Nanoparticle-mediated therapeutic compounds delivery to glioblastoma.

INTRODUCTION: Glioblastoma multiforme is the most common and the most aggressive primary brain tumor, with a median survival of 14 months. This dismal prognostic has turned research toward nanomedicine as a new therapeutic approach that can deliver therapeutic compounds to GBM. AREAS COVERED: The review covers recent advances in the targeted delivery of therapeutic compounds to glioblastoma tumors. To reach the tumors, nanocarriers and their cargo should cross the Blood-Brain Barrier (BBB) standing between the bloodstream and the tumor. For that purpose, different peptides to facilitate BBB crossing have been added to the nanoparticles. As result, an increase in BBB crossing was observed. Other significant effort has been devoted to selectively target direct the nanocarrier and its cargo to GBM tumors. Once again, targeting peptides have been used. EXPERT OPINION: Besides significant advances, a more successful design of nanocarriers for efficient BBB crossing and delivery of diagnostic and/or therapeutic molecules to CNS will be needed to achieve efficient nanomedicine-based therapeutics for glioblastoma. This will require a significant effort in improving the chemical architecture of nanocarriers, identifying the critical design parameters that might play a key role in facilitating both BBB crossing and GBM selective targeting.

Aminophosphine ligands as a privileged platform for development of antitumoral ruthenium(ii) arene complexes.

The rapid and modular synthesis of the aminophosphine core has been exploited as a tool for rapid development of antitumoral metallodrug candidates. Starting with a series of structurally diverse aminophosphines, all obtained in a single step from commercial amines, a family of Ru(ii)-cymene complexes have been generated and tested in vitro for anti-tumoral activity in a series of cell lines, including the platinum-resistant A2780R. Through this approach, Ru(ii)-aminophosphine complexes have been identified with the IC50 value range as low as 10-0.8 µM. Several biological assays were carried out to gain insight into the mechanism of action. Cell death by apoptosis and pH-independent action has been demonstrated. In addition, a selective cytotoxicity profile for tumoral cells over non-tumoral cells has been identified. Importantly, for the key candidates no loss of activity was observed when applied to the Pt-resistant A2780R, which highlights the potential utility of the bis-phospinoamine scaffold as an easily-tunable auxiliary ligand core in both drug discovery and subsequently a logical design of new anticancer metal-containing drugs. The complexes are characterised by NMR spectroscopy, mass spectrometry and single-crystal X-ray diffraction.

Neutral high-generation phosphorus dendrimers inhibit macrophage-mediated inflammatory response in vitro and in vivo.

Inflammation is part of the physiological response of the organism to infectious diseases caused by organisms such as bacteria, viruses, fungi, or parasites. Innate immunity, mediated by mononuclear phagocytes, including monocytes and macrophages, is a first line of defense against infectious diseases and plays a key role triggering the delayed adaptive response that ensures an efficient defense against pathogens. Monocytes and macrophages stimulation by pathogen antigens results in activation of different signaling pathways leading to the release of proinflammatory cytokines. However, inflammation can also participate in the pathogenesis of several diseases, the autoimmune diseases that represent a relevant burden for human health. Dendrimers are branched, multivalent nanoparticles with a well-defined structure that have a high potential for biomedical applications. To explore new approaches to fight against the negative aspects of inflammation, we have used neutral high-generation phosphorus dendrimers bearing 48 (G3) or 96 (G4) bisphosphonate groups on their surface. These dendrimers show no toxicity and have good solubility and chemical stability in aqueous solutions. Here, we present data indicating that neutral phosphorus dendrimers show impressive antiinflammatory activities both in vitro and in vivo. In vitro, these dendrimers reduced the secretion of proinflammatory cytokines from mice and human monocyte-derived macrophages. In addition, these molecules present efficient antiinflammatory activity in vivo in a mouse model of subchronic inflammation. Taken together, these data suggest that neutral G3-G4 phosphorus dendrimers have strong potential applications in the therapy of inflammation and, likely, of autoimmune diseases.

Dendrimers as vectors for genetic material delivery to the nervous system.

Transfection of genetic material into primary neuronal cultures remains a challenge because of the intrinsic difficulty in transfecting this type of cell. This review covers the recent developments in the use of dendrimers for siRNA and DNA transfection in both neuronal and glial cells. Crossing the blood brain barrier crossing represents a challenge for the effective use of dendrimer-mediated delivery of therapeutic agents to the central nervous system. We will discuss the effectiveness, both in vitro and in vivo, of various dendrimers in delivering genetic material to neural tissue and its ability to cross the blood-brain barrier. In addition, the use of dendrimers as a potential new therapy in the treatment of glioblastoma will be presented.

Role of generation, architecture, pH and ionic strength on successful siRNA delivery and transfection by hybrid PPV-PAMAM dendrimers.

Small interfering RNA (siRNA) constitutes an excellent way of knocking down genes. However, it requires the use of delivery systems to reach the target cells, especially to neuronal cells. Dendrimers are one of the most widely used synthetic nanocarriers for siRNA delivery. However, due to the complexity of the dendrimer-siRNA interactions, when a new dendritic carrier is designed it is difficult to predict its efficiency to bind and to deliver siRNA. At the same time it is not easy to understand the origin of eventual limited functionalities. We have modeled the interactions between two dendrimers (TDG-G1 and TDG-G2) and siRNA using molecular dynamics (MD) simulation. The results were compared to experimental physico-chemical parameters such as siRNA complexation, complex stability, size, and zeta potentials and biological effects such as down-regulation of a specific RNA expression in cortical neurons in culture. Data indicate that the combination of rigid core and flexible branches guarantees strong siRNA binding, which is important to have a good transfection profile. However, the successful nanocarrier for siRNA delivery (TDG-G1) is identified not only by a high affinity for siRNA, but by a favorable equilibrium between a strong binding and the ability to release siRNA to exert its biological action. The conditions under which the dendriplex is formed are also relevant for transfection efficiency and biological activity.

Involvement of lipid rafts in the localization and dysfunction effect of the antitumor ether phospholipid edelfosine in mitochondria.

Lipid rafts and mitochondria are promising targets in cancer therapy. The synthetic antitumor alkyl-lysophospholipid analog edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) has been reported to target lipid rafts. Here, we have found that edelfosine induced loss of mitochondrial membrane potential and apoptosis in human cervical carcinoma HeLa cells, both responses being abrogated by Bcl-x(L) overexpression. We synthesized a number of new fluorescent edelfosine analogs, which preserved the proapoptotic activity of the parent drug, and colocalized with mitochondria in HeLa cells. Edelfosine induced swelling in isolated mitochondria, indicating an increase in mitochondrial membrane permeability. This mitochondrial swelling was independent of reactive oxygen species generation. A structurally related inactive analog was unable to promote mitochondrial swelling, highlighting the importance of edelfosine molecular structure in its effect on mitochondria. Raft disruption inhibited mitochondrial localization of the drug in cells and edelfosine-induced swelling in isolated mitochondria. Edelfosine promoted a redistribution of lipid rafts from the plasma membrane to mitochondria, suggesting a raft-mediated link between plasma membrane and mitochondria. Our data suggest that direct interaction of edelfosine with mitochondria eventually leads to mitochondrial dysfunction and apoptosis. These observations unveil a new framework in cancer chemotherapy that involves a link between lipid rafts and mitochondria in the mechanism of action of an antitumor drug, thus opening new avenues for cancer treatment.

Brain-derived neurotrophic factor modulates the severity of cognitive alterations induced by mutant huntingtin: involvement of phospholipaseCgamma activity and glutamate receptor expression.

The involvement of brain-derived neurotrophic factor (BDNF) in cognitive processes and the decrease in its expression in Huntington's disease suggest that this neurotrophin may play a role in learning impairment during the disease progression. We therefore analyzed the onset and severity of cognitive deficits in two different mouse models with the same mutant huntingtin but with different levels of BDNF (R6/1 and R6/1:BDNF+/- mice). We observed that BDNF modulates cognitive function in different learning tasks, even before the onset of motor symptoms. R6/1:BDNF+/- mice showed earlier and more accentuated cognitive impairment than R6/1 mice at 5 weeks of age in discrimination learning; at 5 weeks of age in procedural learning; and at 9 weeks of age in alternation learning. At the earliest age at which cognitive impairment was detected, electrophysiological analysis was performed in the hippocampus. All mutant genotypes showed reduced hippocampal long term potentiation (LTP) with respect to wild type but did not show differences between them. Thus, we evaluated the involvement of BDNF-trkB signaling and glutamate receptor expression in the hippocampus of these mice. We observed a decrease in phospholipaseCgamma activity, but not ERK, in R61, BDNF+/- and R6/1:BDNF+/- hippocampus at the age when LTP was altered. However, a specific decrease in the expression of glutamate receptors NR1, NR2A and GluR1 was detected only in R6/1:BDNF+/- hippocampus. Therefore, these results show that BDNF modulates the learning and memory alterations induced by mutant huntingtin. This interaction leads to intracellular changes, such as specific changes in glutamate receptors and in BDNF-trkB signaling through phospholipaseCgamma.

Increased NR2A expression and prolonged decay of NMDA-induced calcium transient in cerebellum of TgDyrk1A mice, a mouse model of Down syndrome.

Transgenic mice overexpressing Dyrk1A (TgDyrk1A), a Down syndrome (DS) candidate gene, exhibit motor and cognitive alterations similar to those observed in DS individuals. To gain new insights into the molecular consequences of Dyrk1A overexpression underlying TgDyrk1A and possibly DS motor phenotypes, microarray studies were performed. Transcriptome analysis showed an upregulation of the NR2A subunit of the NMDA type of glutamate receptors in TgDyrk1A cerebellum. NR2A protein overexpression was also detected in TgDyrk1A cerebellar homogenates, in the synaptosome-enriched fraction and in TgDyrk1A primary cerebellar granular neuronal cultures (CGNs). In TgDyrk1A synaptosomes, calcium-imaging experiments showed a higher calcium uptake after NMDA stimulation. Similarly, NMDA administration promoted longer calcium transients in TgDyrk1A CGNs. Taken together, these results show that NMDA-induced calcium rise is altered in TgDyrk1A cerebellar neurons and indicate that calcium signaling is dysregulated in TgDyrk1A mice cerebella. These findings suggest that DYRK1A overexpression might contribute to the dysbalance in the excitatory transmission found in the cerebellum of DS individuals and DS mouse models.

The radiologist's role in managing paediatric liver transplantation: personal experience with 40 patients.

PURPOSE: The aim of our study was to evaluate the radiologist's role in managing paediatric orthotopic liver transplantation (OLT) through a retrospective review of our experience in diagnosing and treating post-OLT complications. MATERIALS AND METHODS: Forty children (mean age 4.6 years) underwent 44 OLTs over 71 months. The follow-up period (mean 724 days) was divided into three phases: hospital stay, up to three months after discharge and subsequent period. The number and type of radiological examinations, radiologically detectable complications and interventional procedures were analysed. RESULTS: Most examinations were carried out with ultrasound (US) (859/931 of all radiological studies performed during the first two phases, 92.3%). Colour-Doppler US enabled early detection and treatment of all vascular complications (9/40, 22.5% of patients; 13 complications in nine patients, eight arterial and five portal complications; 1.4 for each patient with complications). Computed tomography (CT) or angiography was very rarely employed. US also detected biliary complications (11 patients, 27.5%: three cases of segmental ducts excluded from the anastomosis, four cases of stenosis of the biliodigestive anastomosis, one lithiasis, three stenoses associated with lithiasis), which were successfully managed in 75% of the cases treated with interventional radiology procedures (percutaneous bilioplasty and/or lithotripsy). At the time of writing this paper, the patient survival rate was 100%, and the organ survival rate was 91% (40/44). There were four re-transplantations: three due to hepatic artery thrombosis and one to biliary stenosis with lithiasis. CONCLUSIONS: The radiologist's role is fundamental for early sonographic diagnosis of post-OLT complications in children. Vascular complications are often associated in a single patient, and early treatment may improve the prognosis. Interventional radiology represents a safe and effective treatment for many biliary complications.

Acetaminophen potentiates staurosporine-induced death in a human neuroblastoma cell line.

BACKGROUND AND PURPOSE: Neuroblastoma is the most common solid tumour in infants characterized by a high resistance to apoptosis. Recently, the cyclo-oxygenase pathway has been considered a potential target in the treatment of different kinds of tumours. The aim of the present work was to investigate a possible relationship between cyclo-oxygenase pathway and stauroporine-induced apoptosis in the neuroblastoma cell line SH-SY5Y. EXPERIMENTAL APPROACH: Cellular viability was measured by release of LDH. DNA fragmentation was visualized by electrophoresis on agarose gel containing ethidium bromide. Cyclo-oxygenase activity was measured in microsomal fractions obtained from cells by quantification of its final product PGE2 by RIA. Caspase-3 activity was measured fluorimetrically and Western blot analysis was performed to assess cytochrome c expression. KEY RESULTS: We have found that staurosporine (500 nM) induced cellular death in a time-dependent manner in SH-SY5Y human neuroblastoma cells. Cyclo-oxygenase enzymatic activity was present in SH-SY5Y human neuroblastoma cells under basal conditions and pharmacological experiments using COX inhibitors indicate that cyclo-oxygenase-1 and cyclo-oxygenase-3 are the active isoforms in these cells. Co-incubation of SH-SY5Y cells with staurosporine (500 nM) and acetaminophen for 24 h potentiated staurosporine-mediated cellular death in a concentration-dependent manner. This process is mediated by an increase in cytochrome c release and caspase 3 activation and is prevented by N-acetylcysteine or the superoxide dismutase mimetic, MnTBAP. CONCLUSIONS AND IMPLICATIONS: Acetaminophen potentiates staurosporine-mediated neuroblastoma cell death. The mechanism of action of acetaminophen seems to be related to production of reactive oxygen species and decreased intracellular glutathione levels.

Involvement of mitochondrial potential and calcium buffering capacity in minocycline cytoprotective actions.

Minocycline, a semisynthetic derivative of tetracycline, displays beneficial activity in neuroprotective in models including, Parkinson disease, spinal cord injury, amyotrophic lateral sclerosis, Huntington disease and stroke. The mechanisms by which minocycline inhibits apoptosis remain poorly understood. In the present report we have investigated the effects of minocycline on mitochondria, due to their crucial role in apoptotic pathways. In mitochondria isolated suspensions, minocycline failed to block superoxide-induced swelling but was effective in blocking mitochondrial swelling induced by calcium. This latter effect might be mediated through dissipation of mitochondrial transmembrane potential and blockade of mitochondrial calcium uptake. Consistently, minocycline fails to protect SH-SY5Y cell cultures against reactive oxygen species-mediated cell death, including malonate and 6-hydroxydopamine treatments, but it is effective against staurosporine-induced cytotoxicity. The effects of this antibiotic on mitochondrial respiratory chain complex were also analyzed. Minocycline did not modify complex IV activity, and only at the higher concentration tested (100 microM) inhibited complex II/III activity. Other members of the minocycline antibiotic family like tetracycline failed to induce these mitochondrial effects.

Adrenal medulla calcium channel population is not conserved in bovine chromaffin cells in culture.

During the stress response adrenal medullary chromaffin cells release catecholamines to the bloodstream. Voltage-activated calcium channels present in the cell membrane play a crucial role in this process. Although the electrophysiological and pharmacological properties of chromaffin cell calcium channels have been studied in detail, the molecular composition of these channels has not been defined yet. Another aspect that needs to be explored is the extent to which chromaffin cells in culture reflect the adrenal medulla calcium channel characteristics. In this sense, it has been described that catecholamine release in the intact adrenal gland recruits different calcium channels than those recruited during secretion from cultured chromaffin cells. Additionally, recent electrophysiological studies show that chromaffin cells in culture differ from those located in the intact adrenal medulla in the contribution of several calcium channel types to the whole cell current. However there is not yet any study that compares the population of calcium channels in chromaffin cells with that one present in the adrenal medulla. In order to gain some insight into the roles that calcium channels might play in the adrenal medullary cells we have analyzed the alpha1 subunit mRNA expression profile. We demonstrate that the expression pattern of voltage-dependent calcium channels in cultured bovine chromaffin cells markedly differs from that found in the native adrenal medulla and that glucocorticoids are only partially involved in those differences. Additionally, we show, for the first time, that the cardiac isoform of L-type calcium channel is present in both bovine adrenal medulla and cultured chromaffin cells and that its levels of expression do not vary during culture.

[The serine proteases and their function in neuronal death processes]. / Las serina proteasas y su funcion en los procesos de muerte neuronal.

AIMS: In this review we analyse the role played by the serine proteases in the nervous system and we focus on the role they play in degenerative processes. DEVELOPMENT: These proteolytic enzymes, together with the caspases, play a vital role in the processes regulating cell functioning, both in the development stages and following the response to a harmful stimulus. This family of proteases includes the granzymes and thrombin (TR). The former, which are closely related to proteases I and II and cathepsin G, are situated in the cytoplasmic granules of the activated T lymphocytes, together with other proteins such as perforin or cytolysin. Granzymes A and B are linked to degenerative processes. These enter the target cells thanks to the action of perforin and once inside they are translocated to the nucleus. Granzyme A has been isolated and identified as the agent responsible for the immediate and complete retraction of neurites in different models. Its physiological substrates include fibronectin, type IV collagen and the proteoglycans. Granzyme B is characterised by its being a cysteine protease with substrates such as prointerleukin 1 beta, TR receptor and poly(ADP ribose) polymerase. The family of TR type proteases includes proteases such as TR itself, plasmin, kallikrein, urokinase plasminogen activator and tissue plasminogen activator. TR is considered to be an early modulator in damaged tissues which acts as an extracellular signal of death, leading to the activation of intracellular mechanisms that appear to be mediated by calcium. Serine protease activity is regulated by endogenous inhibitors, such as plasminogen activator inhibitor, protease nexin 1 and neuroserpin. CONCLUSIONS: Upsets in the protease inhibitor balance are crucial in the processes involved in the neuronal plasticity and death induced by ischemia in the brain and by excitotoxins.

Las serina proteasas y su función en los procesos de muerte neuronal / The serine proteases and their function in neuronal death processes

Objetivo. En esta revisión analizamos el papel de las serina proteasas en el sistema nervioso y nos centramos en su participación en los procesos degenerativos. Desarrollo. Estas enzimas proteolíticas, junto a las caspasas, desempeñan un papel esencial en los procesos de regulación de funciones celulares, tanto en etapas del desarrollo como tras la respuesta ante un estímulo dañino. Dentro de esta familia de proteasas se engloban las granzimas y la trombina (TR). Las primeras, altamente relacionadas con las proteasas I y II y la catepsina G, se localizan en los gránulos citoplasmáticos de los linfocitos T activados, junto a otras proteínas como la perforina o citolisina. Las granzimas A y B se relacionan con los procesos degenerativos. Éstas entran en el interior de las células diana gracias a la acción de la perforina, y una vez en su interior se translocan al núcleo. La granzima A se ha aislado e identificado como el agente responsable de la inmediata y completa retracción de las neuritas en diversos modelos, y entre sus sustratos fisiológicos se encuentran la fibronectina, el colágeno de tipo IV y los proteoglicanos. La granzima B se caracteriza por ser una cisteína proteasa con sustratos como la prointerleucina-1Beta, el receptor de TR y la polimerasa poli(ADP-ribosa). La familia de las proteasas del tipo TR engloba proteasas como la propia TR, la plasmina, la kallikreína, el activador del plasminógeno urocinasa, y el activador del plasminógeno tisular. La TR se considera como un modulador temprano en los tejidos dañados, que sirve como señal extracelular de muerte que conduce a la activación de mecanismos intracelulares por un mecanismo que parece mediarse por calcio. La actividad de las serina proteasas se regula por inhibidores endógenos, como el inhibidor de activador del plasminógeno, la proteasa nexina-1 y la neuroserpina. Conclusión. Alteraciones en el equilibrio proteasainhibidor resultan cruciales en los procesos implicados en plasticidad y muerte neuronal inducidos por isquemia en el cerebro y por excitotoxinas (AU)

Aims. In this review we analyse the role played by the serine proteases in the nervous system and we focus on the role they play in degenerative processes. Development. These proteolytic enzymes, together with the caspases, play a vital role in the processes regulating cell functioning, both in the development stages and following the response to a harmful stimulus. This family of proteases includes the granzymes and thrombin (TR). The former, which are closely related to proteases I and II and cathepsin G, are situated in the cytoplasmic granules of the activated T lymphocytes, together with other proteins such as perforin or cytolysin. Granzymes A and B are linked to degenerative processes. These enter the target cells thanks to the action of perforin and once inside they are translocated to the nucleus. Granzyme A has been isolated and identified as the agent responsible for the immediate and complete retraction of neurites in different models. Its physiological substrates include fibronectin, type IV collagen and the proteoglycans. Granzyme B is characterised by its being a cysteine protease with substrates such as prointerleukin-1β, TR receptor and poly(ADP-ribose) polymerase. The family of TR-type proteases includes proteases such as TR itself, plasmin, kallikrein, urokinase plasminogen activator and tissue plasminogen activator. TR is considered to be an early modulator in damaged tissues which acts as an extracellular signal of death, leading to the activation of intracellular mechanisms that appear to be mediated by calcium. Serine protease activity is regulated by endogenous inhibitors, such as plasminogen activator inhibitor, protease nexin-1 and neuroserpin. Conclusions. Upsets in the proteaseinhibitor balance are crucial in the processes involved in the neuronal plasticity and death induced by ischemia in the brain and by excitotoxins (AU)

Mitochondrial control of neuron death and its role in neurodegenerative disorders.

Genetic or functional mitochondrial alterations can result in the initiation of cell death programs that are believed to contribute to cell death in diabetes, ageing and neurodegenerative disorders. Mitochondria are being considered the main link between cellular stress signals activated during acute and chronic nerve cell injury, and the execution of nerve cell death. This second function of mitochondria is regulated by several families of proteins that can trigger an increase in permeability of the outer and/or inner mitochondrial membrane. One example of this is the formation of the mitochondrial permeability transition pore (MPTP). This process can trigger the release of cell death-inducing factors from mitochondria, as well as a dissipation of the mitochondrial transmembrane potential, depletion of ATP, and increased free radical formation. Among the factors released from mitochondria are cytochrome c, the apoptosis inductor factor (AIF), and caspases. We review the role of the MPTP in diverse physiological and pathological processes, including neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). The design of drugs that could interfere with the functions of the MPTP could allow novel therapeutic approaches for the treatment of acute and chronic nerve cell injury.

Role and regulation of p53 in depolarization-induced neuronal death.

The tumor suppressor gene p53 is a potent transcriptional regulator for genes involved in many cellular activities including cell cycle arrest and apoptosis. In this study, we examined the role of p53 in neuronal death induced by the sodium channel modulator veratridine. We also analyzed the involvement of Ca2+, mitochondria and reactive oxygen species in p53 activation. Exposure of hippocampal neurons to veratridine (0.3-100 microM) resulted in a dose-dependent neuronal death, measured 24 h after treatment. p53-Like immunoreactivity, undetectable in neurons under control conditions, was observed in about 25% of neurons, 7 h after veratridine exposure. Treatments that modified the alkaloid-induced Ca2+ influx including tetrodotoxin or Ca2+ removal, prevented either veratridine-induced cell death or p53 immunoreactivity. Mitochondria were involved in veratridine-induced cell death, as the alkaloid collapsed inner transmembrane mitochondrial potential in a Ca2+ influx dependent manner. Treatments of neuronal cultures with the permeability transitory pore blockers cyclosporin A and bongkrekic acid prevented veratridine-induced p53 immunoreactivity and neuronal death, placing mitochondria upstream of veratridine-induced p53 immunoreactivity. Reactive oxygen species also participated in veratridine-induced neurotoxicity and p53 activation. Antisense knockdown of p53 resulted in a significant increase in neuronal survival after veratridine treatment. This protective effect was maintained on N-methyl-D-aspartate or ischemia-induced death but not on staurosporine cytotoxicity. These results together suggest that p53-expression is involved in veratridine-induced neuronal death and that p53 might be a link between toxic stimuli of different types and neuronal death.

[Pharmacological targets in neurodegenerative diseases]. / Dianas farmacológicas en las enfermedades neurodegenerativas.

The frequency, morbidity and complexity of neurodegenerative diseases (NDD) make them the greatest therapeutic challenge to Medicine today. These diseases are characterized by a decreased number of cells in certain neuronal populations, which is clinically reflected in the appearance of specific symptoms. In this study, we will centre our attention on the two fundamental lines of action that, from a pharmacological point of view, are available for the treatment of NDD. The first is aetiopathogenic, and is aimed at stopping cell death and promoting the recovery of cell populations. The second line is physiopathological and seeks to prevent, delay or palliate the appearance of the symptoms indicating an alteration in the levels of neurotransmitters, and its chief objective is to maintain them. Pharmacology has already provided neurologists with a wide range of tried and tested drugs, yet the results obtained in research laboratories in the last few years seem to indicate that the number of therapeutic possibilities are very likely to rise sharply in the future. Progress made in genomics and the better understanding of cellular biochemical cycles allow us to expect that this century will finally be that of the Neurosciences, and that Neurology, without losing its cognitive essence, will start to be considered to be a speciality that is as therapeutic as it is diagnostic.

Dianas farmacológicas en las enfermedades neurodegenerativas / Pharmacological targets in neurodegenerative diseases

Las enfermedades neurodegenerativas (END), por su frecuencia, morbilidad y complejidad, suponen actualmente el mayor reto terapéutico de la medicina. Estas enfermedades se caracterizan por una disminución en el número de células en determinadas poblaciones neuronales, lo que se refleja clínicamente por la aparición de sintomatologías específicas. En esta revisión nos centraremos en las dos líneas de actuación fundamentales que desde el punto de vista de la farmacología hay abiertas en el tratamiento de las END: la primera, etiopatogénica, con el objetivo de detener la muerte celular y fomentar la recuperación de las poblaciones celulares; la segunda línea, fisiopatológica, busca prevenir, retardar o paliar la aparición de la sintomatología propia de la alteración en los niveles de neurotransmisores, y que presenta como objetivo principal el mantenimiento de los mismos. La farmacología ha dotado ya a los neurólogos de un amplio arsenal de fármacos de probada eficacia; sin embargo, los resultados obtenidos en los laboratorios de investigación en los últimos años hacen muy probable que las posibilidades terapéuticas aumenten considerablemente en el futuro. Los avances de la genómica y la mejor comprensión de los ciclos bioquímicos celulares hacen esperar que este siglo sea, por fin, el de las neurociencias, y que la neurología, sin perder su esencia cognitiva, empiece a considerarse una especialidad tan terapéutica como diagnóstica (AU)

[The role of the mitochondrial permeability transition pore in neurodegenerative processes]. / Papel del poro de permeabilidad transitoria mitocondrial en los procesos neurodegenerativos.

AIMS: To review the role played by the mitochondrial permeability transition pore (MPTP) in different physiological and pathological processes. METHOD: Both genetic and functional alterations in mitochondria can lead to errors that trigger programmed cell death, which in turn give rise to a number of diseases that affect the nervous system. Over the last few years the mitochondrion has been seen as the link between the different signalling pathways involved in some degenerative processes. The mitochondrion seems to play an important part in the cellular decision making that leads, irreversibly, toward the execution phase in cellular death processes. This being the case, the action would be mediated by the permeability of its membranes, through the formation of the mitochondrial permeability transition pore, and would involve phenomena such as the dissipation of the mitochondrial electrochemical potential and the release of substances from within it. These substances include apoptosis inducing factor (AIF), apoptosis protease activating factor 1 (apaf 1), cytochrome c and members of the protease family: the caspases. These alterations have been described in neurodegenerative pathologies such as Alzheimer s and Parkinson s disease, amyotrophic lateral sclerosis and transmissible spongiform encephalopaties. CONCLUSIONS: Designing pharmaceutical products capable of interfering with the functions of MPTP would allow a better therapeutic approach in neurological pathologies.

Papel del poro de permeabilidad transitoria mitocondrialen los procesos neurodegenerativos / The role of the mitochondrial permeability transition pore in neurodegenerative processes

Objetivo. Revisar el papel que desempeña el poro de permeabilidad transitoria mitocondrial (PPTM) en diversos procesos fisiológicos y patológicos. Desarrollo. Alteraciones mitocondriales, tanto genéticas como funcionales, pueden conducir a errores que desencadenan programas de muerte celular, responsables a su vez de numerosas enfermedades del sistema nervioso. Durante los últimos años, la mitocondria se ha considerado el nexo de unión entre diferentes vías de señalización implicadas en algunos procesos degenerativos. La mitocondria parece ocupar un lugar destacado en la toma de decisión celular que conlleva, irreversiblemente, hacia la fase de ejecución en los procesos de muerte celular. Esta acción estaría mediada por la regulación de la permeabilidad de sus membranas, a través de la formación del poro de permeabilidad transitoria mitocondrial, e implicaría fenómenos como la disipación del potencial electroquímico mitocondrial y la liberación de sustancias desde su interior, entre las que se incluyen el factor inductor de apoptosis (AIF), apaf-1, el citocromo c y miembros de la familia de proteasas, las caspasas. Dichas alteraciones se han descrito en patologías neurodegenerativas como la enfermedad de Alzheimer, la de Parkinson, la esclerosis lateral amiotrófica y encefalopatías espongiformes transmisibles. Conclusiones. El diseño de fármacos que pudieran interferir con las funciones del PPTM permitiría un mejor abordaje terapéutico en patologías neurológicas (AU)