Interplay between nitric oxide and gonadotrophin-releasing hormone in the neuromodulation of the corpus luteum during late pregnancy in the rat.

BACKGROUND: Nitric oxide and GnRH are biological factors that participate in the regulation of reproductive functions. To our knowledge, there are no studies that link NO and GnRH in the sympathetic ganglia. Thus, the aim of the present work was to investigate the influence of NO on GnRH release from the coeliac ganglion and its effect on luteal regression at the end of pregnancy in the rat. METHODS: The ex vivo system composed by the coeliac ganglion, the superior ovarian nerve, and the ovary of rats on day 21 of pregnancy was incubated for 180 min with the addition, into the ganglionic compartment, of L-NG-nitro arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor. The control group consisted in untreated organ systems. RESULTS: The addition of L-NAME in the coeliac ganglion compartment decreased NO as well as GnRH release from the coeliac ganglion. In the ovarian compartment, and with respect to the control group, we observed a reduced release of GnRH, NO, and noradrenaline, but an increased production of progesterone, estradiol, and expression of their limiting biosynthetic enzymes, 3ß-HSD and P450 aromatase, respectively. The inhibition of NO production by L-NAME in the coeliac ganglion compartment also reduced luteal apoptosis, lipid peroxidation, and nitrotyrosine, whereas it increased the total antioxidant capacity within the corpora lutea. CONCLUSION: Collectively, the results indicate that NO production by the coeliac ganglion modulates the physiology of the ovary and luteal regression during late pregnancy in rats.

Neurotoxic and convulsant effects induced by jack bean ureases on the mammalian nervous system.

Ureases are microbial virulence factors either because of the enzymatic release of ammonia or due to many other non-enzymatic effects. Here we studied two neurotoxic urease isoforms, Canatoxin (CNTX) and Jack Bean Urease (JBU), produced by the plant Canavalia ensiformis, whose mechanisms of action remain elusive. The neurotoxins provoke convulsions in rodents (LD50 ∼2 mg/kg) and stimulate exocytosis in cell models, affecting intracellular calcium levels. Here, electrophysiological and brain imaging techniques were applied to elucidate their mode of action. While systemic administration of the toxins causes tonic-clonic seizures in rodents, JBU injected into rat hippocampus induced spike-wave discharges similar to absence-like seizures. JBU reduced the amplitude of compound action potential from mouse sciatic nerve in a tetrodotoxin-insensitive manner. Hippocampal slices from CNTX-injected animals or slices treated in vitro with JBU failed to induce long term potentiation upon tetanic stimulation. Rat cortical synaptosomes treated with JBU released L-glutamate. JBU increased the intracellular calcium levels and spontaneous firing rate in rat hippocampus neurons. MicroPET scans of CNTX-injected rats revealed increased [18]Fluoro-deoxyglucose uptake in epileptogenesis-related areas like hippocampus and thalamus. Curiously, CNTX did not affect voltage-gated sodium, calcium or potassium channels currents, neither did it interfere on cholinergic receptors, suggesting an indirect mode of action that could be related to the ureases' membrane-disturbing properties. Understanding the neurotoxic mode of action of C. ensiformis ureases could help to unveil the so far underappreciated relevance of these toxins in diseases caused by urease-producing microorganisms, in which the human central nervous system is affected.

Inhibitors of angiotensin I converting enzyme potentiate fibromyalgia-like pain symptoms via kinin receptors in mice.

Fibromyalgia is a potentially disabling chronic disease, characterized by widespread pain and a range of comorbidities such as hypertension. Among the mechanisms involved in fibromyalgia-like pain symptoms are kinins and their B1 and B2 receptors. Moreover, angiotensin I converting enzyme (ACE) inhibitors, commonly used as antihypertensive drugs, can enhance pain by blocking the degradation of peptides such as substance P and bradykinin, besides enhancing kinin receptors signalling. We investigated the effect of ACE inhibitors on reserpine-induced fibromyalgia-like pain symptoms and the involvement of kinins in this effect in mice. Nociceptive parameters (mechanical and cold allodynia and overt nociception) were evaluated after ACE inhibitors administration in mice previously treated with reserpine. The role of kinin B1 and B2 receptors was investigated using pharmacological antagonism. Additionally, bradykinin levels, as well as the activity of ACE and kininase I, were measured in the sciatic nerve, spinal cord and cerebral cortex of the mice. The ACE inhibitors enalapril and captopril enhanced reserpine-induced mechanical allodynia, and this increase was prevented by kinin B1 and B2 receptor antagonists. Substance P and bradykinin caused overt nociception and increased mechanical allodynia in animals treated with reserpine. Reserpine plus ACE inhibitors increased bradykinin-related peptide levels and inhibited ACE activity in pain modulation structures. Since hypertension is a frequent comorbidity affecting fibromyalgia patients, hypertension treatment with ACE inhibitors in these patients should be reviewed once this could enhance fibromyalgia-like pain symptoms. Thus, the treatment of hypertensive patients with fibromyalgia could include other classes of antihypertensive drugs, different from ACE inhibitors.

Envenomation by Centruroides pococki scorpion with neuromuscular toxicity.

Cases of human envenomation by Centruroides pococki are exceptionally reported in human. We report a Class III human envenomation by C. pococki in Guadeloupe, French West Indies, with neuromuscular toxicity that has never been described before. Symptoms resolved within a few hours, without the need for intravenous scorpion-specific antivenom.

¿Anestesia halogenada o anestesia total endovenosa en neurocirugía? / Volatile or total intravenous anesthesia for neurosurgery?

Total intravenous anesthesia (TIVA) with propofol/remifentanil appears in the literatura as a good option for neurosurgical patients who have increased intracranial pressure (ICP),risk of postoperative nausea and vomiting (PONV), need for neuromonitoring, and in those with impaired brain self-regulation. On the other hand, in patients with normal neurological status, normal ICP, a technique with volatile (halogenated) agents plus an opiiid can be used. This review describes two anesthetic techniques available for use in neurosurgery, highlighting the neurophysiological changes, advantages and disadvantages of each technique. MATERIAL AND METHOD: PubMed search engine was used for bibliographic search. DISCUSSION: The search for an ideal anesthetic in neurosurgery is still a matter of debate. There are numerous investigations aimed at finding an optimal agent that ensure the coupling between cerebral flow (CBF) and metabolism, keeping self-regulation intact without increasing the CBF and intracerebral pressure (ICP). CONCLUSIONS: Both anesthetic techniques, TIVA and volatile agents (halogenated), can be used in neurosurgical procedures and should provide neuroprotection, brain relaxation and a rapid awakening.

La anestesia total endovenosa (TIVA) con propofol/remifentanilo aparece en la literatura como una buena opción para pacientes neuroquirúrgicos que tienen aumento de la presión intracraneana (PIC), riesgo de náuseas y vómitos posoperatorios (NVPO), necesidad de neuromonitoreo, y en aquellos con alteración de la autorregulación cerebral. Por otra parte, en pacientes con estado neurológico normal, PIC normal puede usarse una técnica con agentes volátiles (halogenados) más un opioide. Esta revisión describe dos técnicas anestésicas disponibles para su uso en neurocirugía, destaca los cambios neurofisiológicos, ventajas y desventajas de cada técnica. MATERIAL Y MÉTODO: Para búsqueda bibliográfica se usó buscador PubMed. DISCUSIÓN: La búsqueda de un anestésico ideal en neurocirugía sigue siendo tema de debate. Existen numerosas investigaciones destinadas a buscar un agente óptimo que asegure el acoplamiento entre flujo sanguíneo cerebral (FSC) y metabolismo, manteniendo la autorregulación intacta sin aumentar el FSC y presión intracerebral (PIC). CONCLUSIONES: Ambas técnicas anestésicas, TIVA y agentes volátiles (halogenados), pueden ser usadas en procedimientos neuroquirúrgicos y deben brindar neuroprotección, relajación cerebral y un despertar rápido.

Bergenin Reduces Experimental Painful Diabetic Neuropathy by Restoring Redox and Immune Homeostasis in the Nervous System.

Diabetic neuropathy is a frequent complication of diabetes. Symptoms include neuropathic pain and sensory alterations-no effective treatments are currently available. This work characterized the therapeutic effect of bergenin in a mouse (C57/BL6) model of streptozotocin-induced painful diabetic neuropathy. Nociceptive thresholds were assessed by the von Frey test. Cytokines, antioxidant genes, and oxidative stress markers were measured in nervous tissues by ELISA, RT-qPCR, and biochemical analyses. Single (3.125-25 mg/kg) or multiple (25 mg/kg; twice a day for 14 days) treatments with bergenin reduced the behavioral signs of diabetic neuropathy in mice. Bergenin reduced both nitric oxide (NO) production in vitro and malondialdehyde (MDA)/nitrite amounts in vivo. These antioxidant properties can be attributed to the modulation of gene expression by the downregulation of inducible nitric oxide synthase (iNOS) and upregulation of glutathione peroxidase and Nrf2 in the nervous system. Bergenin also modulated the pro- and anti-inflammatory cytokines production in neuropathic mice. The long-lasting antinociceptive effect induced by bergenin in neuropathic mice, was associated with a shift of the cytokine balance toward anti-inflammatory predominance and upregulation of antioxidant pathways, favoring the reestablishment of redox and immune homeostasis in the nervous system. These results point to the therapeutic potential of bergenin in the treatment of painful diabetic neuropathy.

Neurodevelopmental Outcomes of Neonates Randomized to Morphine or Methadone for Treatment of Neonatal Abstinence Syndrome.

OBJECTIVE: To evaluate the effects of pharmacologic treatment of neonatal abstinence syndrome on neurodevelopmental outcome from a randomized, controlled trial. STUDY DESIGN: Eight sites enrolled 116 full-term newborn infants with neonatal abstinence syndrome born to mothers maintained on methadone or buprenorphine into a randomized trial of morphine vs methadone. Ninety-nine infants (85%) were evaluated at hospital discharge using the NICU Network Neurobehavioral Scale. At 18 months, 83 of 99 infants (83.8%) were evaluated with the Bayley Scales of Infant and Toddler Development-Third Edition and 77 of 99 (77.7%) with the Child Behavior Checklist (CBCL). RESULTS: Primary analyses showed no significant differences between treatment groups on the NICU Network Neurobehavioral Scale, Bayley Scales of Infant and Toddler Development-Third Edition, or CBCL. However in post hoc analyses, we found differences by atypical NICU Network Neurobehavioral Scale profile on the CBCL. Infants receiving adjunctive phenobarbital had lower Bayley Scales of Infant and Toddler Development-Third Edition scores and more behavior problems on the CBCL. In adjusted analyses, internalizing and total behavior problems were associated with use of phenobarbital (P = .03; P = .04), maternal psychological distress (measured by the Brief Symptom Inventory) (both P < .01), and infant medical problems (both P = .02). Externalizing problems were associated with maternal psychological distress (P < .01) and continued maternal substance use (P < .01). CONCLUSIONS: Infants treated with either morphine or methadone had similar short-term and longer term neurobehavioral outcomes. Neurodevelopmental outcome may be related to the need for phenobarbital, overall health of the infant, and postnatal caregiving environment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958476.

2-Aminoethyldiphenyl Borinate: A Multitarget Compound with Potential as a Drug Precursor.

BACKGROUND: Boron is considered a trace element that induces various effects in systems of the human body. However, each boron-containing compound exerts different effects. OBJECTIVE: To review the effects of 2-Aminoethyldiphenyl borinate (2-APB), an organoboron compound, on the human body, but also, its effects in animal models of human disease. METHODS: In this review, the information to showcase the expansion of these reported effects through interactions with several ion channels and other receptors has been reported. These effects are relevant in the biomedical and chemical fields due to the application of the reported data in developing therapeutic tools to modulate the functions of the immune, cardiovascular, gastrointestinal and nervous systems. RESULTS: Accordingly, 2-APB acts as a modulator of adaptive and innate immunity, including the production of cytokines and the migration of leukocytes. Additionally, reports show that 2-APB exerts effects on neurons, smooth muscle cells and cardiomyocytes, and it provides a cytoprotective effect by the modulation and attenuation of reactive oxygen species. CONCLUSION: The molecular pharmacology of 2-APB supports both its potential to act as a drug and the desirable inclusion of its moieties in new drug development. Research evaluating its efficacy in treating pain and specific maladies, such as immune, cardiovascular, gastrointestinal and neurodegenerative disorders, is scarce but interesting.

Hepatic and neurobiological effects of foetal and breastfeeding and adulthood exposure to methylmercury in Wistar rats.

Methylmercury (MeHg) is an organic bioaccumulated mercury derivative that strongly affects the environment and represents a public health problem primarily to riparian communities in South America. Our objective was to investigate the hepatic and neurological effects of MeHg exposure during the phases foetal and breast-feeding and adult in Wistar rats. Wistar rats (n = 10) were divided into 3 groups. Control group received mineral oil; The simple exposure (SE) group was exposed only in adulthood (0.5 mg/kg/day); and double exposure (DE) was pre-exposed to MeHg 0.5 mg/kg/day during pregnancy and breastfeeding (±40 days) and re-exposed to MeHg for 45 days from day 100. After, we evaluated possible abnormalities. Behavioral and biochemical parameters in liver and occipital cortex (CO), markers of liver injury, redox and AKT/GSK3ß/mTOR signaling pathway. Our results showed that both groups treated with MeHg presented significant alterations, such as decreased locomotion and exploration and impaired visuospatial perception. The rats exposed to MeHg showed severe liver damage and increased hepatic glycogen concentration. The MeHg groups showed significant impairment in redox balance and oxidative damage to liver macromolecules and CO. MeHg upregulated the AKT/GSK3ß/mTOR pathway and the phosphorylated form of the Tau protein. In addition, we found a reduction in NeuN and GFAP immunocontent. These results represent the first approach to the hepatotoxic and neural effects of foetal and adult MeHg exposure.

Effect of caffeine on neuromuscular function following eccentric-based exercise.

This study investigated the effect of caffeine on neuromuscular function, power and sprint performance during the days following an eccentric-based exercise. Using a randomly counterbalanced, crossover and double-blinded design, eleven male jumpers and sprinters (age: 18.7 ± 2.7 years) performed a half-squat exercise (4 x 12 repetitions at 70% of 1 RM), with eccentric action emphasized by using a flexible strip attached to their knees (Tirante Musculador®). They ingested either a capsule of placebo or caffeine (5 mg.kg-1 body mass) 24, 48 and 72 h after. Neuromuscular function and muscle power (vertical countermovement-jump test) were assessed before and after the half-squat exercise and 50 min after the placebo or caffeine ingestion at each time-point post-exercise. Sprint performance was measured at pre-test and 75 min after the placebo or caffeine ingestion at each time-point post-exercise. Maximal voluntary contraction (overall fatigue) and twitch torque (peripheral fatigue) reduced after the half-squat exercise (-11 and -28%, respectively, P < 0.05) but returned to baseline 24 h post-exercise (P > 0.05) and were not affected by caffeine ingestion (P > 0.05). The voluntary activation (central fatigue) and sprint performance were not altered throughout the experiment and were not different between caffeine and placebo. However, caffeine increased height and power during the vertical countermovement-jump test at 48 and 72 h post half-squat exercise, when compared to the placebo (P < 0.05). In conclusion, caffeine improves muscle power 48 and 72 h after an eccentric-based exercise, but it has no effect on neuromuscular function and sprint performance.

Introduction to the Special Issue "Neuroactive Steroids".

Steroids are complex molecules, exerting known and still unknown effects in the nervous system. Throughout this volume, the reader will find a wide spectrum of articles, giving an up-to-date account of the molecular, physiological, pharmacological, and clinical aspects of steroid action on the nervous system.

The antidepressant effect of bone marrow mononuclear cell transplantation in chronic stress.

BACKGROUND: Inflammation could be a risk factor for the development of depression and change the outcome of this common chronic-recurrent mental disorder. AIMS: This study aimed to investigate if bone marrow mononuclear cell (BMMC) transplantation is effective in restoring sucrose preference in rats subjected to chronic stress (CS), if it has an anti-inflammatory effect and is able to restore damaged DNA. METHODS: The effect of BMMC transplantation was studied in a controlled protocol (compared with a control group and a selective serotonin reuptake inhibitor escitalopram group) involving sucrose preference in CS in rats. Measurements were taken of the amygdala, hippocampus, frontal cortex, and other brain areas, the spleen and blood pro-inflammatory cytokines, namely interleukin-1ß, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, as well as anti-inflammatory cytokine interleukin-10. Finally, 8-hydroxy-2'-deoxyguanosine (a DNA damage marker) was determined. RESULTS: BMMC transplantation was as effective as escitalopram in restoring sucrose preference. It also had an anti-inflammatory effect and slightly improved damaged DNA after one week. CONCLUSIONS: These findings suggest administration of BMMC in rats subjected to CS restores sucrose preference, resolves inflammation in both the peripheral and central nervous system, as well as diminishes DNA damage. This effect was similar to that of escitalopram, which is effective in the treatment of depressive patients.

Toxicological and pharmacologic effects of farnesol (C15H26O): A descriptive systematic review.

The objective of the present study was to perform a systematic review (SR) composed of preclinical and clinical studies which investigated the toxicological and pharmacologic effects of farnesol [Molecular formula: C15H26O; IUPAC: (3,7,11-Trimethyl-2,6,10-dodecatrien-1-ol]. This SR was performed according to PRISMA guidelines. Literature research was performed using PubMed, MEDLINE, Scopus and Web of Science databases using the descriptor combinations: "farnesol and pharmacological effect" and "farnesol and toxicology". The inclusion criteria used were original articles from preclinical and clinical studies investigating the pharmacological and toxicological effects of farnesol, published between January 1960 and December 2017 which were written in English, Portuguese and Spanish. Primary research identified 414 articles, from which 76 articles were selected for final analysis following the inclusion criteria. After grouping, 51.32 and 22.37% of the articles investigated the antimicrobial and antitumor effect, respectively. Methodological biases have been observed both in pre-clinical studies with non-human animals and in clinical trials, mainly in group allocation and blinding. This SR is the first study developed to compile the studies concerning the pharmacological and toxicological effects of farnesol. This study concludes that farnesol possesses different pharmacological and toxicological features, which permit its use as an active or a coadjuvant drug.

Residential exposure to urban traffic is associated with the poorer neurobehavioral health of Ecuadorian schoolchildren.

PURPOSE: We investigated whether chronic traffic-generated air pollution containing fine and ultrafine particulate matter is associated with reduced neurobehavioral performance and behavioral dysfunction in urban Ecuadorian schoolchildren. Also, we examined the effect of child hemoglobin and sociodemographic risk factors on these neurocognitive outcomes. METHODS: A convenience sample of healthy children aged 8-14 years attending public schools were recruited in Quito, Ecuador. Child residential proximity to the nearest heavily trafficked road was used as a proxy for traffic-related pollutant exposure. These included high exposure (<100 m), medium exposure (100-199 m) and low exposure (≥ 200 m) from the nearest heavily trafficked road. The Behavioral Assessment and Research System (BARS), a computerized test battery assessing attention, memory, learning and motor function was used to evaluate child neurobehavioral performance. The Child Behavior Checklist (CBCL/6-18) was used to assess child behavioral dysfunction as reported by mothers. The data were analyzed using multiple linear regression. RESULTS: Children with the highest residential exposure to traffic pollutants (< 100 m) had significantly longer latencies as measured by match to sample (b = 410.27; p = 0.01) and continuous performance (b = 37.90; p = 0.02) compared to those living ≥ 200 m away. A similar but non-significant association was observed for reaction time latency. Children living within 100 m of heavy traffic also demonstrated higher scores across all CBCL subscales although only the relationship with thought problems (p = 0.05) was statistically significant in the adjusted model. CONCLUSION: The study findings suggest that children living within 100 m of heavy traffic appear to experience subtle neurobehavioral deficits that may result from fine and ultrafine particulate matter exposure.

Topography of the medullary cone of the feline night monkey: Clinical implications in epidural anesthesia / Topografia do cone medular do macaco-da-noite: auxiliando a abordagem peridural

Feline night monkey (Aotus azarae infulatus) is an arboreal primate that sleeps during the day hidden among branches of trees, leaving its hideout after nightfall. Little is known about the morphology of these animals, which leads to some difficulty in clinical and surgical approaches, as there has been substantial growth in the veterinarians role in maintaining the health and well-being of wildlife. Thus, we sought to investigate the topography and morphometry of the medullary cone, a small portion of the nervous system of the feline night monkey, which is of paramount importance in approaches for epidural anesthesia. Specimens from five young females were used, each with eight lumbar vertebrae, three sacral vertebrae, and a medullary cone with an average length of 7.5 cm, located between L5 and S3. Based on this finding, we suggest that a probable site for the application of epidural anesthesia is the space between S3 and Cc1.(AU)

O macaco-da-noite (Aotus azarae infulatus) é um animal arborícola que dorme durante o dia escondido entre os ramos, saindo do esconderijo após o anoitecer. Pouco se sabe sobre a morfologia destes animais, o que gera certa dificuldade nas abordagens clínico-cirúrgicas, uma vez que cresce substancialmente o papel do médico veterinário nas questões de saúde e bem-estar de animais selvagens. Visando contribuir com esses profissionais, buscou-se investigar a topografia e morfometria de uma pequena porção do sistema nervoso do macaco-da-noite, o cone medular, que é de suma importância nas abordagens quanto à anestesia peridural. Foram utilizados cinco espécimes fêmeas, jovens, de macaco-da-noite, que apresentavam oito vértebras lombares e três vértebras sacrais, e cone medular possuindo em média de 7,5 cm de comprimento, localizando-se entre L5 e S3. Este achado nos leva a sugerir como sítio provável para a aplicação de anestesia epidural, o espaço entre S3 e Cc1.(AU)

Acrylamide: A review about its toxic effects in the light of Developmental Origin of Health and Disease (DOHaD) concept.

The endocrine system is highly sensitive to endocrine-disrupting chemicals (EDC) which interfere with metabolism, growth and reproduction throughout different periods of life, especially in the embryonic and pubertal stages, in which gene reprogramming may be associated with impaired development and control of tissues/organs even in adulthood. Acrylamide is considered a potential EDC and its main source comes from fried, baked and roasted foods that are widely consumed by children, teenagers and adults around the world. This review aimed to present some aspects regarding the acrylamide formation, its toxicokinetics, the occurrence of acrylamide in foods, the recent findings about its effects on different systems and the consequences for the human healthy. The challenges to characterize the molecular mechanisms triggered by acrylamide and to establish safe levels of consumption and/or exposure are also discussed in the present review.

Topography of the medullary cone of the feline night monkey: Clinical implications in epidural anesthesia / Topografia do cone medular do macaco-da-noite: auxiliando a abordagem peridural

Feline night monkey (Aotus azarae infulatus) is an arboreal primate that sleeps during the day hidden among branches of trees, leaving its hideout after nightfall. Little is known about the morphology of these animals, which leads to some difficulty in clinical and surgical approaches, as there has been substantial growth in the veterinarian’s role in maintaining the health and well-being of wildlife. Thus, we sought to investigate the topography and morphometry of the medullary cone, a small portion of the nervous system of the feline night monkey, which is of paramount importance in approaches for epidural anesthesia. Specimens from five young females were used, each with eight lumbar vertebrae, three sacral vertebrae, and a medullary cone with an average length of 7.5 cm, located between L5 and S3. Based on this finding, we suggest that a probable site for the application of epidural anesthesia is the space between S3 and Cc1.

O macaco-da-noite (Aotus azarae infulatus) é um animal arborícola que dorme durante o dia escondido entre os ramos, saindo do esconderijo após o anoitecer. Pouco se sabe sobre a morfologia destes animais, o que gera certa dificuldade nas abordagens clínico-cirúrgicas, uma vez que cresce substancialmente o papel do médico veterinário nas questões de saúde e bem-estar de animais selvagens. Visando contribuir com esses profissionais, buscou-se investigar a topografia e morfometria de uma pequena porção do sistema nervoso do macaco-da-noite, o cone medular, que é de suma importância nas abordagens quanto à anestesia peridural. Foram utilizados cinco espécimes fêmeas, jovens, de macaco-da-noite, que apresentavam oito vértebras lombares e três vértebras sacrais, e cone medular possuindo em média de 7,5 cm de comprimento, localizando-se entre L5 e S3. Este achado nos leva a sugerir como sítio provável para a aplicação de anestesia epidural, o espaço entre S3 e Cc1.

Ouabain attenuates oxidative stress and modulates lipid composition in hippocampus of rats in lipopolysaccharide-induced hypocampal neuroinflammation in rats.

Our study aimed to analyze the effect of ouabain (OUA) administration on lipopolysaccharide (LPS)-induced changes in hippocampus of rats. Oxidative parameters were analyzed in Wistar rats after intraperitoneal injection of OUA (1.8 µg/kg), LPS (200 µg/kg), or OUA plus LPS or saline. To reach our goal, activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), in addition to levels of reduced glutathione (GSH), protein carbonyl (PCO) and lipid peroxidation (LPO) were evaluated. We also analyzed the membrane lipid profile and some important lipids for the nervous system, such as phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidic acid and sphingomyelin. The group that received only LPS showed increased oxidative stress, as evidenced by an increase in LPO (about twice), PCO (about three times) levels, and CAT activity (80%). Conversely, administration of LPS decreased GSH levels (55%), and GPx activity (30%), besides a reduction in the amount of PI (60%) and PC (45%). By other side, OUA alone increased the amount of PI (45%), PE (85%), and PC (70%). All harmful effects recorded were attenuated by OUA, suggesting a protective effect against LPS-induced oxidative stress. The relevance of our results extends beyond changes in oxidative parameters induced by LPS, because nanomolar doses of OUA may be useful in neurodegenerative models. Other studies on other cardenolides and substances related issues, as well as the development of new molecules derived from OUA, could also be useful in general oxidative and/or cellular stress, a condition favoring the appearance of neuronal pathologies.

Comparative safety assessments of the biosimilar APZ001 and Erbitux in pre-clinical animal models.

PURPOSE: To evaluate the toxicity of Erbitux as well as its biosimilar APZ001 antibody (APZ001) in pre-clinical animal models including mice, rabbits and cynomolgus monkeys. METHODS: We performed analysis of normal behavior activity, autonomic and non-autonomic nervous functions, nervous-muscle functions, nervous excitability and sensorimotor functions on CD-1 mice. Subsequently, we studied that effects of APZ001 and Erbitux on respiratory system, cardiovascular system and kidney in Cynomolgus monkey models and performed local tolerance experiments on New Zealand rabbits. RESULTS: The comparisons between APZ001 and Erbitux showed no significant differences in mice autonomic nervous system, nervous muscle functions, non-autonomic nervous functions, nervous excitability and sensorimotor functions between treated and untreated group (p>0.05). APZ001 and Erbitux showed negative effect on CD-1 mice in the present of pentobarbital sodium anesthesia (p>0.05). Single administrations of high, medium or low doses of APZ001 did not lead to monkey urine volume alterations (p>0.05). In human tissues, APZ001 and Erbitux showed positive signals in endocardium, lung type II alveolar epithelial cell and surrounding vessels, but showed negative results in kidney and liver tissues. No hemolysis phenomenon and serious side-effects in vessels and muscles were observed in rabbits when administrated with APZ001 and Erbitux respectively. CONCLUSION: The safety comparisons between APZ001 antibody and Erbitux showed that these two antibodies showed highly similarities in mice, rabbits and cynomolgus monkey animal models in consideration of pharmaceutical effects, indicating APZ001 might be a suitable substitute for Erbitux.

Comparative safety assessments of the biosimilar APZ001 and Erbitux in pre-clinical animal models

Abstract Purpose: To evaluate the toxicity of Erbitux as well as its biosimilar APZ001 antibody (APZ001) in pre-clinical animal models including mice, rabbits and cynomolgus monkeys. Methods: We performed analysis of normal behavior activity, autonomic and non-autonomic nervous functions, nervous-muscle functions, nervous excitability and sensorimotor functions on CD-1 mice. Subsequently, we studied that effects of APZ001 and Erbitux on respiratory system, cardiovascular system and kidney in Cynomolgus monkey models and performed local tolerance experiments on New Zealand rabbits. Results: The comparisons between APZ001 and Erbitux showed no significant differences in mice autonomic nervous system, nervous muscle functions, non-autonomic nervous functions, nervous excitability and sensorimotor functions between treated and untreated group (p>0.05). APZ001 and Erbitux showed negative effect on CD-1 mice in the present of pentobarbital sodium anesthesia (p>0.05). Single administrations of high, medium or low doses of APZ001 did not lead to monkey urine volume alterations (p>0.05). In human tissues, APZ001 and Erbitux showed positive signals in endocardium, lung type II alveolar epithelial cell and surrounding vessels, but showed negative results in kidney and liver tissues. No hemolysis phenomenon and serious side-effects in vessels and muscles were observed in rabbits when administrated with APZ001 and Erbitux respectively. Conclusion: The safety comparisons between APZ001 antibody and Erbitux showed that these two antibodies showed highly similarities in mice, rabbits and cynomolgus monkey animal models in consideration of pharmaceutical effects, indicating APZ001 might be a suitable substitute for Erbitux.