nuclear encoded ncx3 and akap121 two novel modulators of mitochondrial calcium efflux in normoxic and hypoxic neurons

Abstract Mitochondria are highly dynamic organelles extremely important for cell survival. Their structure resembles that of prokaryotic cells since they are composed with two membranes, the inner (IMM) and the outer mitochondrial membrane (OMM) delimitating the intermembrane space (IMS) and the matrix which contains mitochondrial DNA (mtDNA). This structure is strictly related to mitochondrial function since they produce the most of the cellular ATP through the oxidative phosphorylation which generate the electrochemical gradient at the two sides of the inner mitochondrial membrane an essential requirement for mitochondrial function. Cells of highly metabolic demand like those composing muscle, liver and brain, are particularly dependent on mitochondria for their activities. Mitochondria undergo to continual changes in morphology since, they fuse and divide, branch and fragment, swell and extend. Importantly, they move throughout the cell to deliver ATP and other metabolites where they are mostly required. Along with the capability to control energy metabolism, mitochondria play a critical role in the regulation of many physiological processes such as programmed cell death, autophagy, redox signalling, and stem cells reprogramming. All these phenomena are regulated by Ca2+ ions within this organelle. This review will discuss the molecular mechanisms regulating mitochondrial calcium cycling in physiological and pathological conditions with particular regard to their impact on mitochondrial dynamics and function during ischemia. Particular emphasis will be devoted to the role played by NCX3 and AKAP121 as new molecular targets for mitochondrial function and dysfunction

Ionic homeostasis in brain conditioning

Most of the current focus on developing neuroprotective therapies is aimed at preventing neuronal death. However, these approaches have not been successful despite many years of clinical trials mainly because the numerous side effects observed in humans and absent in animals used at preclinical level. Recently, the research in this field aims to overcome this problem by developing strategies which induce, mimic, or boost endogenous protective responses and thus do not interfere with physiological neurotransmission. Preconditioning is a protective strategy in which a subliminal stimulus is applied before a subsequent harmful stimulus, thus inducing a state of tolerance in which the injury inflicted by the challenge is mitigated. Tolerance may be observed in ischemia, seizure, and infection. Since it requires protein synthesis, it confers delayed and temporary neuroprotection, taking hours to develop, with a pick at 1-3 days. A new promising approach for neuroprotection derives from post-conditioning, in which neuroprotection is achieved by a modified reperfusion subsequent to a prolonged ischemic episode. Many pathways have been proposed as plausible mechanisms to explain the neuroprotection offered by preconditioning and post-conditioning. Although the mechanisms through which these two endogenous protective strategies exert their effects are not yet fully understood, recent evidence highlights that the maintenance of ionic homeostasis plays a key role in propagating these neuroprotective phenomena. The present article will review the role of protein transporters and ionic channels involved in the control of ionic homeostasis in the neuroprotective effect of ischemic preconditioning and post-conditioning in adult brain, with particular regards to the Na(+)/Ca2(+) exchangers (NCX), the plasma membrane Ca2(+)-ATPase (PMCA), the Na(+)/H(+) exchange (NHE), the Na(+)/K(+)/2Cl(-) cotransport (NKCC) and the acid-sensing cation channels (ASIC). Ischemic stroke is the third leading cause of death and disability. Up until now, all clinical trials testing potential stroke neuroprotectants failed. For this reason attention of researchers has been focusing on the identification of brain endogenous neuroprotective mechanisms activated after cerebral ischemia. In this context, ischemic preconditioning and ischemic post-conditioning represent two neuroprotecive strategies to investigate in order to identify new molecular target to reduce the ischemic damage

Farmaci antivirali

Lo scopo principale degli autori del presente trattato è stato quello di correlare le conoscenze sempre più approfondite sull’azione molecolare dei farmaci con gli effetti farmacologici esercitati nell’uomo e che costituiscono i presupposti razionali della terapia medica. Uno spazio adeguato è stato inoltre riservato alla trattazione degli aspetti farmacocinetici clinici, delle reazioni avverse e delle interazioni tra i farmaci, che rappresentano un aspetto in continuo divenire e che sono spesso alla base di eventi avversi clinicamente rilevanti. L’ intento del testo è stato quello di fornire un’informazione la più completa possibile con l’inserimento nella trattazione di argomenti che hanno assunto negli ultimi anni particolare rilevanza nel campo delle possibili prospettive terapeutiche più moderne. Nel trattato sono presenti infatti capitoli innovativi quali quello sui Farmaci Biotecnologici a bersaglio definito, sulla Farmacogenetica e sulla Terapia Genica. Completano la trattazione argomenti inerenti gli aspetti socio-sanitari , economici e normativi della Farmacologia contenuti nei capitoli sulla Sperimentazione Clinica dei Farmaci, sulla Farmacoeconomia e sulla Farmacologia del Doping. Infine, in considerazione del largo uso che si fa dei prodotti di origine vegetale , si è ritenuto utile affrontare tale problematica nel capitolo Principi di fitoterapia nella pratica clinic

Farmaci Antimicotici

Lo scopo principale degli autori del presente trattato è stato quello di correlare le conoscenze sempre più approfondite sull’azione molecolare dei farmaci con gli effetti farmacologici esercitati nell’uomo e che costituiscono i presupposti razionali della terapia medica. Uno spazio adeguato è stato inoltre riservato alla trattazione degli aspetti farmacocinetici clinici, delle reazioni avverse e delle interazioni tra i farmaci, che rappresentano un aspetto in continuo divenire e che sono spesso alla base di eventi avversi clinicamente rilevanti. L’ intento del testo è stato quello di fornire un’informazione la più completa possibile con l’inserimento nella trattazione di argomenti che hanno assunto negli ultimi anni particolare rilevanza nel campo delle possibili prospettive terapeutiche più moderne. Nel trattato sono presenti infatti capitoli innovativi quali quello sui Farmaci Biotecnologici a bersaglio definito, sulla Farmacogenetica e sulla Terapia Genica. Completano la trattazione argomenti inerenti gli aspetti socio-sanitari , economici e normativi della Farmacologia contenuti nei capitoli sulla Sperimentazione Clinica dei Farmaci, sulla Farmacoeconomia e sulla Farmacologia del Doping. Infine, in considerazione del largo uso che si fa dei prodotti di origine vegetale , si è ritenuto utile affrontare tale problematica nel capitolo Principi di fitoterapia nella pratica clinica

Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation

Ischemia is a major cause of brain damage, and patient management is complicated by the paradoxical injury that results from reoxygenation. We have now explored the generation of reactive oxygen species (ROS) in hippocampal and cortical neurons in culture in response to oxygen and glucose deprivation or metabolic inhibition and reoxygenation. Fluorescence microscopy was used to measure the rate of ROS generation using hydroethidine, dicarboxyfluorescein diacetate, or MitoSOX. ROS generation was correlated with changing mitochondrial potential (rhodamine 123), [Ca2+]c (fluo-4, fura-2, or Indo-1), or ATP consumption, indicated by increased [Mg2+]c. We found that three distinct mechanisms contribute to neuronal injury by generating ROS and oxidative stress, each operating at a different stage of ischemia and reperfusion. In response to hypoxia, mitochondria generate an initial burst of ROS, which is curtailed once mitochondria depolarize or prevented by previous depolarization with uncoupler. A second phase of ROS generation that followed after a delay was blocked by the xanthine oxidase (XO) inhibitor oxypurinol. This phase correlated with a rise in [Mg2+]c, suggesting XO activation by accumulating products of ATP consumption. A third phase of ROS generation appeared at reoxygenation. This was blocked by NADPH oxidase inhibitors and was absent in cells from gp91(phox-/-) knock-out mice. It was Ca2+ dependent, suggesting activation by increased [Ca2+]c during anoxia, itself partly attributable to glutamate release. Inhibition of either the NADPH oxidase or XO was significantly neuroprotective. Thus, oxidative stress contributes to cell death over and above the injury attributable to energy deprivation

Mitochondrial Ca2+ Dysregulation During Stroke and Cell Death

This book illustrates remarkable roles of metal ions in the neuropathophysiology of stroke, which is a major cause of death and disability worldwide. Metal ions have unique chemical properties that allow them to play diverse roles in the brain. They regulate excitability and function as co-factors in cellular and genetic signaling pathways and therefore, have important roles ranging from essential to toxic. For the first time, the dyshomeostasis and pathophysiological actions of these metals in stroke are discussed systematically in thirty-six chapters in one volume