Browsing by Author "Varas, Rodrigo"

Now showing 1 - 11 of 11
  • Thumbnail Image
    Item
    A preclinical mice model of multiple sclerosis based on the toxin-induced double-site demyelination of callosal and cerebellar fibers
    (2024) Vejar, Sebastián; Pizarro, Ignacio S.; Pulgar-Sepúlveda, Raúl; Vicencio, Sinay C.; Polit, Andrés; Amador, Cristian A.; Rio, Rodrigo del; Varas, Rodrigo; Orellana, Juan A.; Ortiz, Fernando C.
    Background: Multiple sclerosis (MS) is an irreversible progressive CNS pathology characterized by the loss of myelin (i.e. demyelination). The lack of myelin is followed by a progressive neurodegeneration triggering symptoms as diverse as fatigue, motor, locomotor and sensory impairments and/or bladder, cardiac and respiratory dysfunction. Even though there are more than fourteen approved treatments for reducing MS progression, there are still no cure for the disease. Thus, MS research is a very active field and therefore we count with different experimental animal models for studying mechanisms of demyelination and myelin repair, however, we still lack a preclinical MS model assembling demyelination mechanisms with relevant clinical-like signs. Results: Here, by inducing the simultaneous demyelination of both callosal and cerebellar white matter fibers by the double-site injection of lysolecithin (LPC), we were able to reproduce CNS demyelination, astrocyte recruitment and increases levels of proinflammatory cytokines levels along with motor, locomotor and urinary impairment, as well as cardiac and respiratory dysfunction, in the same animal model. Single site LPC-injections either in corpus callosum or cerebellum only, fails in to reproduce such a complete range of MS-like signs. Conclusion: We here report that the double-site LPC injections treatment evoke a complex MS-like mice model. We hope that this experimental approach will help to deepen our knowledge about the mechanisms of demyelinated diseases such as MS.
  • Thumbnail Image
    Item
  • Thumbnail Image
    Item
  • No Thumbnail Available
    Item
    ATP- and ACh-induced responses in isolated cat petrosal ganglion neurons
    (2007) Alcayaga, Carmen; Varas, Rodrigo; Valdes, Viviana; Cerpa, Veronica; Arroyo, Jorge; Iturriaga, Rodrigo; Alcayaga, Julio
    Chemoreceptor (glomus) cells of the carotid body are synaptically connected to the sensory nerve endings of petrosal ganglion (PG) neurons. In response to natural stimuli, the glomus cells release transmitters, which acting on the nerve terminals of petrosal neurons increases the chemosensory afferent discharge. Among several transmitter molecules present in glomus cells, acetylcholine (ACh) and adenosine 5'-triphosphate (ATP) are considered to act as excitatory transmitter in this synapse. To test if ACh and ATP play a role as excitatory transmitters in the cat CB, we recorded the electrophysiological responses from PG neurons cultured in vitro. Under voltage clamp, ATP induces a concentration-dependent inward current that partially desensitizes during 20-30 s application pulses. The ATP-induced current has a threshold near 100 nM and saturates between 20-50 mu M. ACh induces a fast, inactivating inward current, with a threshold between 10-50 mu M, and saturates around 1 mM. A large part of the population of PG neurons (60%) respond to both ATP and ACh. Present results support the hypothesis that ACh and ATP act as excitatory transmitters between cat glomus cells and PG neurons. (c) 2006 Elsevier B.V. All rights reserved.
  • Thumbnail Image
    Item
    Carotid Body Type-I Cells Under Chronic Sustained Hypoxia: Focus on Metabolism and Membrane Excitability
    (2018) Pulgar-Sepulveda, Raul; Varas, Rodrigo; Iturriaga Agüera, Rodrigo; Del Rio, Rodrigo; Ortiz, Fernando C.
  • No Thumbnail Available
    Item
    Characterization of a Novel Drosophila SERT Mutant: Insights on the Contribution of the Serotonin Neural System to Behaviors
    (2017) Hidalgo, Sergio; Molina-Mateo, Daniela; Escobedo, Pia; Zarate, Rafaella V.; Fritz, Elsa; Fierro, Angelica; Perez, Edwin G.; Iturriaga-Vasquez, Patricio; Reyes-Parada, Miguel; Varas, Rodrigo; Fuenzalida-Uribe, Nicolas; Campusano, Jorge M.
    A better comprehension on how different molecular components of the serotonergic system contribute to the adequate regulation of behaviors in animals is essential in the interpretation on how they are involved in neuropsychiatric and pathological disorders. It is possible to study these components in "simpler" animal models including the fly Drosophila melanogaster, given that most of the components of the serotonergic system are conserved between vertebrates and invertebrates. Here we decided to advance our understanding on how the serotonin plasma membrane transporter (SERT) contributes to serotonergic neurotransmission and behaviors in Drosophila. In doing this, we characterized for the first time a mutant for Drosophila SERT (dSERT) and additionally used a highly selective serotonin-releasing drug, 4-methylthioamphetamine (4-MTA), whose mechanism of action involves the SERT protein. Our results show that dSERT mutant animals exhibit an increased survival rate in stress conditions, increased basal motor behavior, and decreased levels in an anxiety-related parameter, centrophobism. We also show that 4-MTA increases the negative chemotaxis toward a strong aversive odorant, benzaldehyde. Our neurochemical data suggest that this effect is mediated by dSERT and depends on the 4-MTA-increased release of serotonin in the fly brain. Our in silico data support the idea that these effects are explained by specific interactions between 4-MTA and dSERT. In sum, our neurochemical, in silico, and behavioral analyses demonstrate the critical importance of the serotonergic system and particularly dSERT functioning in modulating several behaviors in Drosophila.
  • No Thumbnail Available
    Item
    Evidence for TGF-β1/Nrf2 Signaling Crosstalk in a Cuprizone Model of Multiple Sclerosis
    (2024) Guevara, Coram; Vicencio, Sinay C.; Pizarro, Ignacio S.; Villavicencio-Tejo, Francisca; Quintanilla, Rodrigo A.; Astudillo, Pablo; Ampuero, Estibaliz; Varas, Rodrigo; Orellana, Juan A.; Ortiz, Fernando C.
    Multiple sclerosis (MS) is a chronic and degenerative disease that impacts central nervous system (CNS) function. One of the major characteristics of the disease is the presence of regions lacking myelin and an oxidative and inflammatory environment. TGF-beta 1 and Nrf2 proteins play a fundamental role in different oxidative/inflammatory processes linked to neurodegenerative diseases such as MS. The evidence from different experimental settings has demonstrated a TGF-beta 1-Nrf2 signaling crosstalk under pathological conditions. However, this possibility has not been explored in experimental models of MS. Here, by using the cuprizone-induced demyelination model of MS, we report that the in vivo pharmacological blockage of the TGF-beta 1 receptor reduced Nrf2, catalase, and TGF beta-1 protein levels in the demyelination phase of cuprizone administration. In addition, ATP production, locomotor function and cognitive performance were diminished by the treatment. Altogether, our results provide evidence for a crosstalk between TGF-beta 1 and Nrf2 signaling pathways under CNS demyelination, highlighting the importance of the antioxidant cellular response of neurodegenerative diseases such as MS.
  • No Thumbnail Available
    Item
    Functional expression of the α7 and α4-containing nicotinic acetylcholine receptors on the neonatal rat carotid body
    (2012) Meza, Rodrigo C.; Ortiz, Fernando C.; Bravo, Eduardo; Iturriaga-Vasquez, Patricio; Eugenin, Jaime L.; Varas, Rodrigo
    The carotid bodies (CBs) are chemosensory organs that respond to hypoxemia with transmitter neurosecretion, leading to a respiratory reflex response. It has been proposed that acetylcholine is a key regulator of transmitter release through activation of presynaptic nicotinic acetylcholine receptors (nAChRs). In the present work, we studied the identity of such nAChRs and their contribution to catecholamine release from CBs.
  • No Thumbnail Available
    Item
    Neonicotinic analogues: Selective antagonists for α4β2 nicotinic acetylcholine receptors
    (2013) Faundez-Parraguez, Manuel; Farias-Rabelo, Nicolas; Pablo Gonzalez-Gutierrez, Juan; Etcheverry-Berrios, Alvaro; Alzate-Morales, Jans; Adasme-Carreno, Francisco; Varas, Rodrigo; Bermudez, Isabel; Iturriaga-Vasquez, Patricio
    Nicotine is an agonist of nicotinic acetylcholine receptors (nAChRs) that has been extensively used as a template for the synthesis of alpha 4 beta 2-preferring nAChRs. Here, we used the N-methyl-pyrrolidine moiety of nicotine to design and synthesise novel alpha 4 beta 2-preferring neonicotinic ligands. We increased the distance between the basic nitrogen and aromatic group of nicotine by introducing an ester functionality that also mimics acetylcholine (Fig. 2). Additionally, we introduced a benzyloxy group linked to the benzoyl moiety. Although the neonicotinic compounds fully inhibited binding of both [alpha-I-125]bungarotoxin to human alpha 7 nAChRs and [H-3]cytisine to human alpha 4 beta 2 nAChRs, they were markedly more potent at displacing radioligand binding to human alpha 4 beta 2 nAChRs than to alpha 7 nAChRs. Functional assays showed that the neonicotinic compounds behave as antagonists at alpha 4 beta 2 and alpha 4 beta 2 alpha 5 nAChRs. Substitutions on the aromatic ring of the compounds produced compounds that displayed marked selectivity for alpha 4 beta 2 or alpha 4 beta 2 alpha 5 nAChRs. Docking of the compounds on homology models of the agonist binding site at the alpha 4/beta 2 subunit interfaces of alpha 4 beta 2 nAChRs suggested the compounds inhibit function of this nAChR type by binding the agonist binding site. (C) 2013 Elsevier Ltd. All rights reserved.
  • No Thumbnail Available
    Item
    Serotonin Receptors Expressed in Drosophila Mushroom Bodies Differentially Modulate Larval Locomotion
    (2014) Silva, Bryon; Goles, Nicolas I.; Varas, Rodrigo; Campusano, Jorge M.
    Drosophila melanogaster has been successfully used as a simple model to study the cellular and molecular mechanisms underlying behaviors, including the generation of motor programs. Thus, it has been shown that, as in vertebrates, CNS biogenic amines (BA) including serotonin (5HT) participate in motor control in Drosophila. Several evidence show that BA systems innervate an important association area in the insect brain previously associated to the planning and/or execution of motor programs, the Mushroom Bodies (MB). The main objective of this work is to evaluate the contribution of 5HT and its receptors expressed in MB to motor behavior in fly larva. Locomotion was evaluated using an automated tracking system, in Drosophila larvae (3rd-instar) exposed to drugs that affect the serotonergic neuronal transmission: alpha-methyl-L-dopa, MDMA and fluoxetine. In addition, animals expressing mutations in the 5HT biosynthetic enzymes or in any of the previously identified receptors for this amine (5HT(1A)R, 5HT(1B)R, 5HT(2)R and 5HT(7)R) were evaluated in their locomotion. Finally, RNAi directed to the Drosophila 5HT receptor transcripts were expressed in MB and the effect of this manipulation on motor behavior was assessed. Data obtained in the mutants and in animals exposed to the serotonergic drugs, suggest that 5HT systems are important regulators of motor programs in fly larvae. Studies carried out in animals pan-neuronally expressing the RNAi for each of the serotonergic receptors, support this idea and further suggest that CNS 5HT pathways play a role in motor control. Moreover, animals expressing an RNAi for 5HT(1B)R, 5HT(2)R and 5HT(7)R in MB show increased motor behavior, while no effect is observed when the RNAi for 5HT(1A)R is expressed in this region. Thus, our data suggest that CNS 5HT systems are involved in motor control, and that 5HT receptors expressed in MB differentially modulate motor programs in fly larvae.
  • Thumbnail Image
    Item
    Wnt5a inhibits K+ currents in hippocampal synapses through nitric oxide production
    (2015) Parodi, Jorge; Montecinos Oliva, Carla; Varas, Rodrigo; Alfaro, Iván E.; Serrano, Felipe G.; Varas Godoy, Manuel; Muñoz, Francisco J.; Cerpa Nebott, Waldo Francisco; Godoy, Juan A.; Inestrosa Cantín, Nibaldo