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Research Interests: Biochemistry, Skeletal muscle biology, Biology, Medicine, Platelet aggregation, and 15 moreSequence alignment, Mice, Animals, Male, Venom, Creatine Kinase, Enzyme, Snake Venom, Crotalus, Skeletal Muscle, Edema, Amino Acid Sequence, Biochemistry and cell biology, Molecular Sequence Data, and Phospholipase
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Epilepsy is a complex neurological syndrome characterized by seizures resulting from neuronal hyperexcitability and sudden and synchronized bursts of electrical discharges. Impaired astrocyte function that results in glutamate... more
Epilepsy is a complex neurological syndrome characterized by seizures resulting from neuronal hyperexcitability and sudden and synchronized bursts of electrical discharges. Impaired astrocyte function that results in glutamate excitotoxicity has been recognized to play a key role in the pathogenesis of epilepsy. While there are 26 drugs marketed as anti-epileptic drugs no current treatments are disease modifying as they only suppress seizures rather than the development and progression of epilepsy. Excitatory amino acid transporters (EAATs) are critical for maintaining low extracellular glutamate concentrations and preventing excitotoxicity. When extracellular glutamate concentrations rise to abnormal levels, glutamate receptor overactivation and the subsequent excessive influx of calcium into the post-synaptic neuron can trigger cell death pathways. In this review we discuss targeting EAAT2, the predominant glutamate transporter in the CNS, as a promising approach for developing therapies for epilepsy. EAAT2 upregulation via transcriptional and translational regulation has proven successful in vivo in reducing spontaneous recurrent seizures and offering neuroprotective effects. Another approach to regulate EAAT2 activity is through positive allosteric modulation (PAM). Novel PAMs of EAAT2 have recently been identified and are under development, representing a promising approach for the advance of novel therapeutics for epilepsy.
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Lychnophora is a genus of South American flowering plants in the daisy family, popularly known as “Brazilian arnica”. It is used in traditional medicine as an anti-inflammatory and analgesic agent, whose active components are derived from... more
Lychnophora is a genus of South American flowering plants in the daisy family, popularly known as “Brazilian arnica”. It is used in traditional medicine as an anti-inflammatory and analgesic agent, whose active components are derived from chlorogenic acid (CGA) and C-flavonoids. Since the drugs currently used are ineffective to treat glaucoma, agents with antioxidant and anti-inflammatory properties may represent new alternatives in preventing cellular lesions in retinal ischemia. In this study, we report the neuroprotective effects of CGA and 4,5-di-O-[E]-caffeoylquinic (CQA) acid, isolated from Lychnophora plants, in a rodent glaucoma model. Wistar rats were administered intravitreally with 10 µg CGA or CGA, and then subjected to acute retinal ischemia (ISC) by increasing intraocular pressure (IPO) for 45 minutes followed (or not) by 15 minutes of reperfusion (I/R). Qualitative and quantitative analyses of neurodegeneration were performed using hematoxylin-eosin or Fluoro-Jade C staining protocols. All retinas submitted to ISC or I/R exhibited matrix disorganization, pyknotic nuclei, and pronounced vacuolization of the cytoplasm in the ganglion cell layer (GCL) and inner nuclear layer (INL). Pretreatment with CGA or CQA resulted in the protection of the retinal layers against matrix disorganization and a reduction in the number of vacuolized cells and pyknotic nuclei. Also, pretreatment with CGA or CQA resulted in a significant reduction in neuronal death in the GCL, the INL, and the outer nuclear layer (ONL) after ischemic insult. Our study demonstrated that CGA and CQA exhibit neuroprotective activities in retinas subjected to ISC and I/R induced by IPO in Wistar rats.
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Epilepsy is considered as one of the major disabling neuropathologies. Almost one third of adult patients with temporal lobe epilepsy (TLE) do not respond to current antiepileptic drugs (AEDs). Additionally, most AEDs do not have... more
Epilepsy is considered as one of the major disabling neuropathologies. Almost one third of adult patients with temporal lobe epilepsy (TLE) do not respond to current antiepileptic drugs (AEDs). Additionally, most AEDs do not have neuroprotective effects against the inherent neurodegenerative process underlying the hippocampal sclerosis on TLE. Dysfunctions in the GABAergic neurotransmission may contribute not only to the onset of epileptic activity but also constitute an important system for therapeutic approaches. Therefore, molecules that enhance GABA inhibitory effects could open novel avenues for the understanding of epileptic plasticity and for drug development. Parawixin2, a compound isolated from Parawixia bistriata spider venom, inhibits both GABA and glycine uptake and has an anticonvulsant effect against a wide range of chemoconvulsants. The neuroprotective potential of Parawixin2 was analyzed in a model of TLE induced by a long-lasting Status Epilepticus (SE), and its eff...
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Arthropod venoms are sources of molecules that may be useful tools to investigate molecular mechanisms of putative new medicines and laboratory drugs. Here we show the effects of the compound agelaiatoxin-8 (AVTx8), isolated from Agelaia... more
Arthropod venoms are sources of molecules that may be useful tools to investigate molecular mechanisms of putative new medicines and laboratory drugs. Here we show the effects of the compound agelaiatoxin-8 (AVTx8), isolated from Agelaia vicina venom, on γ-aminobutyric acid (GABA) neurotransmission in rat brain synaptosomes. Analysis reveals that AvTx8 is composed by 14 amino acid residues with a molecular weight (MW) of 1567 Da. AvTx8 increased GABA release and inhibited GABA uptake in synaptosomes from rat cerebral cortex. AvTx8 inhibited GABA uptake and increased GABA release in the presence of Ca(+) , Na(+) , and K(+) channel blockers, suggesting that it acts directly on GABA transporters. In addition, AvTx8 significantly decreases GABA binding in synaptic membranes from rat brain cortex, suggesting that it also modulates the activity of GABA receptors. Moreover, AvTx8 decreased GAT-1- and GAT-3-mediated GABA uptake in transfected COS-7 cells. Accordingly, we suggest that AvTx8 ...
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Natural products, sources of new pharmacological substances, have large chemical diversity and architectural complexity. In this context, some toxins obtained from invertebrate venoms have anticonvulsant effects. Epilepsy is a... more
Natural products, sources of new pharmacological substances, have large chemical diversity and architectural complexity. In this context, some toxins obtained from invertebrate venoms have anticonvulsant effects. Epilepsy is a neurological disorder that affects about 65 million people worldwide, and approximately 30% of cases are resistant to pharmacological treatment. Previous studies from our group show that the denatured venom of the ant Dinoponera quadriceps (Kempt) protects mice against bicuculline (BIC)-induced seizures and death. The aim of this study was to investigate the anticonvulsant activity of compounds isolated from D. quadriceps venom against seizures induced by BIC in mice. Crude venom was fractionated by high-performance liquid chromatography (HPLC) resulting in six fractions referred to as DqTx1-DqTx6. A liquid chromatography-mass spectrometry (LC/MS) analysis revealed a major 431 Da compound in fractions DqTx1 and DqTx2. Fractions DqTx3 and DqTx4 showed a compoun...
Research Interests: Chemistry, Biology, Medicine, Ants, Mice, and 9 moreAnimals, Natural Product, Male, Venom, Toxins, Seizures, Bicuculline, Ant Venom, and tonic clonic seizures
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Mygalin, a diacylspermidine that is naturally found in the hemolymph of the spider Acanthoscurria gomesiana, is of interest for development as a potential analgesic. Previous studies have shown that acylpolyamines modulate glutamatergic... more
Mygalin, a diacylspermidine that is naturally found in the hemolymph of the spider Acanthoscurria gomesiana, is of interest for development as a potential analgesic. Previous studies have shown that acylpolyamines modulate glutamatergic receptors with the potential to alter pain pathways. This study aimed to evaluate the effects of mygalin on acute and chronic pain in rodents. For evaluation of acute pain, Wistar rats were subjected to tail‐flick and hot‐plate nociceptive tests. For the evaluation of chronic neuropathic pain, a partial ligation of the sciatic nerve was performed and, 21 days later, animals were examined in hot‐plate, tail‐flick, acetone, and von Frey tests. Either Mygalin or vehicle was microinjected in the dorsal raphe nucleus (DRN) before the tests. Another group was pretreated with selective antagonists of glutamate receptors (LY 235959, MK‐801, CNQX, and NBQX). Mygalin decreases nociceptive thresholds on both acute and chronic neuropathic pain models in all the tests performed. The lowest dose of mygalin yielded the most effective nociception, showing an increase of 63% of the nociceptive threshold of animals with neuropathic chronic pain. In conclusion, mygalin microinjection in the DRN results in antinociceptive effect in models of neuropathic pain, suggesting that acylpolyamines and their derivatives, such as this diacylspermidine, could be pursued for the treatment of neuropathic pain and development of selective analgesics.
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The ability of venom-derived peptides to disrupt physiological processes in mammals provides an exciting source for pharmacological development. Our research group has identified a new class of neuroactive peptides from the venom of a... more
The ability of venom-derived peptides to disrupt physiological processes in mammals provides an exciting source for pharmacological development. Our research group has identified a new class of neuroactive peptides from the venom of a Brazilian social wasp, Polybia occidentalis, with the potential pharmacological profile to treat epilepsies. The study was divided into five phases: Phase 1 concerned the extraction, isolation and purification of Occidentalin-1202(n) from the crude venom, followed by the synthesis of an identical analogue peptide, named Occidentalin-1202(s). In Phase 2, we described the effects of both peptides in two acute models of epilepsy—kainic acid and pentylenetetrazole-induced model of seizures—and measured estimated ED50 and therapeutic index values, electroencephalographic studies and C-fos evaluation. Phase 3 was a compilation of advanced tests performed with Occidentalin-1202(s) only, reporting histopathological features and its performance in the pilocarpi...
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J.L. Liberato, L.D. Godoy, M.R. Mortari, L. Gobbo-Neto, N.P. Lopes, W.F. Santos Departamento de Biologia, Faculdade de Filosofia Ciencias e Letras de Ribeirao Preto, Universidade de Sao Paulo, Brazil Instituto de Neurociencias e... more
J.L. Liberato, L.D. Godoy, M.R. Mortari, L. Gobbo-Neto, N.P. Lopes, W.F. Santos Departamento de Biologia, Faculdade de Filosofia Ciencias e Letras de Ribeirao Preto, Universidade de Sao Paulo, Brazil Instituto de Neurociencias e Comportamento (IneC), Brazil Instituto de Ciencias Biologicas, Universidade de Brasilia, Brazil Departamento de Quimica e Fisica, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Brazil
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1 Launching Current Ethology is the latest step to improve visibility of ethology in Brazil and abroad. From a humble start at the Instituto de Psicologia (IP), University of São Paulo, at the laboratory of Prof. Walter Hugo de Andrade... more
1 Launching Current Ethology is the latest step to improve visibility of ethology in Brazil and abroad. From a humble start at the Instituto de Psicologia (IP), University of São Paulo, at the laboratory of Prof. Walter Hugo de Andrade Cunha, ethology in Brazil shows its strength through its graduation programs and institutionalized features, such as regular meetings, a sound society and a journal, Revista de Etologia, converted into Current Ethology from now on (Fuchs, 1995; Ades, 2010; Otta et al., 2013; Spinelli de Oliveira et al., 2014; Spinelli de Oliveira and Magrini, 2015; Magrini and Spinelli de Oliveira, 2015). Prof. Cesar Ades, another name from the IP, was one of the key figures whose work stimulated interest in ethology among Brazilians from the seventies until his premature death in 2012. He was responsible for bringing G. Baerendsas as guest of the I Congresso Latinoamericano de Psicologia in 1973, in São Paulo, the same year in which the Noble Prize in Medicine or Phy...
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Research Interests: Kinetics, Mass Spectrometry, Glutamate, Wasps, Cerebral Cortex, and 14 moreAnimals, Calcium channels, Biochemical, Neurotoxins, Rats, Voltage-Gated Sodium Channels, Potassium Channels, SYNAPTOSOMES, Wistar Rats, Biochemical and Molecular Toxicology, Glutamic Acid, sodium channels, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
Venoms from several arthropods are recognized as useful sources of bioactive substances, such as peptides, acylpolyamines, and alkaloids, which show a wide range of pharmacological effects on synaptic transmission. In this work, we... more
Venoms from several arthropods are recognized as useful sources of bioactive substances, such as peptides, acylpolyamines, and alkaloids, which show a wide range of pharmacological effects on synaptic transmission. In this work, we summarize and compile several biochemical and pharmacological aspects related to spider and wasp neurotoxins. Their inhibitory and stimulatory actions on ion channels, receptors, and transporters involved in mammalian and insect neurotransmission are considered.
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Polyamines are compounds that interact with ionotropic receptors, mainly modulating the NMDA receptor, which is strictly related to many neurologic diseases such as epilepsy. Consequently, polyamines rise as potential neuropharmacological... more
Polyamines are compounds that interact with ionotropic receptors, mainly modulating the NMDA receptor, which is strictly related to many neurologic diseases such as epilepsy. Consequently, polyamines rise as potential neuropharmacological tools in the prospection of new therapeutic drugs. In this paper, we report on the biological activity of synthetic polyamine Mygalin, which was tested as an anticonvulsant in model of chemically induced seizures. Male Wistar rats were injected with vehicle, diazepam, MK-801 or Mygalin at different doses followed by Pentylenetetrazole or N-Methyl-D-Aspartate administration. Mygalin presented protection against seizures induced by both NMDA injections and PTZ administration by 83.3% and 16.6%, respectively. Moreover, it prolonged the onset of tonic-clonic seizures induced by PTZ. Furthermore, it was tested in neuroethological schedule evaluating possible side-effects and it presented mild changes in Open Field, Rotarod and Morris Water Maze tests when compared to available anticonvulsant drugs. The mechanism underlying the anticonvulsant effect of Mygalin is noteworthy of further investigation, nevertheless, based on these findings, we hypothesize that it may be wholly or in part due to a possible NMDA receptor antagonism. Altogether, the results demonstrate that Mygalin has an anticonvulsant activity that may be an important tool in the study of prospection of therapeutics in epilepsy neuropharmacology.
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ABSTRACT
ABSTRACT