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Abstract: Ion channels play critical roles in generating and propagating action potentials and in neurotransmitter release at a subset of excitatory and inhibitory synapses. Dysfunction of these channels has been linked to various health conditions, such as neurodegenerative diseases and chronic pain. Neurodegeneration is one of the underlying causes of a range of neurological pathologies, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), cerebral ischemia, brain injury, and retinal ischemia. Pain is a symptom that can serve as an index of the severity and activity of a disease condition, a prognostic indicator, and a criterion of treatment efficacy. Neurological disorders and pain are conditions that undeniably impact a patient's survival, health, and quality of life, with possible financial consequences. Venoms are the best-known natural source of ion channel modulators. Venom peptides are increasingly recognized as potential therapeutic tools due to their high selectivity and potency gained through millions of years of evolutionary selection pressure. Spiders have been evolving complex and diverse repertoires of peptides in their venoms with vast pharmacological activities for more than 300 million years. These include peptides that potently and selectively modulate a range of targets, such as enzymes, receptors, and ion channels. Thus, components of spider venoms hold considerable capacity as drug candidates for alleviating or reducing neurodegeneration and pain. This review aims to summarize what is known about spider toxins acting upon ion channels, providing neuroprotective and analgesic effects.

Background: Diseases associated to Candida spp. are recurrent and can be difficult to treat, mainly due to the new strains resistant to the limited number of available antifungals. Objective: The objective of this study is to evaluate the in vitro and in vivo activity of Brazilian green propolis (GrProp) and red propolis (RdProp) ethanolic extracts against standard strains of Candida albicans, C. tropicalis, C. krusei, C. glabrata, C. parapsilosis and 10 clinical isolates of C. albicans. Methods: Antifungal activity in vitro was tested using the M-27-A3/CLSI protocol. The in vivo antifungal activity was evaluated using Tenebrio molitor model and, the effect of extracts on adhesion of C. albicans in human buccal epithelial cells (BECs) was also studied. Results: GrProp and RdProp exhibited antifungal activity against at least one of the Candida strains tested. The adhesion inhibition of C. albicans in BECs was 45% (GrProp28), 60% (Gr- Prop50) and 82% (RdProp), in comparison to amphotericin B (82%). All propolis extracts showed synergistic activity with fluconazole and amphotericin B. GrProp50 (10 mg/kg) showed better protection of T. molitor, blocking the progression of C. albicans infection, increasing survival and delayed the larvae death. Conclusion: Brazilian GrProp and RdProp extracts inhibit the in vitro C. albicans growth and protect T. molitor against infection by this yeast. The physiochemical parameters found for the analyzed samples were in accordance to the standards established by the Brazilian Legislation for propolis and derivatives. GrProp and RdProp have potential to be used against Candida spp. infections, mainly in association with fluconazole or amphotericin B.

Diabetic neuropathy is a common cause of painful diabetic neuropathy (PDN). C-X-C chemokine receptor type 4 (CXCR4) expression is increased in peripheral nerve samples from diabetes patients, suggesting a role for CXCR4 in PDN. Therefore, we evaluated the effects of Phα1β, ω-conotoxin MVIIA, and AMD3100 in a model of streptozotocin (STZ)-induced PDN in rodents and naive model of rats with the activation of the CXCR4/stromal cell-derived factor 1 (SDF-1) signal. Diabetic neuropathy was induced by intraperitoneal (ip) injection of STZ in Wistar rats. Naive rats were intrathecally injected with SDF-1 to test the CXCR4/SDF-1 signal. The effects of Phα1β intrathecal (it), ω-conotoxin MVIIA intrathecal (it), and AMD3100 intraperitoneal (ip) on rat hypersensitivity, IL-6, and the intracellular calcium [Ca2+]i content of diabetic synaptosomes were studied. The drugs reduced the hypersensitivity in diabetic rats. SDF-1 (1.0 µg/it) administration in naive rats induced hypersensitivity. Phα1β (100 pmol/it) or AMD3100 (2.5 µg/ip) reduced this hypersensitivity after 2 h treatments, while ω-conotoxin MVIIA did not have an effect. IL-6 and [Ca2+]i content increased in the spinal cord synaptosomes in diabetic rats. The drug treatments reduced IL-6 and the calcium influx in diabetic synaptosomes. Phα1β, ω-conotoxin MVIIA, and AMD3100, after 2 h of treatment of STZ-induced PDN, reduced hypersensitivity in diabetic rats. In naive rats with CXCR4/SDF-1 activation, the induced hypersensitivity decreased after 2 h treatments with Phα1β or AMD-3100, while ω-conotoxin MVIIA did not affect. The inhibitory effects of Phα1β on PDN may involve voltage-dependent calcium channels.

Ivermectin is a broad spectrum antiparasitic drug widely used in human and veterinary medicine. It is the drug of choice for the treatment of onchocerciasis, in addition to being approved for the treatment of lymphatic filariasis, strongyloidiasis, ascariasis, scabies and pediculosis. Ivermectin has antiparasitic activity in nanomolar concentrations, affecting the motility, feeding and reproduction of nematodes. Studies evaluated the antitumoral, antibacterial and antiviral effects of ivermectin, and also to treat metabolic diseases. Currently, the global interest on ivermectin is its potential benefit to treat COVID-19. In this study, the general aspects of pharmacology, physical and chemical characteristics, treatment protocols, safety aspects and toxicology of ivermectin were described, as well as properties that could or could not corroborate with its use in the treatment of COVID-19. A narrative review based on publications from the Pubmed database was performed using descriptors such as ivermectin, pharmacology, therapeutic use, safety, toxicity and COVID-19. It was observed that in addition to the broad therapeutic indication, ivermectin has extensive off-label use. Its antiviral activity seems to be due, both to its ability to stimulate the immune response, and to inhibit viral replication. However, its therapeutic safety to prevent or for COVID-19 treatment was not yet stablished, since the effective concentrations showed to be effective against the virus in in vitro studies indicate higher concentrations to be used than that approved for humans, what could enhance the side effects. In Brazil, the National Health Surveillance Agency (Anvisa) and the Brazilian Society of Clinical Pharmacy (SBFC) recently warned health professionals about ivermectin use off-label, and treatment protocols are not yet established for COVID-19. These official organizations support the use of ivermectin only for therapeutic indications registered at ANVISA.

Phα1β is a neurotoxin purified from spider venom that acts as a high-voltage-activated (HVA) calcium channel blocker. This spider peptide has shown a high selectivity for N-type HVA calcium channels (NVACC) and an analgesic effect in several animal models of pain. Its activity was associated with a reduction in calcium transients, glutamate release, and reactive oxygen species production from the spinal cord tissue and dorsal ganglia root (DRG) in rats and mice. It has been reported that intrathecal (i.t.) administration of Phα1β to treat chronic pain reverted opioid tolerance with a safer profile than ω-conotoxin MVIIA, a highly selective NVACC blocker. Following a recent development of recombinant Phα1β (CTK 01512-2), a new molecular target, TRPA1, the structural arrangement of disulphide bridges, and an effect on glial plasticity have been identified. CTK 01512-2 reproduced the antinociceptive effects of the native toxin not only after the intrathecal but also after the intravenous administration. Herein, we review the Phα1β antinociceptive activity in the most relevant pain models and its mechanisms of action, highlighting the impact of CTK 01512-2 synthesis and its potential for multimodal analgesia.

A hipertensão arterial e o diabetes mellitus tipo 2 (DM2) são enfermidades importantes do ponto de vista da saúde em escala mundial. As alterações na pressão arterial (PA) e glicemia podem contribuir para eventos cardiovasculares graves, além do quadro tornar-se mais preocupante quando o mesmo paciente apresenta ambas as doenças. Diuréticos tiazídicos (DT) são fármacos anti-hipertensivos utilizados para reduzir a PA, e prevenir eventos cardiovasculares. Entretanto, podem causar efeitos adversos, sendo a hipocalemia e a hiperglicemia os mais relevantes para esse estudo, cujo objetivo é analisar dados que associem o uso de DT com o possível desenvolvimento de DM2. Essa revisão integrativa de literatura internacional selecionou oito estudos, dentre os quais observou-se possível relação entre o uso de DT, principalmente em altas doses, e a elevação da glicemia, que pode ocorrer com poucas semanas de uso contínuo. A partir desse estudo foi possível identificar como fatores que influenciam o desenvolvimento da hiperglicemia: a dose administrada; a duração do tratamento; o desenvolvimento da hipocalemia, e a variabilidade genética populacional. O principal mecanismo relacionado ao aumento dos níveis de glicose sanguínea é a hipocalemia ocasionada pela classe farmacológica, devido a essencial participação do potássio na exocitose de insulina. A elevação da glicose gerada pelos DT é pouco discutida até o momento, e ainda não é um fator preponderante para a interrupção do tratamento. No entanto, a atuação do farmacêutico e equipe multiprofissional é necessária para acompanhamento da adequada indicação clínica de DT e observação das contraindicações, como a presença prévia de hiperglicemia.

In this work were determining the total phenolic content, total flavonoids and antioxidant capacity in formulations of red fruit juice supplemented with different concentrations of aqueous extract of Brazilian green propolis. And, also was investigate the formulation sensory acceptance by volunteers’ consumers. The addition of propolis to red fruit juice increased the content of total phenolic compounds and flavonoids, enhanced the antioxidant activity of the final product as assessed by radical scavenging DPPH and ABTS and FRAP methods, and no negative effect on consumer taste. All red fruit juice formulations containing propolis presented significant results through overall acceptability test and were approved in relation to purchase intent by the volunteer consumers. Formulation F3 (6.1 mg.mL-1) showed the best results. The antioxidant activity increment was proportional to the concentration of aqueous green propolis extracts added to the juice. The positive purchase intention reached up 64.75% of participants' acceptance. A new, sugar-free drink with pleasurable sensory and functional properties, combined with health benefits, has been obtained.

Agents that modulate the activity of high-voltage gated calcium channels (HVCCs) exhibit experimentally and clinically significant effect by relieving visceral pain. Among these agents, the toxins Phα1β and ω-conotoxin MVIIA effectively reduce chronic pain in rodent models. The molecular mechanisms underlying the chronic pain associated with acute pancreatitis (AP) are poorly understood. Hypercalcemia is a risk factor; the role of cytosolic calcium is considered to be a modulator of pancreatitis. Blockade of Ca2+ signals may be useful as a prophylactic treatment of pancreatitis. We explored the pathophysiological roles of three peptide toxins: Phα1β and its recombinant form CTK 01512-2-blockers of TRPA1 receptor and HVCCs and ω-conotoxin MVIIA, a specific blocker of N-type calcium channels in cerulein-induced AP. Cerulein injection elicits AP in rats, evidenced by an increase in hyperalgesic pain, inflammatory infiltration, amylase and lipase secretion, and reactive oxygen species, TNF-α, and p65 NF-κB levels. These effects of cerulein-induced AP were abolished by Phα1β and its recombinant form CTK 01512-2, whereas ω-conotoxin MVIIA had no effect on the induced increase in pancreatic enzyme secretion. Our results demonstrate that Phα1β and CTK 01512-2 toxins-antagonists of HVCCs and TRPA1 receptor presented an effective response profile, in the control of nociception and inflammatory process in the AP model in rats, without causing changes in spontaneous locomotion of the rats.

Background Propolis has been used as a natural health product mainly due to the presence of polyphenols, flavonoids, phenolic aldehydes, amino acids, vitamins and others bioactive constituents. To this natural substance are attributed different biological and pharmacological properties which are influenced by its chemical composition and organoleptic properties. The aim of this work was to evaluate the physicochemical properties and parameters of green propolis collected during a period of six years (2008-2013) in the state of Minas Gerais, located at the southeastern region of Brazil. Methods The methodology were in accordance with Brazilian legislation on the identity and quality standards of propolis. The evaluated parameters of hydroalcoholic from green propolis were total flavonoids, antioxidant activity - DPPH method, oxidation index, wax content, humidity and insoluble impurities. Results Propolis samples collected in different seasons during the years 2008 to 2013 presented mean values of total flavonoids (3.4 ± 0.11 mg/g), antioxidant activity DPPH (4.76 ± 0.16 μg/mL), oxidation index (3, 4 ± 0.33 seconds) and wax (15.14 ± 0.78% m/m), which are in accordance with Brazilian legislation. Conclusion Green propolis did not show abrupt seasonal changes during the six years of investigation, and may be considered as an adequate functional ingredient.

Capsaicin, an agonist of TRPV1, evokes intracellular [Ca2+] transients and glutamate release from perfused trigeminal ganglion. The spider toxin PnTx3-5, native or recombinant is more potent than the selective TRPV1 blocker SB-366791 with IC50 of 47 ± 0.18 nM, 45 ± 1.18 nM and 390 ± 5.1 nM in the same experimental conditions. PnTx3-5 is thus more potent than the selective TRPV1 blocker SB-366791. PnTx3-5 (40 nM) and SB-366791 (3 μM) also inhibited the capsaicin-induced increase in intracellular Ca2+ in HEK293 cells transfected with TRPV1 by 75 ± 16% and 84 ± 3.2%, respectively. In HEK293 cells transfected with TRPA1, cinnamaldehyde (30 μM) generated an increase in intracellular Ca2+ that was blocked by the TRPA1 antagonist HC-030031 (10 μM, 89% inhibition), but not by PnTx3-5 (40 nM), indicating selectivity of the toxin for TRPV1. In whole-cell patch-clamp experiments on HEK293 cells transfected with TRPV1, capsaicin (10 μM) generated inward currents that were blocked by SB-366791 and by both native and recombinant PnTx3-5 by 47 ± 1.4%; 54 ± 7.8% and 56 ± 9.0%, respectively. Intradermal injection of capsaicin into the rat left vibrissa induced nociceptive behavior that was blocked by pre-injection with either SB-366791 (3 nmol/site i.d., 83.3 ± 7.2% inhibition) or PnTx3-5 (100 fmol/site, 89 ± 8.4% inhibition). We conclude that both native and recombinant PnTx3-5 are potent TRPV1 receptor antagonists with antinociceptive action on pain behavior evoked by capsaicin.

This study evaluates whether intrathecal MVIIA injection after spinal cord injury (SCI) elicits neuroprotective effects. The test rats were randomly distributed into six groups— sham, placebo, MVIIA 2.5 μM, MVIIA 5 μM, MVIIA 10 μM, and MVIIA 20 μM—and were administered the treatment four hours after SCI. After the optimal MVIIA dose (MVIIA 10 μM) was defined, the best time for application, one or four hours, was analyzed. Locomotor hind limb function and side effects were assessed. Forty-eight hours after the injury and immediately after euthanasia, spinal cord segments were removed from the test rats. Cell viability, reactive oxygen species, lipid peroxidation, and glutamate release were investigated. To examine the MVIIA mechanism of action, the gene expressions of pro-apoptotic (Bax, nNOS, and caspase-3, -8, -9, -12) and anti-apoptotic (Bcl-xl) factors in the spinal cord tissue samples were determined by real-time PCR, and the activities of antioxidant enzymes were also investigated. Application of intrathecal MVIIA 10 μM four hours after SCI prompted a neuroprotective effect: neuronal death decreased (22.46%), oxidative stress diminished, pro-apoptotic factors (Bax, nNOS, and caspase-3, -8) were expressed to a lesser extent, and mitochondrial viability as well as anti-apoptotic factor (Bcl-xl) expression increased. These results suggested that MVIIA provided neuroprotection through antioxidant effects. Indeed, superoxide dismutase (188.41%), and glutathione peroxidase (199.96%), reductase (193.86%), and transferase (175.93%) expressions increased. Therefore, intrathecal MVIIA (MVIIA 10 μM, 4 h) application has neuroprotective potential, and the possible mechanisms are related to antioxidant agent modulation and to intrinsic and extrinsic apoptotic pathways.

Sulforaphane (SFN) is a molecule within the isothiocyanate (ITC) group of organosulfur compounds. SFN is a phytochemical commonly found in cruciferous vegetables such as broccoli, brussels sprouts and cabbages. It has been widely studied in order to evaluate its chemopreventive properties and some of those have already been established by means of animal and human models. The SFN induces Phase I and II enzymes involved in detoxification processes of chemical carcinogens in order to prevent the start of carcinogenesis. It also presents anti-tumor action at post-initiation Phase, suggesting supplementary roles in cancer prevention. In a dose dependent manner, ITC inhibits the viability of human cancer cells, modifies epigenetic events that occur in cancer cells and present antiinflammatory effect acting during the initial of uncontrolled cell proliferation. This protective effect may be due to its antioxidant status, its recognized capacity to induce the expression and/or activity of of different cytoprotective proteins involved in the activating "Nuclear factor erythroid-derived 2-like 2" (Nrf2). Nevertheless, the effects on health and the possible connections among different diet constituents in humans must be carefully studied as there are limitations in the current data in order to better understand the molecular mechanisms responsible for those effects. This survey also includes relevant patents on the use of SFN, like its use in skin cancer treatment (US2015038580); and as an adjuvant in anti-cancer treatment (US2014228419). The use of SFN as an antioxidant dietary supplement, methods for compositions that promote glutathione production (WO2015002279) and methods for extracting and purifying SFN from broccoli seeds (CN104086469) are also included in this review.

The effects of intrathecal administration of the toxins Phα 1 β and ω-conotoxin MVIIA were investigated in visceral nociception induced by an intraperitoneal injection of acetic acid and an intracolonic application of capsaicin. The pretreatments for 2 h with the toxins reduced the number of writhes or nociceptive behaviors compared with the control mice. Phα1β administration resulted in an Imax of 84 ± 6 and an ID 50 of 12 (5–27), and ω-conotoxin MVIIA resulted in an Imax of 82 ± 9 and an ID 50 of 11 (4–35) in the contortions induced by the intraperitoneal injection of acetic acid. The administration of Phα1β resulted in an Imax of 64 ± 4 and an ID 50 of 18 (9–38), and ω-conotoxin MVIIA resulted in an Imax of 71 ± 9 and an ID 50 of 9 (1–83) in the contortions induced by intracolonic capsaicin administration. Phα1β (100/site) or ω-conotoxin MVIIA (30 pmol/site) pretreatments caused a reduction in CSF glutamate release in mice intraperitoneally injected with acetic acid or treated with intracolonic capsaicin. The toxin pretreatments reduced the ROS levels induced by intraperitoneal acetic acid injection. Phα1β, but not ω-conotoxin MVIIA, reduced significantly the ROS levels induced by intracolonic capsaicin administration. Perspective: Phα1β is a ω-toxin with high therapeutic index and a broader action on calcium channels. It shows analgesic effect in several rodents' models of pain, including visceral pain, suggesting that this toxin has the potential to be used in clinical setting as a drug in the control of persistent pathological pain.

GABA is an inhibitory neurotransmitter that appears to be associated with the action of volatile anesthetics. These anesthetics potentiate GABA-induced postsynaptic currents by synaptic GABAA receptors, although recent evidence suggests that these agents also significantly affect extrasynaptic GABA receptors. However, the effect of volatile anesthetics on the extracellular concentration of GABA in the central nervous system has not been fully established. In the present study, rat brain cortical slices loaded with [(3)H]GABA were used to investigate the effect of halothane and sevoflurane on the extracellular accumulation of this neurotransmitter. The accumulation of [(3)H]GABA was significantly increased by sevoflurane (0.058, 0.11, 0.23, 0.46, and 0.93 mM) and halothane (0.006, 0.012, 0.024, 0.048, 0072, and 0.096 mM) with an EC50 of 0.26 mM and 35 μM, respectively. TTX (blocker of voltage-dependent Na(+) channels), EGTA (an extracellular Ca(2+) chelator) and BAPTA-AM (an intracellular Ca(2+) chelator) did not interfere with the accumulation of [(3)H]GABA induced by 0.23 mM sevoflurane and 0.048 mM halothane. SKF 89976A, a GABA transporter type 1 (GAT-1) inhibitor, reduced the sevoflurane- and halothane-induced increase in the accumulation of GABA by 57 and 63 %, respectively. Incubation of brain cortical slices at low temperature (17 °C), a condition that inhibits GAT function and reduces GABA release through reverse transport, reduced the sevoflurane- and halothane-induced increase in the accumulation of [(3)H]GABA by 82 and 75 %, respectively, relative to that at normal temperature (37 °C). Ouabain, a Na(+)/K(+) ATPase pump inhibitor, which is known to induce GABA release through reverse transport, abolished the sevoflurane and halothane effects on the accumulation of [(3)H]GABA. The effect of sevoflurane and halothane did not involve glial transporters because β-alanine, a blocker of GAT-2 and GAT-3, did not inhibit the effect of the anesthetics. In conclusion, the present study suggests that sevoflurane and halothane increase the accumulation of GABA by inducing the reverse transport of this neurotransmitter. Therefore, volatile anesthetics could interfere with neuronal excitability by increasing the action of GABA on synaptic and extrasynaptic GABA receptors.

The in vivo neuroprotective effect of PhTx3-4, a spider toxin N-P/Q calcium channel blocker, was studied in a rat model of NMDA-induced injury of the retina. NMDA (N-Methyl-d-Aspartate)-induced retinal injury in rats reduced the b-wave amplitude by 62% ± 3.6%, indicating the severity of the insult. PhTx3-4 treatment increased the amplitude of the b-wave, which was almost equivalent to the control retinas that were not submitted to injury. The PhTx3-4 functional protection of the retinas recorded on the ERG also was observed in the neuroprotection of retinal cells. NMDA-induced injury reduced live cells in the retina layers and the highest reduction, 84%, was in the ganglion cell layer. Notably, PhTx3-4 treatment caused a remarkable reduction of dead cells in the retina layers, and the highest neuroprotective effect was in the ganglion cells layer. NMDA-induced cytotoxicity of the retina increased the release of glutamate, reactive oxygen species (ROS) production and oxidative stress. PhTx3-4 treatment reduced glutamate release, ROS production and oxidative stress measured by malondialdehyde. Thus, we presented for the first time evidence of in vivo neuroprotection from NMDA-induced retinal injury by PhTx3-4 (-ctenitoxin-Pn3a), a spider toxin that blocks N-P/Q calcium channels.

The mechanism underlying pain symptoms in fibromyalgia (FM) is not fully understood. Oxidative stress has emerged as pathophysiological event occurring during the development of the disease. The present study aimed at investigating the efficacy of resveratrol associated with rice bran oil on fibromyalgia-like mice model. Subcutaneous injection of reserpine (0.25 mg/Kg) during 3 days produced fibromyalgia-like symptoms. Resveratrol and/or rice oil or pregabalin were administered through oral route in therapeutic (single dose) and preventive (four doses) schemes. In both schemes, treatment with resveratrol associated with rice bran oil and pregabalin significantly reduced mechanical allodynia and thermal hyperalgesia in animals. The preventive scheme displayed antidepressant effect which was demonstrated by the forced swimming test as well as reduced reactive species in the cerebrospinal fluid of reserpinized animals. Taken together, our data provide evidences that the intake of resveratrol associated with rice bran oil plays antinociceptive and antidepressant actions probably through reducing reactive species and suggests the involvement of oxidative stress in this model of FM as possible underlying mechanism of pathogenesis of the disease.

Brain ischemic tolerance is a protective mechanism induced by a preconditioning stimulus, which prepare the tissue against harmful insults. Preconditioning with N-methyl-d-aspartate (NMDA) agonists induces brain tolerance and protects it against glutamate excitotoxicity. Recently, the glycine transporters type 1 (GlyT-1) have been shown to potentiate glutamate neurotransmission through NMDA receptors suggesting an alternative strategy to protect against glutamate excitotoxicity. Here, we evaluated the preconditioning effect of sarcosine pre-treatment, a GlyT-1 inhibitor, in rat hippocampal slices exposed to ischemic insult. Sarcosine (300mg/kg per day, i.p.) was administered during seven consecutive days before induction of ischemia in hippocampus by oxygen/glucose deprivation (OGD). To access the damage caused by an ischemic insult, we evaluated cells viability, glutamate release, nitric oxide (NO) production, lactate dehydrogenase (LDH) levels, production of reactive oxygen species (ROS), and antioxidant enzymes as well as the impact of oxidative stress in the tissue. We observed that sarcosine reduced cell death in hippocampus submitted to OGD, which was confirmed by reduction on LDH levels in the supernatant. Cell death, glutamate release, LDH levels and NO production were reduced in sarcosine hippocampal slices submitted to OGD when compared to OGD controls (without sarcosine). ROS production was reduced in sarcosine hippocampal slices exposed to OGD, although no changes were found in antioxidant enzymes activities. This study demonstrates that preconditioning with sarcosine induces ischemic tolerance in rat hippocampal slices submitted to OGD.

PURPOSE To investigate the effect of calcium channel blockers, spider toxins, on cell viability and the glutamate content of ischemic retinal slices. METHODS Rat retinal slices were subjected to ischemia via exposure to oxygen-deprived low-glucose medium for 45 minutes. Slices were either treated or not treated with the toxins PhTx3, Tx3-3, and Tx3-4. After oxygen-deprived low-glucose insult, glutamate content and cell viability were assessed in the slices by confocal and optical microscopy. RESULTS In the retinal ischemic slices that were treated with PhTx3, Tx3-3, and Tx3-4, confocal imaging showed a decrease in cell death of 79.5 ± 3.1%, 75.5 ± 5.8%, and 61 ± 3.8%, respectively. Neuroprotective effects were also observed 15, 30, 60, and 90 minutes after the onset of the retinal ischemic injury. As a result of the ischemia, glutamate increased from 6.2 ± 1.0 nMol/mg protein to 13.2 ± 1.0 nMol/mg protein and was inhibited by PhTx3, Tx3-3, and Tx3-4 to 8.6 ± 0.7, 8.8 ± 0.9, and 7.4 ± 0.8 nMol/mg protein, respectively. Histologic analysis of the live cells in the outer, inner, and ganglion cell layers of the ischemic slices showed a considerable reduction in cell death by the toxin treatment. CONCLUSION Spider toxins reduced glutamate content and cell death of retinal ischemic slices.

Propolis is a resinous material collected by honeybees from numerous plants and serves as a defense against intruders. Because of its relevant curative properties, it is now gaining popularity in health foods and in cosmetic products. Understanding the underlying molecular mechanisms of phytochemicals has become a good strategy in bioprospection for new anti-inflammatory compounds. The biological activity of propolis derives from its high levels of phenolic acids, while flavonoids are thought to account for the activity of propolis extracts. The comprehension of the relationship between propolis and the immune system has progressed in the last years, recent articles have provided important contributions to this investigation field. Studies have shown that propolis suppressed the "IL-6-induced phosphorylation of signal transducer and STAT3", an essential cytokine-activated transcription factor in Th17 development. Therefore, action mechanisms of "propolis on Th17 differentiation could be instrumental in controlling disturbed cytokine networks in inflammation, autoimmune diseases, and infections." The use of propolis has been proposed in some patents as: WO201363714; CN102885854, WO2013142936, US20130266521, and US20130129808, which are related to the treatment of dental diseases; adjuvant in anti-cancer treatment; in cosmetic products; as an anti-inflammatory agent and natural antibiotic. Although there are many publications regarding the propolis efficacy, its applicability to human health and mechanisms of action are not completely understood, creating opportunities for new studies.

Vários trabalhos sugerem que o propofol e o etomidato, anestésicos intravenosos, são capazes de reduzir a injúria neuronal decorrente da isquemia cerebral. Porém, resultados dessa neuroproteção em modelos de isquemia cerebral, tanto in vitro quanto in vivo, têm sido conflitantes. Além disso, os mecanismos envolvidos na neuroproteção do propofol e do etomidato ainda não foram esclarecidos. Esse estudo teve como objetivo investigar o efeito neuroprotetor do propofol e do etomidato em um modelo de isquemia cerebral in vitro e os prováveis mecanismos envolvidos. Metódos: Para avaliar o efeito neuroprotetor, foi utilizado o modelo de fatias de hipocampo submetidas à deprivação de glicose e oxigênio durante 20 minutos. Para investigar os possíveis locais de ação desse anestésico na neuroproteção avaliamos a liberação de glutamato, vias envolvendo cálcio e sódio e o estresse oxidativo. Resultados: Em todas as concentrações avaliadas do propofol (1-300 M) e do etomidato (1-100 M) foram capazes de reduzir a morte neuronal na região CA1 do hipocampo. O propofol e o etomidato foram capazes de reduzir a liberação de glutamato após o insulto isquêmico. E sse efeito parece ser dependente da redução pelo propofol do influxo de Na+ pelos canais de Na+ dependentes de voltagem sensíveis à tetrodotoxina e do influxo de Ca2+ do meio extracelular, pelos canais -P/Q e N. Já o etomidato reduz o influxo de Ca2+ do meio extracelular, pelos canais -P/Q e N, atuando em maior extensão sobre os canais N do que em P/Q, mas não atua sobre os canais de Na+ dependentes de voltagem. No ensaio para quantificar as ERO, tanto o propofol, quanto o etomidato na concentração de 10 M reduziram a quantidade de ERO em relação ao grupo isquemia. Na avaliação da peroxidação lipídica, o propofol e o etomidato conseguiram reduzir o conteúdo de MDA ao nível observado no grupo controle. Ao avaliar a ação desses anestésicos sobre o sistema de defesa antioxidante observou-se o seguinte resultado: o propofol e o etomidato foram capazes de aumentar a atividade das enzimas do sistema glutationa, como a glutationa peroxidase e redutase, além de aumentar o nível de glutationa reduzida disponível. Somente o propofol foi capaz de modular positivamente a atividade da glutationa S-transferase. Somente o etomidato foi capaz de aumentar a atividade da superóxido dismutase da catalase, efeito não observado com o grupo tratado com propofol. Além disso, foi verificada a atividade antioxidante per si da molécula de propofol. Conclusão: Os anestésicos intravenoso propofol e etomidato possuem efeito neuroprotetor em um modelo de fatias de hipocampo submetidas à privação de oxigêe baixa de glicose, e este efeito neuroprotetor pode estar relacionado à redução da liberação de glutamato e atenuação da lesão por estresse oxidativo. A redução da liberação de glutamato pelo propofol parece ocorrer devido à redução do influxo de sódio dependentes de voltagem sensíveis à tetrodotoxina e cálcio do subtipo P/Q e N do meio extracelular. Já redução da liberação de glutamato pelo etomidato parece ocorrer somente devido à redução do influxo cálcio do subtipo P/Q e N do meio extracelular. A atenuação da lesão por estresse oxidativo está diretamente relacionada à capacidade destes anestésicos reduzirem a quantidade de espécies reativas de oxigênio e a peroxidação lipídica após o insulto isquêmico. Este fato se explica pela modulação positiva na atividade das enzimas do sistema antioxidante e pela atividade antioxidante per si do propofol. Several studies shows that propofol and etomidate, intravenous anesthetic, reduces neuronal injury due to brain ischemia. However, the results of such neuroprotection in ischemic models have been conflicting, both in vitro and in vivo studies. In addition, the mechanisms involved in propofol and etomidato neuroprotection have not been clarified. The aim of the present study was to investigate the neuroprotector effect of propofol and etomidate in a model of brain ischemia in vitro, as well as probable mechanisms involved. Methods: To investigate the neuroprotector effect of propofol and etomidate, we used the model hippocampus slices submitted to glucose and oxigen deprivation for 20 minutes. To investigate the possible sites of action of anesthetic neuroprotection, we evaluate the release of glutamate pathways involving calcium and sodium and oxidative stress. Results: In all the concentrations of propofol (1-300 M) and etomidate (1-100 M) evaluated were efficient in reducing neuronal death in the CA1 region of the hippocampus. Propofol and etomidate were able to reduce glutamate release after ischemic insult. This effect appears to be dependent on the reduction of propofol by the influx of Na+ by the Na+ channels voltage dependent tetrodotoxin-sensitive and the reduction on Ca2+ influx by the P/Q and N subtypes channels, from the extracellular environment. However etomidate reduces only Ca2+ influx by the P/Q and N subtypes channels, from the extracellular environment, acting on a greater extent than N channel P/Q. Etomidate has no effect on Na+ channels voltage dependent . In assay for quantifying ROS both, propofol and etomidato, in the concentration of 10 uM reduced ROS amount in relation to ischemia group. Lipid peroxidation assessment, propofol and etomidato, managed to reduce the MDA content to the level observed in the control group. In assessing the action of these anesthetics on the antioxidant defense system observed the following result: propofol and etomidate were able to increase the activity of the glutathione system enzymes, such as glutathione peroxidase and reductase, and increase the level of glutathione reduced available. Only propofol was able to positively modulate the activity of glutathione S-transferase. While only etomidate was able to increase the activity of superoxide dismutase and catalase, an effect not observed in the group treated with propofol. In addition, the antioxidant activity was observed per molecule of propofol itself. Conclusion: The intravenous anesthetic, propofol and etomidato, have neuroprotective effect in a model of hippocampal slices subjected to oxygen deprivation and low glucose, and this neuroprotective effect may be related to reduced glutamate release and attenuation of oxidative stress injury. The reduction in glutamate release in propofol group treated appears to occur due to the reduced influx of sodium by sodiumdependent voltage sensitive to tetrodotoxina channels and calcium P/Q and N subtype channels, from the extracellular medium. Already reduced glutamate release by etomidate seems to occur only due to reduced calcium influx of P/Q and N subtype channels, from the extracellular medium. The attenuation of oxidative stress injury is directly related to the ability of these anesthetics reduce the amount of reactive oxygen species and lipid peroxidation after the ischemic insult. This fact is explained by the positive modulation of the activity of the enzymes of the antioxidant system and the antioxidant activity of propofol itself.

Vários trabalhos sugerem que o propofol, um anestésico intravenoso, é capaz de reduzir a injúria neuronal decorrente da isquemia cerebral. Porém, resultados dessa neuroproteção em modelos de isquemia cerebral, tanto in vitro quanto in vivo, têm sido conflitantes. Além disso, os mecanismos envolvidos na neuroproteção do propofol ainda não foram esclarecidos. Esse estudo teve como objetivo investigar o efeito neuroprotetor do propofol em um modelo de isquemia cerebral in vitro e os prováveis mecanismos envolvidos. Para avaliar o efeito neuroprotetor, foi utilizado o modelo de fatias de hipocampo submetidas à deprivação de glicose e oxigênio durante 20 minutos. Para investigar os possíveis locais de ação desse anestésico na neuroproteção usamos as seguintes ferramentas farmacológicas: conotoxina MVIIC, bloqueador de canais de cálcio do tipo N, -P/Q, tetrodotoxina, bloqueador de canais de sódio e EGTA, quelante de cálcio extracelular. Em todas as concentrações avaliadas (1-300 M) o propofol foi capaz de reduzir a morte neuronal na região CA1 do hipocampo. O efeito máximo do propofol na redução da morte neuronal (47,02%) foi atingido com a concentração de 100 M. Esse efeito parece ser dependente do influxo de Na+ pelos canais de Na+ sensíveis à voltagem e do influxo de Ca2+ do meio extracelular. A conotoxina MVIIC e o propofol apresentam efeitos somatórios em relação à neuroproteção, indicando que o propofol possa estar bloqueando canais de Ca2+ dependentes de voltagem diferentes do tipo N e P/Q. Concluindo, esse estudo sugere que o propofol apresenta efeito neuroprotetor em fatias de hipocampo submetidas à deprivação de glicose e oxigênio. O mecanismo desta neuroproteção parece envolver a redução do influxo de Na+ e Ca2+ neuronal independente de canais de Ca2+ dos tipos -N, -P/Q. There are several studies that propofol, an intravenous anesthetic, reduces neuronal injury due to brain ischemia. However, the results of such neuroprotection in ischemic models have been conflicting, both in vitro and in vivo studies. In addition, the mechanisms involved in propofol neuroprotection have not been clarified. The aim of the present study was to investigate the neuroprotector effect of propofol in a model of brain ischemia in vitro, as well as probable mechanisms involved. To investigate the neuroprotector effect of propofol, we used the model hippocampus slices submitted to glucose and oxigen deprivation for 20 minutes. To assess the possible action locations of the anesthetic neuroprotection we used the following pharmacological tools: conotoxin MVIIC, N, -P/Q type calcium channel blockers, tetrodotoxin, a sodium channel blockers and EGTA, extracelular calcium quelator. In all concentrations assessed (1-300 M), propofol was able to reduce neuronal death in the CA1 region of the hippocampus. The maximum effect of propofol in neuronal death reduction (47,02%) was obtained with the concentration of 100 M. This effect seems to be dependent on the influx of Na+ through the Na+ ion channels sensible to voltage and extracellular Ca2+ influx. conotoxin MVIIC and propofol presented additional effects regarding neuroprotection, indicating that neuroprotetion by propofol could be independent of blocking voltage-dependent -N and -P/Q type Ca2+ channels. Therefore, this study suggests that propofol presents neuroprotector effects in hippocampus slices submitted to deprivation of glucose and oxigen. The mechanism of this neuroprotection seems to involve the reduction of the neuronal Na+ and Ca2+ influx independent of -N, -P/Q type Ca2+ channels.

Introdução: A maioria das intervenções em saúde envolve o uso de medicamentos e isto pode ser determinante para a obtenção dos resultados terapêuticos. A garantia de acesso aos medicamentos é particularmente importante no âmbito da Atenção Primária à Saúde e a disponibilidade física destes insumos é relevante e desafiadora para o acesso, principalmente quando se consideram sistemas universais com financiamento público. Objetivo: Verificar a influência da estrutura organizacional e das atividades técnico-gerenciais na disponibilidade de medicamentos essenciais traçadores em serviços da assistência farmacêutica na atenção primária do Sistema Único de Saúde. Métodos: Estudo transversal, exploratório, de natureza avaliativa, integrante da Pesquisa Nacional Sobre Acesso, Utilização e Promoção do Uso Racional de Medicamentos – Serviços, 2015. Para a análise de disponibilidade física dos medicamentos essenciais, foram verificados 50 itens selecionados da Relação Nacional de Medicamentos Essenciais 2012, conforme parâmetros estabelecidos pela Organização Mundial de Saúde. Os dados foram obtidos por meio de entrevistas com os responsáveis pela dispensação de medicamentos e de roteiros de observação na amostra de farmácias dos serviços da atenção primária. O índice de disponibilidade foi apresentado como o percentual de unidades de dispensação, em que os medicamentos essenciais padronizados nos municípios estavam disponíveis naquele momento. As variáveis categóricas foram apresentadas como frequências absolutas e relativas, e os índices de disponibilidade como média e intervalos de confiança de 95%. Para a comparação de grupos utilizou-se modelo linear para amostras complexas. Resultados: Foram realizadas 1.139 entrevistas com responsáveis pela dispensação de medicamentos e preenchidos roteiros de observação em 1.175 unidades de dispensação. A disponibilidade média de medicamentos traçadores padronizados, em âmbito nacional, foi de 83,3%, e as médias foram superiores a 80% nos três estratos de municípios (capitais, municípios de maior e menor porte). Dentre os grupos terapêuticos avaliados, as mais baixas disponibilidades médias foram na classe dos tuberculostáticos (24,1%), seguido pelos psicotrópicos/controle especial (30,3%). A disponibilidade média nacional para os medicamentos de compra centralizada foi de 73,3%, sendo que, dentre os estratos de municípios, a única média abaixo de 80% foi a dos municípios de menor porte (72,1%). De modo geral, ter farmacêutico responsável pela unidade de dispensação, haver sistema informatizado para registro de atividades da assistência farmacêutica e realizar inventário bimestralmente ou com menor frequência associaram-se à maior disponibilidade média em todos os grupos de medicamentos avaliados. Conclusão: O estudo apontou que a maioria dos municípios dispõe de Remume, mas que isto isoladamente não foi suficiente para garantir a disponibilidade média acima de 80% em todos os quesitos avaliados. A disponibilidade média dos medicamentos essenciais foi influenciada positivamente pela presença de farmacêutico responsável e pela existência de sistema informatizado na unidade dispensadora, e negativamente, foi associada à aquisição centralizada e influenciada pela logística de distribuição aos municípios de menor porte. A baixa disponibilidade média dos medicamentos psicotrópicos/controle especial e tuberculostáticos evidencia a necessidade de melhorias na assistência farmacêutica pública e de estudos que possibilitem avaliar o impacto desta em duas áreas importantes da Atenção Primária à Saúde: a saúde mental e as doenças infectocontagiosas de notificação compulsória. Introduction: Most health interventions involve the use of medications and this could be determinant for obtaining therapeutic results. Ensuring access to medicines is particularly important in Primary Health Care and their physical availability is relevant and challenging for access, especially when considering universal systems and public funding. Objective: To verify the influence of organizational structure and technical-managerial activities on the availability of essential tracer medicines in pharmaceutical services in the primary care of the Unified Health System. Methods: A cross-sectional, exploratory, evaluative study, part of the Pesquisa Nacional Sobre Acesso, Utilização e Promoção do Uso Racional de Medicamentos - Serviços, 2015 (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services, 2015). For the analysis of availability of essential medicines, 50 items selected from the Relação Nacional de Medicamentos Essenciais (Rename - National List of Essential Medicines) were verified, according to parameters established by the World Health Organization. The data were obtained throughout interviews with those responsible for dispensing medications and observation scripts in the pharmacy sample of the primary health care services. The availability rate was presented as the percentage of dispensing units, where essential medicines standardized in the municipalities were available. The categorical variables were presented as absolute and relative frequencies, and the availability rates as mean and 95% confidence intervals. The comparison of groups was carried out by linear model for complex samples. Results: There were conducted 1,139 interviews with medicine dispensers and observation scripts were completed at 1,175 dispensing units. The average availability of standardized essential medicines in Brazil was 83.3%, and the averages were higher than 80% in the three groups of municipalities (capitals, major and minor municipalities). Among the therapeutic groups evaluated, the lowest average availabilities were in the tuberculostatic class (24.1%), followed by psychotropic / special control medicines (30.3%). The national average availability of essential medicines purchased centrally by the Brazilian Ministry of Health was 73.3%. Among the municipalities’ strata, the only mean below 80% was for the smaller municipalities (72.1%). As a whole, having a pharmacist responsible for the medicine dispensing unit, having a computerized system for recording pharmaceutical care activities, and conducting inventories bimonthly or less frequently were associated with higher average availability in all groups of medicines evaluated. Conclusion: The study pointed out that most municipalities have the Relação Municipal de Medicamentos Essenciais (Remume - Municipal Relation of Essential Medicines), but it was not enough to guarantee the average availability above 80% in all the evaluated aspects. The availability of essential medicines was positively influenced by the presence of the pharmacist as responsible for the dispensing unit and by the computerized system deployed, and negatively associated with essential medicines purchased centrally by the federal government and influenced by logistics of distribution to smaller municipalities. The low average availability of psychotropic/special control and tuberculostatics medicines evidences the need for improvements in public pharmaceutical assistance and studies that could evaluate its impact in two important areas of the Primary Health Care: mental health and infectious diseases of compulsory notification.

O trauma medular é afecção comum nas medicinas humana e veterinária, com graves consequências para o indívudo acometido e para a sociedade. A lesão à medula espinhal ocasiona dano ao tecido nervoso por mecanismos primários e secundários, sendo o influxo exacerbado de cálcio, principalmente devido à ativação de canais para cálcio voltagem-dependentes (CCVD), um evento secundário considerado crítico na fisiopatogenia da injúria medular. O peptídeo Ph1 obtido da purificação do veneno total da aranha armadeira Phoneutria nigriventer é capaz de bloquear CCVD e, assim, reduzir o influxo de cálcio. Objetivou-se avaliar o efeito da aplicação intratecal de diferentes doses da toxina Ph1 recombinante em ratos submetidos a trauma medular agudo experimental. Foram utilizados 30 ratos machos adultos, variedade Wistar, aleatoriamente divididos em cinco grupos. Os animais do grupo CN foram submetidos à laminectomia dorsal. Nos demais grupos, além da laminectomia, os animais foram submetidos à trauma medular agudo contusivo. Realizou-se aplicação intratecal de placebo nos animais dos grupos controle e das doses de 25,50 e 100 pmol da toxina Ph1 recombinante nos animais tratados. 48 horas após a intervenção cirúrgica, os animais foram eutanasiados e foram coletadas amostras de sangue, urina e segmentos de medula espinhal, para quantificação de espécies reativas de oxigênio e peroxidação lipídica e avaliação da expressão gênica de fatores relacionados à apoptose através de técnica de qRT-PCR. Observou-se redução de peroxidação lípica nos três grupos submetidos ao tratamento, o que sugere ação neuroprotetora desta toxina. Spinal cord injury is a common disease in human and veterinary medicine, with serious consequences for the one affected and for society. It causes damage to the nervous tissue by primary and secondary mechanisms, being exacerbated influx of calcium, mainly due to the activation voltage-dependent calcium channels, a secondary event considered critical in the pathogenesis of spinal cord injury. The Ph1 peptide obtained from the purification of the whole venom of Phoneutria nigriventer spider is able to block voltage-dependent calcium channels and thereby reduce calcium influx. This study aimed to evaluate the effect of intrathecal administration of different doses of recombinant Ph1 toxin in spinal cord experimentally injured rats. Thirty male Wistar rats were randomly distributed into five groups. Animals belonging to CN group underwent dorsal laminectomy. In other groups, beyond laminectomy, animals underwent acute spinal cord contusive trauma. Animals belonging the control groups received placebo intrathecally administered and treated animals received 25, 50 e 100 pmol of the toxin by the same via. Forty-eight hours after surgery animals were euthanized and were collected blood and urine samples, besides and spinal cord segments, for reactive oxygen species and lipid peroxidation quantification and to assess gene expression of apoptosis- related genes by qRT-PCR. It showed reduction in lipid peroxidation in all three groups who had received the toxin, wich suggests neuroprotector effect.

Transtornos psiquiátricos como a esquizofrenia e o transtorno afetivo bipolar compartilham várias características em comum, como genes de risco, alterações neurofisiológicas, desregulação do sistema de defesa antioxidante e déficit de glutationa (GSH) no córtex pré-frontal. Alterações nos componentes da matriz extracelular (ECM) do sistema nervoso central (SNC) também são relatadas nas doenças neurológicas e vem sendo frequentemente discutidas nos transtornos psiquiátricos. A ECM do SNC possui importantes funções como manutenção das sinapses e controle da plasticidade neuronal, proteção dos neurônios contra estresse oxidativo, sinalização celular e reservatório de fatores de crescimento. No entanto, após sucessivas lesões, estresse ou doença, a capacidade de remodelação exercida pela ECM torna-se comprometida prejudicando a comunicação neuronal e a capacidade regenerativa da própria ECM. O estresse oxidativo vem sendo apontado como um possível causador das anomalias observadas na ECM na esquizofrenia. A proposta do presente estudo foi validar alguns genes relacionados à matriz extracelular que estavam diferentemente expressos entre pacientes com esquizofrenia e controles observados no estudo de microarranjo, previamente realizado pelo nosso grupo. Além disso, perguntamos como o estresse oxidativo pode regular alguns genes na esquizofrenia e se há alguma similaridade na regulação desses genes no transtorno bipolar. Para isto, utilizamos cultura de fibroblastos dérmicos de pacientes com esquizofrenia residual e transtorno afetivo bipolar eutímicos. As culturas foram tratadas com pró-oxidante tBHQ para simular um estresse oxidativo e após o tratamento extraímos o RNAm para avaliarmos a expressão gênica de cinco genes:MMP16, GALNT6, SULF1, ADAMTS1 e ACSL1. Não foi possível validar a diferença de expressão dos níveis dos cinco genes selecionados em pacientes com esquizofrenia comparados aos controles e pacientes bipolares comparados com seus respectivos controles. Porém, observou-se que o estresse oxidativo foi capaz de regular os níveis de expressão dos cinco genes selecionados em pacientes com esquizofrenia ou transtorno bipolar. A análise protéica revelou que os níveis da enzima Galnac transferase 6 estão diminuídos em pacientes com esquizofrenia, sugerindo uma diminuição da glicosilação dos componentes da ECM, o que pode conferir perda da estabilidade da matriz. Já os níveis do gene ADAMTS1 possuem uma tendência de aumento nos pacientes bipolares, sugerindo também um comprometimento da integridade dos componentes da ECM. Em geral, os resultados da expressão gênica nas amostras dos pacientes com esquizofrenia se assemelham com os resultados obtidos das amostras de pacientes bipolares. O estresse oxidativo altera a regulação de genes associados à matriz extracelular na esquizofrenia e no transtorno bipolar. Estudos funcionais relacionados as enzimas codificadas pelos genes GALNT6 e ADAMTS1 são necessários para o melhor entendimento da relação de ambas na fisiopatologia dos transtornos psiquiátricos. Psychiatric disorders such schizophrenia and bipolar disorder share importante aspects like commom gene risk, neurophisiologic deficit, defense antioxidante system deregulation and prefrontal cortex glutathione deficit. Extracellular matrix (ECM) components anomalies from central nervous system (CNS) are observed in neurological disorders and have been discuted in psychiatric disorders. The ECM from SNC has important functions such synaptic maintenance, control of neuronal plasticity, protection of neurons againts oxidative stress, cellular sinalization and growth factores resevoir. However, after multiple injuries, stress or disease, the remodelation capacity exerced by ECM becomes compromized, leading to failures in the neuron comunication and ECM regenerative capacity. Oxidative stress have been suggested as causes for anomalies seen in schizophrenia ECM. The propose of this study was validate some genes related to extracellular matrix which were differentially expressed between schizophrenic patients and controls observed in our previous study using microarray. Furthemore, we asked how oxidative stress can regulate these genes in schizophrenia and if this regulation is it similiar with bipolar disorder. For this, we used skin fibroblastos culture from residual schizophrenic and bipolar euthimic patients. The culture were treated with tBHQ, a compound which induces oxidative stress, and after the treatment we extracted the mRNA for genetic expression of MMP16, GALNT6, SULF1, ADAMTS1 and ACSL1. We can not validade the expression diferences of five genes selected between schizophrenic patients and controles and bipolar patients compared to respectives controls. But, it was observed that the five genes selected are regulated by oxidative stress in schizophrenic and bipolar patients. Besides, the protein analysis revealed galnac transferase 6 levels are decreased in schizophrenic patients, suggesting a glycosylation reduced of ECM components, which can be compromise the matrix stability. ADAMTS1 gene levels have a tendency of increase in bipolar patients, also suggesting a impairment in integrity ECM componentes. In general, the data from gene expression of schizoprenic and bipolar patients are similar. Oxidative stress alter the regulation of gene extracelular matrix associated in schizophrenia and bipolar disorder. Functional studies related to enzymes codified by GALNT6 and ADAMTS1 are necessary to better understand the relation of both in schizophrenia and bipolar disorder pathophysiology