RESUMEN
Egg dehydration can kill terrestrial frog embryos, and this threat is increasing with climate change and deforestation. In several lineages that independently evolved terrestrial eggs, and retained aquatic tadpoles, embryos accelerate hatching to escape from drying eggs, entering the water earlier and less developed. However, the cues that stimulate drying-induced early hatching are unknown. Ammonia is a toxic, water-soluble metabolic waste that accumulates within eggs as embryos develop and concentrates as eggs dehydrate. Thus, increasing ammonia concentration may be a direct threat to embryos in drying eggs. We hypothesized that it could serve as a cue, stimulating embryos to hatch and escape. The embryos of red-eyed treefrogs, Agalychnis callidryas, hatch early to escape from many threats, including dehydration, and are known to use mechanosensory, hypoxia, and light cues. To test if they also use high ammonia as a cue to hatch, we exposed stage-matched pairs of hatching-competent, well-hydrated sibling embryos to ammonia and control solutions in shallow water baths and recorded their behavior. Control embryos remained unhatched while ammonia-exposed embryos showed a rapid, strong hatching response; 95% hatched, on average in under 15 min. This demonstrates that elevated ammonia can serve as a hatching cue for A. callidryas embryos. This finding is a key step in understanding the mechanisms that enable terrestrial frog embryos to escape from egg drying, opening new possibilities for integrative and comparative studies on this growing threat.
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Amoníaco , Anuros , Señales (Psicología) , Embrión no Mamífero , Óvulo , Animales , Amoníaco/toxicidad , Anuros/embriología , Anuros/fisiología , Óvulo/fisiología , Embrión no Mamífero/fisiología , Deshidratación , Reacción de Fuga/fisiología , Reacción de Fuga/efectos de los fármacosRESUMEN
Psychedelic compounds have potentially rapid, long-lasting anxiolytic, antidepressive and anti-inflammatory effects. We investigated whether the psychedelic compound (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI], a selective 5-HT2A receptor partial agonist, decreases stress-related behavior in male mice exposed to repeated social aggression. Additionally, we explored the likelihood that these behavioral changes are related to anti-inflammatory properties of [(R)-DOI]. Animals were subjected to the Stress Alternatives Model (SAM), an escapable social stress paradigm in which animals develop reactive coping strategies - remaining in the SAM arena (Stay) with a social aggressor, or dynamically initiated stress coping strategies that involve utilizing the escape holes (Escape) to avoid aggression. Mice expressing these behavioral phenotypes display behaviors like those in other social aggression models that separate animals into stress-vulnerable (as for Stay) or stress-resilient (as for Escape) groups, which have been shown to have distinct inflammatory responses to social stress. These results show that Stay animals have heightened cytokine gene expression, and both Stay and Escape mice exhibit plasma and neural concentrations of the inflammatory cytokine tumor necrosis factor-α (TNFα) compared to unstressed control mice. Additionally, these results suggest that a single administration of (R)-DOI to Stay animals in low doses, can increase stress coping strategies such as increasing attention to the escape route, promoting escape behavior, and reducing freezing during socially aggressive interaction in the SAM. Lower single doses of (R)-DOI, in addition to shifting behavior to suggest anxiolytic effects, also concomitantly reduce plasma and limbic brain levels of the inflammatory cytokine TNFα.
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Adaptación Psicológica , Agresión , Anfetaminas , Alucinógenos , Estrés Psicológico , Animales , Masculino , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Alucinógenos/administración & dosificación , Alucinógenos/farmacología , Adaptación Psicológica/efectos de los fármacos , Adaptación Psicológica/fisiología , Ratones , Agresión/efectos de los fármacos , Agresión/fisiología , Anfetaminas/farmacología , Anfetaminas/administración & dosificación , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Agonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Reacción de Fuga/efectos de los fármacos , Habilidades de AfrontamientoRESUMEN
This study aims to investigate the effects of tanshinone on improving the impaired cognition and motor function in MCAO model mice with ischemic penumbra. MWM test was carried out to evaluate the spatial learning and memory performance and the cognitive function of mice. The area of cerebral infarction was analyzed by immunohistochemistry. The TUNEL apoptosis detection kit was used to detect neuronal apoptosis. On the 25th day, the induction model group had lower body weight than the control group and the tanshinone treatment group; the induction model group had decreased walking deficiency and correct area escape times than the other two groups; while, tanshinone treatment group had higher movement distance, movement speed, periphery entry frequency, grooming rate, decreased center entry frequency, infarction area, apoptotic neuron number, latent escape time than induction model group; additionally, the control group had increased periphery and corner entry frequency, but decreased center entry frequency and latent escape time than the other two groups. Tanshinone can reduce neuronal damage in the ischemic penumbra after stroke, improve the integrity of white and gray matter, and restore connectivity in motor and cognitive functions, thereby supporting recovery from ischemic stroke.
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Abietanos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Apoptosis/efectos de los fármacos , Cognición/efectos de los fármacos , Infarto de la Arteria Cerebral Media/fisiopatología , Movimiento/efectos de los fármacos , Neuronas/efectos de los fármacos , Animales , Reacción de Fuga/efectos de los fármacos , Aseo Animal/efectos de los fármacos , Etiquetado Corte-Fin in Situ , Accidente Cerebrovascular Isquémico/fisiopatología , Ratones , Microglía/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Neuronas/patología , Fármacos Neuroprotectores/farmacologíaRESUMEN
Serotonin (5-HT) receptors have been implicated in responses to aversive stimuli in mammals and fish, but its precise role is still unknown. Moreover, since at least seven families of 5-HT receptors exist in vertebrates, the role of specific receptors is still debated. Aversive stimuli can be classified as indicators of proximal, distal, or potential threat, initiating responses that are appropriate for each of these threat levels. Responses to potential threat usually involve cautious exploration and increased alertness, while responses to distal and proximal threat involve a fight-flight-freeze reaction. We exposed adult zebrafish to a conspecific alarm substance (CAS) and observed behavior during (distal threat) and after (potential threat) exposure, and treated with the 5-HT2C receptor agonists MK-212 or WAY-161503 or with the antagonist RS-102221. The agonists blocked CAS-elicited defensive behavior (distal threat), but not post-exposure increases in defensive behavior (potential threat), suggesting inhibition of responses to distal threat. MK-212 blocked changes in freezing elicited by acute restraint stress, a model of proximal threat, while RS-102221 blocked changes in geotaxis elicited this stressor. We also found that RS-102221, a 5-HT2C receptor antagonist, produced small effect on behavior during and after exposure to CAS. Preprint: https://www.biorxiv.org/content/10.1101/2020.10.04.324202; Data and scripts: https://github.com/lanec-unifesspa/5-HT-CAS/tree/master/data/5HT2C.
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Conducta Animal/efectos de los fármacos , Reacción de Fuga/efectos de los fármacos , Miedo/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Pez CebraRESUMEN
The article presents a study of the effect of a modified fragment of neuropeptide Y (H-L-Ile-L-Asn-L-Leu-L-Nle-L-Ser- L-Arg-L-Asn-L-Arg-L-Tyr-NH2) named nonapeptide NP9 on the memory phases and extrapolation escape of animals. The study was performed in the passive avoidance test with intact animals, scopolamine-treated animals, and the extrapolation escape task. NP9 was investigated in the dose range of 0.04-0.4 mg/kg with a single intranasal administration. The comparison drug used peptide nootropic medicine Semax® (Met-Glu-His-Phe-Pro-Gly-Pro) at a dose of 0.1 mg/kg. Efficiency was assessed by the retention latency, the percentage of animals that have reached the learning criterion, the number of incomplete attempts to enter, the antiamnestic activity index calculated by Butlers formula, and the number of animals that successfully performed the extrapolation escape task. Peptide NP9 was superior to Semax® in most indicators. It demonstrated the ability to improve memorization due to its effect on I phase of memory and facilitated extinction of negative experiences when administered after a stress stimulus. NP9 also increased the cognitive ability of animals in the conditions an aversive environment in the extrapolation escape test. Thus, peptide NP9 is promising for a further study as a potential drug for the treatment of cognitive impairment and therapy of post-traumatic stress disorder.
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Reacción de Fuga/efectos de los fármacos , Memoria/efectos de los fármacos , Neuropéptido Y , Oligopéptidos , Fragmentos de Péptidos , Secuencia de Aminoácidos , Animales , Neuropéptido Y/administración & dosificación , Neuropéptido Y/farmacología , Oligopéptidos/administración & dosificación , Oligopéptidos/farmacología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/farmacologíaRESUMEN
Individual differences in the effects of a chronic neuropathic injury on social behaviours characterize both the human experience and pre-clinical animal models. The impacts of these changes to the well-being of the individual are often underappreciated. Earlier work from our laboratory using GeneChip® microarrays identified increased cholecystokinin (CCK) gene expression in the periaqueductal gray (PAG) of rats that showed persistent changes in social interactions during a Resident-Intruder encounter following sciatic nerve chronic constriction injury (CCI). In this study, we confirmed these gene regulation patterns using RT-PCR and identified the anatomical location of the CCK-mRNA as well as the translated CCK peptides in the midbrains of rats with a CCI. We found that rats with persistent CCI-induced changes in social behaviours had increased CCK-mRNA in neurons of the ventrolateral PAG and dorsal raphe nuclei, as well as increased CCK-8 peptide expression in terminal boutons located in the lateral and ventrolateral PAG. The functional significance of these changes was explored by microinjecting small volumes of CCK-8 into the PAG of uninjured rats and observing their Resident-Intruder social interactions. Disturbances to social interactions identical to those observed in CCI rats were evoked when injection sites were located in the rostral lateral and ventrolateral PAG. We suggest that CCI-induced changes in CCK expression in these PAG regions contributes to the disruptions to social behaviours experienced by a subset of individuals with neuropathic injury.
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Colecistoquinina/biosíntesis , Reacción de Fuga/fisiología , Sustancia Gris Periacueductal/metabolismo , Neuropatía Ciática/metabolismo , Interacción Social , Animales , Reacción de Fuga/efectos de los fármacos , Masculino , Microinyecciones/métodos , Sustancia Gris Periacueductal/efectos de los fármacos , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de los Nervios Periféricos/patología , Traumatismos de los Nervios Periféricos/psicología , Ratas , Ratas Sprague-Dawley , Neuropatía Ciática/patología , Neuropatía Ciática/psicología , Sincalida/administración & dosificaciónRESUMEN
The amyloid-beta (Aß) fibrillation process seems to execute a principal role in the neuropathology of Alzheimer's disease (AD). Accordingly, novel therapeutic plans have concentrated on the inhibition or degradation of Aß oligomers and fibrils. Biocompatible nanoparticles (NPs), e.g., gold and iron oxide NPs, take a unique capacity in redirecting Aß fibrillation kinetics; nevertheless, their impacts on AD-related memory impairment have not been adequately evaluated in vivo. Here, we examined the effect of commercial PEGylated superparamagnetic iron oxide nanoparticles (SPIONs) on the learning and memory of an AD-animal model. The outcomes demonstrated the dose-dependent effect of SPIONs on Aß fibrillation and learning and memory processes. In vitro and in vivo findings revealed that Low doses of SPIONs inhibited Aß aggregation and ameliorated learning and memory deficit in the AD model, respectively. Enhanced level of hippocampal proteins, including brain-derived neurotrophic factor, BDNF, phosphorylated-cAMP response element-binding protein, p-CREB, and stromal interaction molecules, e.g., STIM1 and STIM2, were also observed. However, at high doses, SPIONs did not improve the detrimental impacts of Aß fibrillation on spatial memory and hippocampal proteins expression. Overall, we revealed the potential capacity of SPIONs on retrieval of behavioral and molecular manifestations of AD in vivo, which needs further investigations to determine the mechanistic effect of SPIONs in the AD conundrum.
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Enfermedad de Alzheimer/tratamiento farmacológico , Aprendizaje/efectos de los fármacos , Nanopartículas Magnéticas de Óxido de Hierro/administración & dosificación , Trastornos de la Memoria/tratamiento farmacológico , Polietilenglicoles/administración & dosificación , Moléculas de Interacción Estromal , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Reacción de Fuga/efectos de los fármacos , Reacción de Fuga/fisiología , Aprendizaje/fisiología , Masculino , Trastornos de la Memoria/metabolismo , Fragmentos de Péptidos/toxicidad , Ratas , Ratas Wistar , Molécula de Interacción Estromal 1/metabolismo , Molécula de Interacción Estromal 2/metabolismo , Moléculas de Interacción Estromal/metabolismoRESUMEN
Escaping aversive stimuli is essential for complex organisms, but prolonged exposure to stress leads to maladaptive learning. Stress alters neuronal activity and neuromodulatory signaling in distributed networks, modifying behavior. Here, we describe changes in dopaminergic neuron activity and signaling following aversive learning in a learned helplessness paradigm in mice. A single dose of ketamine suffices to restore escape behavior after aversive learning. Dopaminergic neuron activity in the ventral tegmental area (VTA) systematically varies across learning, correlating with future sensitivity to ketamine treatment. Ketamine's effects are blocked by chemogenetic inhibition of dopamine signaling. Rather than directly altering the activity of dopaminergic neurons, ketamine appears to rescue dopamine dynamics through actions in the medial prefrontal cortex (mPFC). Chemogenetic activation of Drd1 receptor positive mPFC neurons mimics ketamine's effects on behavior. Together, our data link neuromodulatory dynamics in mPFC-VTA circuits, aversive learning, and the effects of ketamine.
Over 264 million people around the world suffer from depression, according to the World Health Organization (WHO). Depression can be debilitating, and while anti-depressant drugs are available, they do not always work. A small molecule drug mainly used for anesthesia called ketamine has recently been shown to ameliorate depressive symptoms within hours, much faster than most anti-depressants. However, the molecular mechanisms behind this effect are still largely unknown. Most anti-depressant drugs work by restoring the normal balance of dopamine and other chemical messengers in the brain. Dopamine is released by a specialized group of cells called dopaminergic neurons, and helps us make decisions by influencing a wide range of other cells in the brain. In a healthy brain, dopamine directs us to rewarding choices, while avoiding actions with negative outcomes. During depression, these dopamine signals are perturbed, resulting in reduced motivation and pleasure. But it remained unclear whether ketamine's anti-depressant activity also relied on dopamine. To investigate this, Wu et al. used a behavioral study called "learned helplessness" which simulates depression by putting mice in unavoidable stressful situations. Over time the mice learn that their actions do not change the outcome and eventually stop trying to escape from unpleasant situations, even if they are avoidable. The experiment showed that dopaminergic neurons in an area of the brain that is an important part of the "reward and aversion" system became less sensitive to unpleasant stimuli following learned helplessness. When the mice received ketamine, these neurons recovered after a few hours. Individual mice also responded differently to ketamine. The most 'resilient', stress-resistant mice, which had distinct patterns of dopamine signaling, also responded most strongly to the drug. Genetic and chemical manipulation of dopaminergic neurons confirmed that ketamine needed intact dopamine signals to work, and revealed that it acted indirectly on dopamine dynamics via another brain region called the medial prefrontal cortex. These results shed new light on how a promising new anti-depressant works. In the future, they may also explain why drugs like ketamine work better for some people than others, ultimately helping clinicians select the most effective treatment for individual patients.
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Reacción de Prevención/efectos de los fármacos , Neuronas Dopaminérgicas/fisiología , Reacción de Fuga/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Ketamina/farmacología , Animales , Reacción de Prevención/fisiología , Neuronas Dopaminérgicas/efectos de los fármacos , Reacción de Fuga/fisiología , Femenino , Desamparo Adquirido , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Environmental contexts can inform animals of potential threats, though it is currently unknown how context biases the selection of defensive behavior. Here we investigated context-dependent flight responses with a Pavlovian serial-compound stimulus (SCS) paradigm that evokes freeze-to-flight transitions. Similar to previous work in mice, we show that male and female rats display context-dependent flight-like behavior in the SCS paradigm. Flight behavior was dependent on contextual fear insofar as it was only evoked in a shock-associated context and was reduced in the conditioning context after context extinction. Flight behavior was only expressed to white noise regardless of temporal order within the compound. Nonetheless, rats that received unpaired SCS trials did not show flight-like behavior to the SCS, indicating it is associative. Finally, we show that pharmacological inactivation of two brain regions critical to the expression of contextual fear, the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST), attenuates both contextual fear and flight responses. All of these effects were similar in male and female rats. This work demonstrates that contextual fear can summate with cued and innate fear to drive a high fear state and transition from post-encounter to circa-strike defensive modes.
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Conducta Animal/fisiología , Encéfalo/fisiología , Condicionamiento Clásico , Reacción de Fuga , Estimulación Acústica , Amígdala del Cerebelo/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/anatomía & histología , Encéfalo/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Señales (Psicología) , Reacción de Fuga/efectos de los fármacos , Reacción de Fuga/fisiología , Miedo , Femenino , Masculino , Muscimol/farmacología , Ratas , Ratas Long-Evans , Núcleos Septales/efectos de los fármacosRESUMEN
Lanthanum is a rare-earth element that has been used in various fields including medicine, agriculture and industry. Previously, in utero lanthanum exposure to dams was shown to alter neurobehavior and neurotransmitter levels in rat offspring; however, the effects of postweaning exposure to lanthanum on neurological behavior is still limited. The purpose of this study was to investigate the effects of postweaning exposure to lanthanum on neurological behavior during early adulthood in rats. Rats were orally exposed to 0, 2, 20, 60 mg/kg BW of lanthanum nitrate from postnatal day (PND) 24 to PND60. Our results indicated that lanthanum treatment significantly decreased body weight and food intake. Morris water maze test results showed that lanthanum significantly decreased escape latency and travel distance. Lanthanum treatment also significantly decreased grip strength, hindlimb strength, and running time & distance in motor activity test. Further results showed that lanthanum treatment significantly decreased plasma neurotransmitter levels of acetylcholine and norepinephrine as well as the number of neurons in the CA1 area of the hippocampus. These results suggest that postweaning exposure to lanthanum have adverse effects on neurobehaviors and the central nervous system, with no-observed-adverse-effect level at 2 mg/kg BW and benchmark dose lower confidence limit at 1.7 mg/kg BW.
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Conducta Animal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Lantano/toxicidad , Neuronas/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Acetilcolina/metabolismo , Animales , Ingestión de Alimentos/efectos de los fármacos , Reacción de Fuga/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Femenino , Hipocampo/metabolismo , Hipocampo/patología , Hipocampo/fisiopatología , Masculino , Prueba del Laberinto Acuático de Morris/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/fisiopatología , Norepinefrina/metabolismo , Destete , Aumento de Peso/efectos de los fármacosRESUMEN
This study aimed to observe the recent spatial recall ability and the changes of expression of hippocampal apolipoprotein E (ApoE) and amyloid ß protein (Aß) in adult rats after inhaling sevoflurane anesthetic drugs, and to analyze the mechanism of action. For this purpose, a total of 54 adult SD clean-grade rats were selected in this study and were randomly divided into the sevoflurane anesthesia group, carrier gas group and control group, 18 rats in each group. The rats in the carrier gas group were inhaled with 1 L/min of oxygen O2+1 L/min air mixed carrier gas for 2 h, and the rats in the sevoflurane anesthesia group were given 3.2%sevoflurane for 2 hours based on the carrier gas group, the control rats were naturally reared. Before the model was copied, the Morris water maze experiment was performed before the material was taken. Some rat brain tissues were extracted on the first day (T1), the third day (T3), and the seventh day (T7) after model replication. The immunohistochemistry was used to measure the mean optical density (MOD) value of APOE and Aß in hippocampal CA1, CA3 and DG regions. The indicators above at different time points of each group were compared and analyzed. Results showed that the number of crossing the original platform at each time point, the residence time of the original platform quadrant, the number of entering the original platform quadrant, and the percentage of the original platform quadrant residence time in the sevoflurane anesthesia group and the carrier gas group were compared, and there were no significant differences between two groups (P>0.05). Compared with the carrier gas group, the MOD values of APOE in the hippocampus at T1 and T3 time points in the sevoflurane anesthesia group were decreased (P<0.05), the MOD values of Aß in the hippocampus at the T7 time point were increased (P<0.05). It concluded that Inhalation of 3.2%sevoflurane has no obvious damage to the recent spatial recall ability of adult rats. Within 7 days after inhalation of 3.2% sevoflurane, it can inhibit hippocampus Aß deposition through down-regulating APOE expression level. The critical time point for hippocampal Aß increasing was 7 days after anesthesia.
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Péptidos beta-Amiloides/metabolismo , Apolipoproteínas E/metabolismo , Hipocampo/metabolismo , Recuerdo Mental/efectos de los fármacos , Sevoflurano/farmacología , Anestesia , Animales , Reacción de Fuga/efectos de los fármacos , Masculino , Modelos Animales , Ratas Sprague-DawleyRESUMEN
Diazinon is one of the insecticides that represent a high risk for Costa Rican estuarine environments due to its widespread use in pineapple plantations. In estuaries, organisms are frequently submitted to stress caused by natural factors (e.g., continuous changes in salinity levels) and, additionally, to stress due to contamination. Therefore, the driving question of this study was: will organisms be more susceptible to suffer the deleterious effects caused by diazinon because of the stress resulting from the salinity changes? The estuarine shrimp Penaeus vannamei was used as the model organism and two responses were measured: osmoregulation (the physiological effect after a forced and continuous 24 h-exposure) and avoidance [the behavioural effect after a short (3 h) non-forced, multi-compartmented exposure]. Juveniles were exposed to diazinon (0.1, 1, 10 and 100 µg/L) at three different salinities (10, 20 and 30). Disruption in the capacity to regulate the haemolymph osmotic pressure was observed at a salinity of 30 in individuals exposed to diazinon and methanol (used as vehicle). At that salinity, the ability of shrimps to detect and avoid the highest diazinon concentrations was impaired. P. vannamei juveniles inhabit environments with a high variation in salinity, but with an optimum osmotic point close to a salinity of 20; therefore, the higher the salinity, the greater the vulnerability of shrimps to the effects of diazinon. From an ecological point of view, this combined effect of salinity and contamination might also limit the spatial distribution of the organisms.
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Diazinón/toxicidad , Reacción de Fuga/efectos de los fármacos , Insecticidas/toxicidad , Osmorregulación/efectos de los fármacos , Penaeidae/fisiología , Animales , Estuarios , Hemolinfa/efectos de los fármacos , Hemolinfa/metabolismo , Penaeidae/efectos de los fármacos , Penaeidae/metabolismo , Salinidad , Contaminantes Químicos del Agua/toxicidadRESUMEN
Diabetic retinopathy (DR) is progressive damage to the retina and it's caused by damage to the blood-retinal barrier. Quercetin has pleiotropic action like anti-oxidant, regulation cell cycle &vascular integrity, and preventive effect of neuroinflammation. The present study is designed to investigate the nano-formulation of quercetin (NQ) in a zebrafish model of DR. The DR was developed by a single intraperitoneal injection of streptozotocin (STZ; 350 mg/kg). The acceleration of retinopathy was made on 7 days of diabetic zebrafish by intravitreal injection of STZ (20 µL of 7 % w/v of STZ stock solution). The treatment of NQ (5 and 10 mg/kg; i.p.) was administered for 21 consecutive days. The reference control i.e., dexamethasone (DEX, 10 mg/kg; i.p.) was also administered for 21 consecutive days. The sign of DR was assessed by eyeball/body weight ratio, eyeball weight, optomotor response (OMR), startle response (SR), phototactic response (PTR), and escape response (ER). Furthermore, the biochemical changes like plasma glucose and homocysteine (HCY) levels; and eye retinal tissue lipid peroxidation, reduced glutathione (GSH), and arginase reductase (AR) activity levels were assessed. The NQ found to attenuate the effect of STZ induced DR along with the regulation of biochemical abnormalities. And, it also comparable with reference drug treatment i.e., DEX treated group. Hence, NQ can be used for the treatment of diabetic associated retinopathy and neurosensory disorder visits anti-hyperglycemic, regulation of homocysteine pathway, reduction of lipid peroxidation, and free radical scavenging actions.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Retinopatía Diabética/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Quercetina/uso terapéutico , Animales , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Reacción de Fuga/efectos de los fármacos , Ojo/efectos de los fármacos , Masculino , Nanomedicina , Tamaño de los Órganos/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , Pez CebraRESUMEN
HIV-1 often acquires drug-resistant mutations in spite of the benefits of antiretroviral therapy (ART). HIV-1 integrase (IN) is essential for the concerted integration of HIV-1 DNA into the host genome. IN further contributes to HIV-1 RNA binding, which is required for HIV-1 maturation. Non-catalytic-site integrase inhibitors (NCINIs) have been developed as allosteric IN inhibitors, which perform anti-HIV-1 activity by a multimodal mode of action such as inhibition of the IN-lens epithelium-derived growth factor (LEDGF)/p75 interaction in the early stage and disruption of functional IN multimerization in the late stage of HIV-1 replication. Here, we show that IN undergoes an adaptable conformational change to escape from NCINIs. We observed that NCINI-resistant HIV-1 variants have accumulated 4 amino acid mutations by passage 26 (P26) in the IN-encoding region. We employed high-performance liquid chromatography (HPLC), thermal stability assays, and X-ray crystallographic analysis to show that some amino acid mutations affect the stability and/or dimerization interface of the IN catalytic core domains (CCDs), potentially resulting in the severely decreased multimerization of full-length IN proteins (IN undermultimerization). This undermultimerized IN via NCINI-related mutations was stabilized by HIV-1 RNA and restored to the same level as that of wild-type HIV-1 in viral particles. Recombinant HIV-1 clones with IN undermultimerization propagated similarly to wild-type HIV-1. Our study revealed that HIV-1 can eventually counteract NCINI-induced IN overmultimerization by IN undermultimerization as one of the escape mechanisms. Our findings provide information on the understanding of IN multimerization with or without HIV-1 RNA and may influence the development of anti-HIV-1 strategies.IMPORTANCE Understanding the mechanism of HIV-1 resistance to anti-HIV-1 drugs could lead to the development of novel drugs with increased efficiency, resulting in more effective ART. ART composed of more potent and long-acting anti-HIV-1 drugs can greatly improve drug adherence and also provide HIV-1 prevention such as preexposure prophylaxis. NCINIs with a multimodal mode of action exert potent anti-HIV-1 effects through IN overmultimerization during HIV-1 maturation. However, HIV-1 can acquire some mutations that cause IN undermultimerization to alleviate NCINI-induced IN overmultimerization. This undermultimerized IN was efficiently stabilized by HIV-1 RNA and restored to the same level as that of wild-type HIV-1. Our findings revealed that HIV-1 eventually acquires such a conformational escape reaction to overcome the unique NCINI actions. The investigation into drug-resistant mutations associated with HIV-1 protein multimerization may facilitate the elucidation of its molecular mechanism and functional multimerization, allowing us to develop more potent anti-HIV-1 drugs and unique treatment strategies.
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Regulación Alostérica/efectos de los fármacos , Fármacos Anti-VIH/farmacología , Reacción de Fuga/efectos de los fármacos , Inhibidores de Integrasa VIH/farmacología , VIH-1/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales , Regulación Alostérica/genética , Células HEK293 , Infecciones por VIH/tratamiento farmacológico , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/química , VIH-1/genética , VIH-1/fisiología , Humanos , Péptidos y Proteínas de Señalización Intercelular , Mutación , Multimerización de Proteína/efectos de los fármacos , Proteínas Recombinantes , Factores de Transcripción , Virión/química , Virión/genética , Replicación Viral/efectos de los fármacosRESUMEN
The purpose of this study was to investigate whether the panicolyticlike effect of different doses of anandamide microinjected into the anterior hypothalamus (AH) follows the same pattern of a bellshaped doseresponse curve observed with the same dose treatment in dorsomedial and ventromedial hypothalamus. We investigated this assumption by administering the cannabinoid and vanilloid receptor agonist anandamide into the anterior hypothalamus of mice and exposing them to the real threatening situation by using our experimental model based on confrontations between rodents and wild snakes. Our findings showed a gradual decay of response, with a significant attenuation of the panic attacklike responses with anandamide at the highest dose but no effect was found after anandamide at the lowest or intermediate doses. An immunohistochemical procedure showed a lower degree of TRPV1 receptor and moderate to higher degree of Cb1 receptors in anterior hypothalamus. In conclusion, the pattern of doseresponse curve of anandamide microinjected in the AH does not seem to be the same classical pattern compared with other hypothalamic nuclei.
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Ácidos Araquidónicos/farmacología , Bicuculina/farmacología , Endocannabinoides/farmacología , Reacción de Fuga/efectos de los fármacos , Hipotálamo Anterior/efectos de los fármacos , Alcamidas Poliinsaturadas/farmacología , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Receptor Cannabinoide CB1/efectos de los fármacos , Canales Catiónicos TRPV/efectos de los fármacosRESUMEN
BACKGROUND: Trimethyltin (TMT) is a potent neurotoxin affecting various regions of the central nervous system, including the neocortex, the cerebellum, and the hippocampus. Phosphatidylserine (PS) is a membrane phospholipid, which is vital to brain cells. We analyzed the neuroprotective effects of soybean-derived phosphatidylserine (Bean-PS) on cognitive function, changes in the central cholinergic systems, and neural activity in TMT-induced memory deficits in a rat model. METHODS: The rats were randomly divided into an untreated normal group, a TMT group (injected with TMT + vehicle), and a group injected with TMT + Bean-PS. The rats were treated with 10% hexane (TMT group) or TMT + Bean-PS (50 mg·kg-1, oral administration (p.o.)) daily for 21 days, following a single injection of TMT (8.0 mg/kg, intraperitoneally (i.p.)). The cognitive function of Bean-PS was assessed using the Morris water maze (MWM) test and a passive avoidance task (PAT). The expression of acetylcholine transferase (ChAT) and acetylcholinesterase (AchE) in the hippocampus was assessed via immunohistochemistry. A positron emission tomography (PET) scan was used to measure the glucose uptake in the rat brain. RESULTS: Treatment with Bean-PS enhanced memory function in the Morris water maze (MWM) test. Consistent with the behavioral results, treatment with Bean-PS diminished the damage to cholinergic cells in the hippocampus, in contrast to those of the TMT group. The TMT+Bean-PS group showed elevated glucose uptake in the frontal lobe of the rat brain. CONCLUSION: These results demonstrate that Bean-PS protects against TMT-induced learning and memory impairment. As such, Bean-PS represents a potential treatment for neurodegenerative disorders, such as Alzheimer's disease.
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Trastornos del Conocimiento/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Fosfatidilserinas/uso terapéutico , Acetilcolinesterasa/biosíntesis , Acetilcolinesterasa/genética , Animales , Reacción de Prevención/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Colina O-Acetiltransferasa/biosíntesis , Colina O-Acetiltransferasa/genética , Trastornos del Conocimiento/inducido químicamente , Reacción de Fuga/efectos de los fármacos , Glucosa/farmacocinética , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Prueba del Laberinto Acuático de Morris/efectos de los fármacos , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Fármacos Neuroprotectores/farmacología , Fosfatidilserinas/farmacología , Tomografía de Emisión de Positrones , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Glycine max/química , Compuestos de Trimetilestaño/toxicidadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: According to the theory of traditional Chinese medicine (TCM), Alzheimer's disease (AD) is identified as "forgetfulness" or "dementia", and is mainly caused by "kidney essence deficiency" which ultimately induces "encephala reduction". Therefore, herbal formulas possessing the efficacy of nourishing kidney essence or replenishing brain marrow are commonly served as effective strategies for AD treatment. Shenzao jiannao oral liquid (SZJN), a traditional Chinese preparation approved by the China Food and Drug Administration (CFDA), is used for the treatment of insomnia and mind fatigue at present for its efficacy of nourishing kidneys. In present study, we found that SZJN could improve cognitive function of AD-like mice. AIMS OF STUDY: This study aims to investigate the effects of SJZN on ameliorating cognitive deficits of AD-like mouse model, and to illuminate the underlying mechanisms from the perspective of neuroprotection and neurogenesis. MATERIALS AND METHODS: Kunming mice (28 ± 2 g) were randomly allocated into seven groups: control, sham, model, donepezil and SZJN groups (low, middle and high). The AD mouse model was established by Aß42 combined with scopolamine. SZJN were intragastrically administrated at doses of 0.3, 1.5 and 7.5 g/kg for 28 days. Morris water maze (MWM) test was applied to determine the cognitive function. Hematoxylin eosin (HE) and Nissl staining were carried out to evaluate pathological damages in the cortex and hippocampal tissues. To explore the protective effects of SZJN on multiple pathogenic factors of AD, protein levels of Aß42, glial fibrillary acidic protein (GFAP), Bax, Bcl-2, Caspase-3, synaptophysin (SYP), brain-derived neurotrophic factor (BDNF), and neurogenesis related proteins were assessed using Immunofluorescence (IF) and western blot analysis. In vitro, the AD cell model was established by transduction of APP695swe genes into Neural stem cells (NSCs) isolated from the hippocampal tissues of neonatal C57BL/6 mice. Cell viability assay and neurosphere formation assay were carried out to verify the efficacy of SZJN on proliferation of NSCs. RESULTS: Our results demonstrated that SZJN (1.5 g/kg and 7.5 g/kg) treatment significantly ameliorated cognitive deficits of AD-like mice. SZJN (7.5 g/kg) treatment significantly retarded the pathological damages including neuronal degeneration, neuronal apoptosis, Aß peptides aggregation and reaction of astrocytes in AD-like mice. In addition, SZJN (7.5 g/kg) increased the expression of BDNF and SYP, and restored the abnormal level of MDA and SOD in the brain of AD-like mice. Furthermore, SZJN treatment for 28 days remarkably increased the proliferation of NSCs evidenced by more Nestin+ and BrdU+ cells in the hippocampal DG regions, and increased the amount of mature neurons marked by NeuN both in the cortex and hippocampal DG regions. In vitro, SZJN treatement (16, 32, 64 mg/ml) promoted the proliferation of NSCs evidenced by the increased amount and enlarged size of the neurospheres (p < 0.05). CONCLUSIONS: Our findings indicated that SZJN could ameliorate cognitive deficits by protecting neurons from death and triggering endogenous neurogenesis. Therefore, SZJN may be considered as a promising agent to restore neuronal loss and deter the deterioration in AD patients.
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Enfermedad de Alzheimer/prevención & control , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Nootrópicos/farmacología , Administración Oral , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides , Animales , Encéfalo/metabolismo , Encéfalo/patología , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/administración & dosificación , Reacción de Fuga/efectos de los fármacos , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/administración & dosificación , Nootrópicos/administración & dosificación , Fragmentos de Péptidos , Escopolamina , Transducción de SeñalRESUMEN
The application of nano-level passivating agents in the remediation of soil heavy metal pollution has received widespread attention, but its harm to soil animals should also be addressed. This study explored the effect of three nanomaterials-nanohydroxyapatite apatite (n-HAP), nano zeolite (n-zeolite), and nanometer iron oxide (n-Fe3O4), on catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD) activity and malondialdehyde (MDA) content through filter paper contact test. The effects of nanomaterials spiked at 1.5%wt of soils on earthworm avoidance behavior were also be studied, and the crystallinity and surface charge of three nanomaterials were characterized. The results showed that the activities of CAT, SOD and POD and the content of MDA have been changed at different level. And earthworms have obvious avoidance behavior to the three kinds of nanomaterials. Therefore, nanomaterials do have adverse effects on earthworms, and their biological toxicity should be considered when selecting passivating agents for soil heavy metal pollution remediation.
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Reacción de Prevención/efectos de los fármacos , Restauración y Remediación Ambiental/métodos , Reacción de Fuga/efectos de los fármacos , Nanoestructuras/toxicidad , Oligoquetos/efectos de los fármacos , Contaminantes del Suelo/toxicidad , Suelo/química , Animales , Catalasa/metabolismo , Malondialdehído/metabolismo , Nanoestructuras/química , Oligoquetos/metabolismo , Peroxidasa/metabolismo , Contaminantes del Suelo/química , Superóxido Dismutasa/metabolismoRESUMEN
INTRODUCTION AND OBJECTIVES: Oxytocin (OT) has been widely linked to positive social interactions, and there is great interest in OT as a therapy for a variety of neuropsychiatric conditions. Recent evidence also suggests that OT can play an important role in the mediation of anxiety-associated defensive responses, including a role for serotonin (5-HT) neurotransmission in this action. However, it is presently unknown whether OT additionally regulates the expression of panic-related behaviors, such as escape, by acting in the dorsal periaqueductal gray (dPAG), a key panic-regulating area. This study aimed to investigate the consequence of OT injection in the dPAG on escape expression and whether facilitation of 5-HT neurotransmission in this midbrain area is implicated in this action. METHODS: Male Wistar rats were injected with OT in the dPAG and tested for escape expression in the elevated T-maze (ETM) and dPAG electrical stimulation tests. Using the latter test, OT's effect was also investigated after previous intra-dPAG injection of the OT receptor antagonist atosiban, the preferential antagonists of 5-HT1A and 5-HT2A receptors, WAY-100635 and ketanserin, respectively, or systemic pretreatment with the 5-HT synthesis inhibitor p-CPA. RESULTS: OT impaired escape expression in the two tests used, suggesting a panicolytic-like effect. In the ETM, the peptide also facilitated inhibitory avoidance acquisition, indicating an anxiogenic effect. Previous administration of atosiban, WAY-100635, ketanserin, or p-CPA counteracted OT's anti-escape effect. CONCLUSIONS: OT and 5-HT in the dPAG interact in the regulation of panic- and anxiety-related defensive responses. These findings open new perspectives for the development of novel therapeutic strategies for the treatment of anxiety disorders.
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Ansiolíticos/farmacología , Oxitocina/farmacología , Pánico/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Serotonina/fisiología , Animales , Conducta Animal/efectos de los fármacos , Estimulación Eléctrica , Electrodos Implantados , Reacción de Fuga/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptores de Oxitocina/antagonistas & inhibidores , Antagonistas de la Serotonina/farmacología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Vasotocina/análogos & derivados , Vasotocina/farmacologíaRESUMEN
BACKGROUND: Chemokine C-C motif ligand 2 (CCL2) is one of the most widely recognised proinflammatory chemokines in cognitive disorders. Currently, CCL2-targeting drugs are extremely limited. Thus, this study aimed to explore the neuroprotection afforded by naringin in CCL2-induced cognitive impairment in rats. METHODS: Before the CCL2 intra-hippocampal injection, rats were treated with naringin for 3 consecutive days via intraperitoneal injection. Two days post-surgery, the Morris water maze (MWM) and novel object recognition (NORT) tests were performed to detect spatial learning and memory and object cognition, respectively. Nissl staining and dUTP nick-end labelling (TUNEL) staining were performed to assess histopathological changes in the hippocampus. Commercial kits were used to measure the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and the content of malondialdehyde (MDA). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to examine the relative mRNA expression of interleukin 1ß, (IL-1ß), interleukin 6 (IL-6), glutamate/aspartate transporter (GLAST), glutamate transporter-1 (GLT-1), phosphate-activated glutaminase (PAG), cysteine aspartic acid-specific protease 8 (caspase-8), cysteine aspartic acid-specific protease 3 (caspase-3), cell lymphoma/leukaemia-2 (Bcl-2), and Bcl-2 associated X protein (Bax). RESULTS: In the MWM, the average escape latency and average swimming distance were significantly reduced and the crossing times were increased in the naringin-treated groups, compared with the CCL2 group. The NORT results revealed that, compared with the CCL2 rats, the discrimination index in the naringin-treated rats increased significantly. Nissl and TUNEL staining revealed that naringin protected the structure and survival of the neurons in the CA1 zone of the hippocampus. In the naringin-treated groups, the SOD and GSH-Px activities were increased, whereas the MDA levels were decreased. Furthermore, in the naringin-treated groups, the relative mRNA expression of IL-1ß and IL-6 was significantly decreased; GLAST and GLT-1 mRNA expression levels were increased, whereas PAG was decreased. In the naringin-treated groups, the relative mRNA expression levels of caspase-8, caspase-3, and Bax were decreased, whereas that of Bcl-2 was increased. CONCLUSION: Collectively, these data indicated that naringin alleviated the CCL2-induced cognitive impairment. The underlying mechanisms could be associated with the inhibition of neuroinflammation, oxidative stress, apoptosis, and the regulation of glutamate metabolism.