patients reporting symptoms of transient ischemic attack should be sent to an emergency department. Patients who arrive at the emergency department within 180 minutes of symptom onset should undergo an expedited history and physical examination, as well as selected laboratory tests, to determine if they are candidates for thrombolytic therapy. Initial testing should include complete blood count with platelet count, prothrombin time, International Normalized Ratio, partial thromboplastin time, and electrolyte and glucose levels. Computed tomographic scanning of the head should be performed immediately to ensure that there is no evidence of brain hemorrhage or mass. A transient ischemic attack can be misdiagnosed as migraine, seizure, peripheral neuropathy, or anxiety.

Diagnosis, Differential↗
PubMed2004

Transient ischemic attacks: Part II. Treatment.

Risk factors for stroke should be evaluated in patients who have had a transient ischemic attack. Blood pressure, lipid levels, and diabetes mellitus should be controlled. When applicable, smoking cessation and weight loss also are important. Angiotensin-converting enzyme inhibitor therapy may help prevent stroke. Aspirin is the treatment of choice for stroke prevention in patients who do not require anticoagulation. Clopidogrel is an alternative therapy in patients who do not tolerate aspirin. Atrial fibrillation, a known cardioembolic source (confirmed thrombus), or a highly suspected cardioembolic source (e.g., recent large myocardial infarction, dilated cardiomyopathy, mechanical valve, rheumatic mitral valve stenosis) are indications for anticoagulation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Nitric-oxide-induced depolarization of neuronal mitochondria: implications for neuronal cell death.

Nitric oxide (NO(*)) has known toxic effects on central nervous system neurons. This study characterized the effect of NO(*) on mitochondrial membrane changes by exploring the relationship among NO(*), excitatory receptor activation, and the induction of peroxynitrite, a highly toxic NO(*) reactant, to neuronal injury. Cultured rat cortical neurons were exposed to the NO(*) generator, diethylenetriamine/nitric oxide adduct, and were examined for signs of cell death, mitochondrial membrane potential changes (Deltapsi(m)), and the induction of a mitochondrial permeability transition (MPT). Neurons were also examined for nitrotyrosine (NT) immunoreactivity, a marker of reactive nitrogen species (RNS) formation. Neurons exposed to NO(*) or to N-methyl-D-aspartate (NMDA) exhibited similar rapid depolarization of mitochondria, which was prevented by an NMDA receptor antagonist. Electrophysiological studies demonstrated NO(*) potentiation of NMDA-induced NMDA receptor currents. NO(*) and NMDA-treated neurons had evidence of mitochondrial-specific NT immunoreactivity that was prevented by a SOD/catalase mimetic (EUK-134). EUK-134 treatment reduced both NO(*) and NMDA-induced NT formation and neuronal cell death. EUK-134 did not prevent NO-induced Deltapsi(m) but partially prevented NMDA-induced Deltapsi(m) loss. Although NO(*) and NMDA both induced MPT and MPT inhibitors prevented NO-induced Deltapsi(m), they did not result in significant neuroprotection, in contrast to treatment designed to decrease peroxynitrite formation. These data suggest that NO-induced NMDA receptor activation is closely linked to intramitochondrial NO-peroxynitrite/RNS formation and thereby acts as a major mediator of neuronal cell death.

Animals↗
PubMed2003

Neurotoxic nitric oxide rapidly depolarizes and permeabilizes mitochondria by dynamically opening the mitochondrial transition pore.

Exposure of SH-SY5Y neuroblastoma or rat cortical neurons to diethylenetriamine-NO (DETA-NO) rapidly depolarized mitochondria. In SH-SY5Y DETA-NO activated caspase 3 and produced cell death. Mitochondrial depolarization in SH-SY5Y was visualized both with JC-1 accumulation and as dequenching of calcein fluorescence in mitochondria initially loaded with calcein-AM and tetramethylrhodamine methyl ester (TMRM). Calcein/TMRM-visualized mitochondrial depolarization was prevented by cyclosporin A (CsA) or approximately two-fold increased levels of BclXL protein. Dynamic imaging of mitochondrial potential (Deltapsi M) with TMRM showed that DETA-NO induced cycles of mitochondrial depolarization/repolarization ("flickering"). Fifteen-30 min of DETA-NO exposure caused high-frequency flickering with small peak size; 2 h of DETA-NO produced large peaks with prolonged depolarization. NO-induced flickering but not that from Bax was blocked by the calcium uniporter antagonist Ru360. Our findings show rapid-onset, dynamic regulation of Deltapsi M by NO, implying that neuroprotective therapies for brain ischemia target cell death processes downstream of effects of NO on mitochondria.

Animals↗
PubMed2002

Ultrastructural changes of neuronal mitochondria after transient and permanent cerebral ischemia.

BACKGROUND AND PURPOSE: Mitochondrial swelling is one of the most striking and initial ultrastructural changes after acute brain ischemia. The purpose of the present study was to examine the role of reperfusion of the cerebral cortex after transient focal cerebral ischemia on neuronal mitochondrial damage. METHODS: Male Sprague-Dawley rats (n=16) were subjected to either temporary or permanent occlusion of the middle cerebral artery and bilateral carotid arteries. Three experimental conditions were compared: group I, permanent ischemia (3, 5, and 24 hours); group II, transient ischemia (2, 24 hours of reperfusion); and sham surgery. Anesthetized rats were killed by cardiac perfusion, and brain tissue was removed ipsilaterally and contralaterally from the ischemic core section of the frontoparietal cortex. Fixed tissue was prepared for electron microscopic examination, and electron microscopic thin sections of random neurons were photographed. Perinuclear neuronal mitochondria were analyzed in a blinded manner for qualitative ultrastructural changes (compared with sham control) by 2 independent investigators using an objective grading system. RESULTS: Cortical neuronal mitochondria exposed to severe ischemic/reperfusion conditions demonstrated dramatic signs of injury in the form of condensation, increased matrix density, and deposits of electron-dense material followed by disintegration by 24 hours. In contrast, mitochondria exposed to an equivalent time of permanent ischemia demonstrated increasing loss of matrix density with pronounced swelling followed by retention of their shape by 24 hours. CONCLUSIONS: Neuronal mitochondria undergoing transient versus permanent ischemia exhibit significantly different patterns of injury. Structural damage to neuronal mitochondria of the neocortex occurs more acutely and to a greater extent during the reperfusion phase in comparison to ischemic conditions alone. Further research is in progress to delineate the role of oxygen free radical production in the observed mitochondrial damage during postischemic reoxygenation.

Animals↗