RESUMEN

Population aging is a global reality driven by increased life expectancy. This demographic phenomenon is intrinsically linked to the epidemic of cognitive disorders such as dementia and Alzheimer's disease, posing challenges for elderly and their families. In this context, the search for new therapeutic strategies to prevent or minimize cognitive impairments becomes urgent, as these deficits are primarily associated with oxidative damage and increased neuroinflammation. Ferulic acid (FA), a natural and potent antioxidant compound, is proposed to be nanoencapsulated to target the central nervous system effectively with lower doses and an extended duration of action. Here, we evaluated the effects of the nanoencapsulated FA on d-galactose (d-Gal)- induced memory impairments. Male Wistar adult rats were treated with ferulic acid-loaded nanocapsules (FA-Nc) or non-encapsulated ferulic acid (D-FA) for 8 weeks concurrently with d-Gal (150 mg/kg s.c.) injection. As expected, our findings showed that d-Gal injection impaired memory processes and increased anxiety behavior, whereas FA-Nc treatment ameliorated these behavioral impairments associated with the aging process induced by d-Gal. At the molecular level, nanoencapsulated ferulic acid (FA-Nc) ameliorated the decrease in ACh and glutamate induced by d-galactose (d-Gal), and also increased GABA levels in the dorsal hippocampus, indicating its therapeutic superiority. Additional studies are needed to elucidate the mechanisms underlying our current promising outcomes. Nanoscience applied to pharmacology can reduce drug dosage, thereby minimizing adverse effects while enhancing therapeutic response, particularly in neurodegenerative diseases associated with aging. Therefore, the strategy of brain-targeted drug delivery through nanoencapsulation can be effective in mitigating aging-related factors that may lead to cognitive deficits.

Asunto(s)

Envejecimiento , Ansiedad , Ácidos Cumáricos , Galactosa , Ácido Glutámico , Trastornos de la Memoria , Ratas Wistar , Ácido gamma-Aminobutírico , Animales , Ácidos Cumáricos/farmacología , Ácidos Cumáricos/uso terapéutico , Masculino , Envejecimiento/efectos de los fármacos , Envejecimiento/metabolismo , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Ácido Glutámico/metabolismo , Ratas , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Nanoestructuras , Nanocápsulas

RESUMEN

Morphine is among the most powerful analgesics and pain-relieving agents. However, its addictive properties limit their medical use because patients may be susceptible to abuse and reinstatement. Morphine addiction occurs because of dopamine release in the mesolimbic brain area, implying in an increase in oxidative stress. Ferulic acid (FA), a phenolic phytochemical found in a variety of foods, has been reported to exert antioxidant and neuroprotective effects; however, its low bioavailability makes its nano-encapsulated form a promising alternative. This study aimed to evaluate the protective effects of a novel nanosystem with FA on morphine reinstatement and the consequent molecular neuroadaptations and oxidative status in the mesolimbic region. Rats previously exposed to morphine in conditioned place preference (CPP) paradigm were treated with ferulic acid-loaded nanocapsules (FA-Nc) or nonencapsulated FA during morphine-preference extinction. Following the treatments, animals were re-exposed to morphine to induce the reinstatement. While morphine-preference extinction was comparable among all experimental groups, FA-Nc treatment prevented morphine reinstatement. In the dorsal striatum, while morphine exposure increased lipid peroxidation (LP) and reactive species (RS), FA-Nc decreased LP and FA decreased RS levels. Morphine exposure increased the dopaminergic markers (D1R, D3R, DAT) and ΔFosB immunoreactivity in the ventral striatum; however, FA-Nc treatment decreased D1R, D3R, and ΔFosB and increased D2R, DAT, and NRF2. In conclusion, FA-Nc treatment prevented the morphine reinstatement, promoted antioxidant activity, and modified the dopaminergic neurotransmission, NRF2, and ΔFosB, what may indicate a neuroprotective and antioxidant role of this nanoformulation.

Asunto(s)

Dopamina , Morfina , Ratas , Animales , Morfina/farmacología , Factor 2 Relacionado con NF-E2 , Antioxidantes/farmacología , Encéfalo

RESUMEN

The serotonin transporter (SERT) gene, especially the short allele of the human serotonin transporter linked polymorphic region (5-HTTLPR), has been associated with the development of stress-related neuropsychiatric disorders. In line, exposure to early life stress in SERT knockout animals contributes to anxiety- and depression-like behavior. However, there is a lack of investigation of how early-life exposure to beneficial stimuli, such as tactile stimulation (TS), affects later life behavior in these animals. In this study, we investigated the effect of TS on social, anxiety, and anhedonic behavior in heterozygous SERT knockouts rats and wild-type controls and its impact on gene expression in the basolateral amygdala. Heterozygous SERT+/- rats were submitted to TS during postnatal days 8-14, for 10 min per day. In adulthood, rats were assessed for social and affective behavior. Besides, brain-derived neurotrophic factor (Bdnf) gene expression and its isoforms, components of glutamatergic and GABAergic systems as well as glucocorticoid-responsive genes were measured in the basolateral amygdala. We found that exposure to neonatal TS improved social and affective behavior in SERT+/- animals compared to naïve SERT+/- animals and was normalized to the level of naïve SERT+/+ animals. At the molecular level, we observed that TS per se affected Bdnf, the glucocorticoid-responsive genes Nr4a1, Gadd45ß, the co-chaperone Fkbp5 as well as glutamatergic and GABAergic gene expression markers including the enzyme Gad67, the vesicular GABA transporter, and the vesicular glutamate transporter genes. Our results suggest that exposure of SERT+/- rats to neonatal TS can normalize their phenotype in adulthood and that TS per se alters the expression of plasticity and stress-related genes in the basolateral amygdala. These findings demonstrate the potential effect of a supportive stimulus in SERT rodents, which are more susceptible to develop psychiatric disorders.

RESUMEN

Depression is considered a common mental disorder that affects more than 300 million people worldwide. Despite this high incidence, its etiology is not completely elucidated instigating further studies. For this purpose, different animal models are used to study routes and molecular changes involved in depression, among them the chronic administration of corticosterone. However, the knowledge about neurochemical changes after this protocol is still controversial. In this work, we evaluated serum corticosterone levels, adrenal/body weight ratio, as well as glucocorticoid receptor and brain-derived neurotrophic factor protein expression and its receptor, tropomyosin-receptor kinase B. These analyzes were performed on prefrontal cortex, hippocampus, and striatum samples taken of mice after 21 days of administration of corticosterone. Exposure to corticosterone reduced the serum corticosterone levels and the adrenal/body weight ratio. Moreover, the glucocorticoid receptor and tyrosine-receptor kinase B expression were increased in the hippocampus while the brain-derived neurotrophic factor expression was reduced in the prefrontal cortex. We also found a positive correlation between the expression of glucocorticoid receptor and tyrosine-receptor kinase B and our results suggest a possible relationship between the glucocorticoid/glucocorticoid receptor and brain-derived neurotrophic factor/tropomyosin-receptor kinase B routes after chronic corticosterone administration. To our knowledge, this is the first study that evaluate these parameters concomitantly in important mood-related structures. In addition, these results may be useful to other research groups seeking to explore new pathways and substances with therapeutic potential to treat this silent epidemic.

Asunto(s)

Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Corticosterona/efectos adversos , Depresión/inducido químicamente , Glándulas Suprarrenales/fisiología , Animales , Peso Corporal/fisiología , Cuerpo Estriado/metabolismo , Corticosterona/sangre , Depresión/sangre , Hipocampo/metabolismo , Masculino , Ratones , Corteza Prefrontal/metabolismo , Receptor trkB/biosíntesis , Receptores de Glucocorticoides/biosíntesis

RESUMEN

Haloperidol (Hal) is an antipsychotic related to movement disorders. Magnesium (Mg) showed benefits on orofacial dyskinesia (OD), suggesting its involvement with N-methyl-D-aspartate receptors (NMDAR) since it acts blocking calcium channels. Comparisons between nifedipine (NIF; a calcium channel blocker) and Mg were performed to establish the Mg mechanism. Male rats concomitantly received Hal and Mg or NIF for 28 days, and OD behaviors were weekly assessed. Both Mg and NIF decreased Hal-induced OD. Hal increased Ca2+-ATPase activity in the striatum, and Mg reversed it. In the cortex, both Mg and NIF decreased such activity. Dopaminergic and glutamatergic immunoreactivity were modified by Hal and treatments: i) in the cortex: Hal reduced D1R and D2R, increasing NMDAR immunoreactivity. Mg and NIF reversed this Hal influence on D1R and NMDAR, while only Mg reversed Hal effects on D2R levels; ii) in the striatum: Hal decreased D2R and increased NMDAR while Mg and NIF decreased D1R and reversed the Hal-induced decreasing D2R levels. Only Mg reversed the Hal-induced increasing NMDAR levels; iii) in the substantia nigra (SN): while Hal increased D1R, D2R, and NMDAR, both Mg and NIF reversed this influence on D2R, but only Mg reversed the Hal-influence on D1R levels. Only NIF reversed the Hal effects on NMDAR immunoreactivity. These findings allow us to propose that Mg may be useful to minimize Hal-induced movement disturbances. Mg molecular mechanism seems to be involved with a calcium channel blocker because the NIF group showed less expressive effects than the Mg group.

Asunto(s)

Discinesias/tratamiento farmacológico , Haloperidol/farmacología , Magnesio/farmacología , Animales , Antipsicóticos/farmacología , Encéfalo/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/metabolismo , Cuerpo Estriado/metabolismo , Haloperidol/efectos adversos , Magnesio/metabolismo , Masculino , Movimiento/efectos de los fármacos , Trastornos del Movimiento/tratamiento farmacológico , Neostriado/metabolismo , Nifedipino/farmacología , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Sustancia Negra/metabolismo

RESUMEN

Opioids are addictive drugs, whose misuse evoke withdrawal and relapse. Mediterranean-based diet (MBD) is rich in n-3 polyunsaturated fatty acids (PUFA), while Western based diets (WBDs) contain saturated fatty acids including interesterified fat (IF) and palm oil (PO), influencing neural functions. We compared MBD and WBDs on morphine-induced addiction parameters. Rats fed with MBD (chow plus 20% soybean- and fish-oil- n-6/n-3 PUFA 1:1) or WBD (WBD- PO or WBD-IF: chow plus 20% of palm oil or interesterified fat, respectively; high n-6/n-3 PUFA ratio) were exposed to morphine in conditioned place preference (CPP) paradigm. Anxiety-like behavior, locomotion and thermal sensitivity were evaluated during withdrawal. After morphine-CPP extinction, animals were challenged to morphine-reinstatement to induce relapse. All groups showed morphine-CPP, WBDs favored anxiety-like behaviors per se, locomotor sensitization and thermal hipersensitivity during withdrawal, resulting in increased morphine-reinstatement in comparison to MBD, which did not show relapse. WBDs increased glucocorticoid receptor immunoreactivity in the pre-frontal cortex, increasing corticosterone (CORT) and adrenocorticotrophic hormone (ACTH) per se and after morphine-reinstatement. In the nucleus accumbens, WBDs increased dopamine transporter (DAT) and dopamine receptor-2 (D2R) immunoreactivity and decreased dopamine receptor-1 (D1R). These findings indicate that WBDs facilitate morphine-reinstatement, unlike MBD, preserving the DA system mesolimbic neuroplasticity.

Asunto(s)

Dieta Mediterránea , Dieta Occidental/efectos adversos , Dependencia de Morfina/dietoterapia , Síndrome de Abstinencia a Sustancias/prevención & control , Animales , Ansiedad/prevención & control , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Dieta Mediterránea/psicología , Dieta Occidental/psicología , Modelos Animales de Enfermedad , Hipersensibilidad/prevención & control , Hipersensibilidad/psicología , Masculino , Morfina/administración & dosificación , Dependencia de Morfina/psicología , Actividad Motora/efectos de los fármacos , Ratas Wistar , Recurrencia

RESUMEN

Depression is a common psychiatric disease which pharmacological treatment relieves symptoms, but still far from ideal. Tactile stimulation (TS) has shown beneficial influences in neuropsychiatric disorders, but the mechanism of action is not clear. Here, we evaluated the TS influence when applied on adult female rats previously exposed to a reserpine-induced depression-like animal model. Immediately after reserpine model (1 mg/kg/mL, 1×/day, for 3 days), female Wistar rats were submitted to TS (15 min, 3×/day, for 8 days) or not (unhandled). Imipramine (10 mg/kg/mL) was used as positive control. After behavioral assessments, animals were euthanized to collect plasma and prefrontal cortex (PFC). Behavioral observations in the forced swimming test, splash test, and sucrose preference confirmed the reserpine-induced depression-like behavior, which was reversed by TS. Our findings showed that reserpine increased plasma levels of adrenocorticotropic hormone and corticosterone, decreased brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B, and increased proBDNF immunoreactivity in the PFC, which were also reversed by TS. Moreover, TS reestablished glial fibrillary acidic protein and glucocorticoid receptor levels, decreased by reserpine in PFC, while glial cell line-derived neurotrophic factor was increased by TS per se. Our outcomes are showing that TS applied in adulthood exerts a beneficial influence in depression-like behaviors, modulating the HPA axis and regulating neurotrophic factors more effectively than imipramine. Based on this, our proposal is that TS, in the long term, could be considered a new therapeutic strategy for neuropsychiatric disorders improvement in adult life, which may represent an interesting contribution to conventional pharmacological treatment.

Asunto(s)

Envejecimiento/fisiología , Conducta Animal , Depresión/fisiopatología , Sistema Hipotálamo-Hipofisario/fisiopatología , Factores de Crecimiento Nervioso/metabolismo , Sistema Hipófiso-Suprarrenal/fisiopatología , Transducción de Señal , Tacto , Hormona Adrenocorticotrópica/sangre , Animales , Peso Corporal/efectos de los fármacos , Corticosterona/sangre , Depresión/sangre , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Ratas Wistar , Reserpina/farmacología , Transducción de Señal/efectos de los fármacos , Sacarosa , Natación

RESUMEN

Recent studies have shown that tactile stimulation (TS) in pups is able to prevent and/or minimize fear, anxiety behaviors, and addiction to psychostimulant drugs in adult rats. In these studies, animals have been exposed to handling from postnatal day (PND) 1-21. This study was designed to precisely establish which period of preweaning development has a greater influence of TS on neuronal development. After birth, male pups were exposed to TS from PND1-7, PND8-14, and PND15-21. In adulthood, the different periods of postnatal TS were assessed through behavioral, biochemical, and molecular assessments. Animals that received TS from PND8-14 showed lower anxiety-like symptoms, as observed by decreased anxiety index in elevated plus maze. This same TS period was able to improve rats' working memory by increasing the percentage of alternation rate in Y-maze, and induce better ability to cope with stressful situations, as showed in the defensive burying test by a reduced time of burying behavior. On the other hand, animals receiving TS in the first week of life showed longest cumulative burying time, which is directly related to increased anxiety-like behavior. Moreover, TS from PND8-14 showed lower corticosterone levels and better oxidative status, as observed by decreased lipid peroxidation and increased catalase activity in the hippocampus. Brain-derived neurotrophic factor (BDNF) immunocontent was increased in the hippocampus of animals receiving TS from PND8-14, while glucocorticoid receptors immunocontent was decreased in both TS1-7 and TS15-21 , but not TS8-14 . To the best of our knowledge, this study is the first to show TS can be more efficient if applied over a focused period of neonatal development (PND8-14) and this beneficial influence can be reflected on reduced emotionality and increased ability to address stressful situations in adulthood. © 2016 Wiley Periodicals, Inc.

Asunto(s)

Factor Neurotrófico Derivado del Encéfalo/metabolismo , Manejo Psicológico , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Receptores de Glucocorticoides/metabolismo , Tacto , Adaptación Psicológica/fisiología , Animales , Animales Recién Nacidos , Ansiedad/metabolismo , Catalasa/metabolismo , Corticosterona/sangre , Conducta Exploratoria/fisiología , Peroxidación de Lípido/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Memoria a Corto Plazo/fisiología , Actividad Motora/fisiología , Estimulación Física , Distribución Aleatoria , Ratas Wistar , Método Simple Ciego

RESUMEN

Chronic use of typical antipsychotic haloperidolis related to movement disturbances such as parkinsonism, akathisia and tardive dyskinesia which have been related to excitotoxicity in extrapyramidal brain areas, requiring their prevention and treatment. In the current study we evaluated the influence of the magnesium on prevention (for 28days before-), reversion (for 12days after-) and concomitant supplementation on haloperidol-induced movement disorders in rats. Sub-chronic haloperidol was related to orofacial dyskinesia (OD) and catalepsy development, increased generation of reactive species (RS) and levels of protein carbonyl (PC) in cortex, striatum and substantia nigra (SN) in all experimental protocols. When provided preventatively, Mg reduced the increase of OD and catalepsy time 14 and 7days after haloperidol administration, respectively. When supplemented after haloperidol-induced OD establishment, Mg reversed this behavior after 12days, while catalepsy was reversed after 6days of Mg supplementation.When Mg was concomitantly supplemented with haloperidol administration, OD and catalepsy were prevented. Moreover, Mg supplementation was able to prevent the RS generation in both cortex and SN, reducing PC levels in all brain areas evaluated. When supplemented after haloperidol, Mg reversed RS generation in cortex and striatum, decreasing PC levels in SN and striatum.The co-administration of haloperidol and Mg supplementation prevented RS generation in cortex, striatum and SN, and PC levels in the SN.These outcomes indicate that Mg supplementation may be a useful alternative to prevent movement disturbances resulting of classic antipsychotic pharmacotherapy as haloperidol.

Asunto(s)

Antipsicóticos/farmacología , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Discinesias/tratamiento farmacológico , Haloperidol/farmacología , Magnesio/farmacología , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Embrión de Pollo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Discinesias/etiología , Haloperidol/administración & dosificación , Masculino , Carbonilación Proteica/efectos de los fármacos , Ratas , Ratas Wistar , Factores de Tiempo

RESUMEN

This work aimed to develop nanocapsules (NC) coated with polysorbate 80 (P80), cationic chitosan (CS) or polyethylene glycol (PEG) using clozapine (CZP) as the drug model. The zeta potential, pH and encapsulation efficiency were directly affected by the CS coating. Using the bag dialysis method, the in vitro CZP release from CS-coated nanocapsules was similar to the PEG-coated at pH 7.4. Nanocapsules coated with PEG and CS exhibited an increased action duration compared to the P80-coated nanocapsules in pseudo-psychosis induced by d,l-amphetamine in rats. When comparing both groups, the group administered CS-coated nanocapsules showed better activity than the PEG-coated nanocapsules at 6, 10 and 12h after d,l-amphetamine administration. The pharmacokinetic assessment in rats demonstrated that the observed half-lives were free CZP

Asunto(s)

Clozapina/química , Portadores de Fármacos/química , Quitosano/química , Concentración de Iones de Hidrógeno , Nanocápsulas/química , Polietilenglicoles/química , Polisorbatos/química

RESUMEN

PURPOSE: To evaluate the toxicity of chronic consumption of processed foods that are rich in trans fat on the lipid composition of brain membranes, as well as its functional repercussions. METHODS: A second generation of male rats born from mothers and grandmothers supplemented with soybean oil (SOC, an isocaloric control group) or hydrogenated vegetable fat (HVF, rich in TFA) (3g/kg; p.o.) were kept under oral treatment until 90 days of age, when they were exposed to an AMPH-induced model of mania. RESULTS: The HVF group presented 0.38% of TFA incorporation in the striatum, affecting Na(+)/K(+) ATPase activity, which was decreased per se and following AMPH-exposure. The HVF group also showed increased protein carbonyl (PC) and brain-derived neurotrophic factor (BDNF) mRNA levels after AMPH administration, while these oxidative and molecular changes were not observed in the other experimental groups. Additionally, a negative correlation between striatal Na(+)/K(+) ATPase activity and PC levels (r(2)=0.49) was observed. CONCLUSION: The prolonged consumption of trans fat allows TFA incorporation and increases striatal oxidative status, thus impairing the functionality of Na(+)/K(+)-ATPase and affecting molecular targets as BDNF mRNA. We hypothesized that the chronic intake of processed foods (rich in TFA) facilitates the development of neuropsychiatric diseases, particularly bipolar disorder.

Asunto(s)

Trastorno Bipolar/metabolismo , Encéfalo/metabolismo , ARN Mensajero/biosíntesis , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Ácidos Grasos trans/toxicidad , Anfetamina/farmacología , Animales , Trastorno Bipolar/inducido químicamente , Trastorno Bipolar/enzimología , Trastorno Bipolar/genética , Encéfalo/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Factor Neurotrófico Derivado del Encéfalo/genética , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Expresión Génica , Masculino , Membranas/metabolismo , Actividad Motora/efectos de los fármacos , Carbonilación Proteica , ARN Mensajero/genética , Ratas , Aceite de Soja/administración & dosificación , Ácidos Grasos trans/administración & dosificación , Ácidos Grasos trans/metabolismo

RESUMEN

Reserpine administration results in a predictable animal model of orofacial dyskinesia (OD) that has been largely used to access movement disturbances related to extrapyramidal oxidative damage. Here, OD was acutely induced by reserpine (two doses of 0.7 mg/kg subcutaneous (s.c.)), every other day for 3 days), which was administered after (experiment 1) and before (experiment 2) magnesium (Mg) supplementation (40 mg/kg/mL, peroral (p.o.)). In experiment 1, Mg was administered for 28 days before reserpine treatment, while in experiment 2, it was initiated 24 h after the last reserpine administration and was maintained for 10 consecutive days. Experiment 1 (prevention) showed that Mg supplementation was able to prevent reserpine-induced OD and catalepsy development. Mg was also able to prevent reactive species (RS) generation, thus preventing increase of protein carbonyl (PC) levels in both cortex and substantia nigra, but not in striatum. Experiment 2 (reversion) showed that Mg was able to decrease OD and catalepsy at all times assessed. In addition, Mg was able to decrease RS generation, with lower levels of PC in both cortex and striatum, but not in substantia nigra. These outcomes indicate that Mg is an important metal that should be present in the diet, since its intake is able to prevent and minimize the development of movement disorders closely related to oxidative damage in the extrapyramidal brain areas, such as OD.

Asunto(s)

Encéfalo/metabolismo , Magnesio/farmacología , Magnesio/uso terapéutico , Trastornos del Movimiento/tratamiento farmacológico , Animales , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Trastornos del Movimiento/etiología , Ratas , Ratas Wistar , Reserpina/toxicidad

RESUMEN

The influence of trans fatty acids (TFA) on lipid profile, oxidative damage and mitochondrial function in the skin of rats exposed to ultraviolet radiation (UVR) was assessed. The first-generation offspring of female Wistar rats supplemented from pregnancy with either soybean oil (C-SO, rich in n-6 FA; control group) or hydrogenated vegetable fat (HVF, rich in TFA) were continued with the same supplements until adulthood, when half of each group was exposed to UVR for 12 weeks. The HVF group showed higher TFA cutaneous incorporation, increased protein carbonyl (PC) levels, decreased functionality of mitochondrial enzymes and antioxidant defenses of the skin. After UVR, the HVF group showed increased skin thickness and reactive species (RS) generation, with decreased skin antioxidant defenses. RS generation was positively correlated with skin thickness, wrinkles and PC levels. Once incorporated to skin, TFA make it more susceptible to developing UVR-induced disorders.

Asunto(s)

Suplementos Dietéticos , Mitocondrias/efectos de los fármacos , Aceites de Plantas/administración & dosificación , Envejecimiento de la Piel/efectos de los fármacos , Piel/efectos de los fármacos , Aceite de Soja/administración & dosificación , Animales , Antioxidantes/metabolismo , Catalasa/metabolismo , Femenino , Hidrogenación , Mitocondrias/efectos de la radiación , Embarazo , Carbonilación Proteica/efectos de los fármacos , Carbonilación Proteica/efectos de la radiación , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Piel/química , Piel/metabolismo , Piel/efectos de la radiación , Envejecimiento de la Piel/efectos de la radiación , Superóxido Dismutasa/metabolismo , Rayos Ultravioleta

RESUMEN

Recently, we have described the influence of dietary fatty acids (FA) on mania-like behavior of first generation animals. Here, two sequential generations of female rats were supplemented with soybean oil (SO, rich in n-6 FA, control group), fish oil (FO, rich in n-3 FA) and hydrogenated vegetable fat (HVF, rich in trans FA) from pregnancy and during lactation. In adulthood, half of each group was exposed to an amphetamine (AMPH)-induced mania animal model for behavioral, biochemical and molecular assessments. FO supplementation was associated with lower reactive species (RS) generation and protein carbonyl (PC) levels and increased dopamine transporter (DAT) levels, while HVF increased RS and PC levels, thus decreasing catalase (CAT) activity and DAT levels in hippocampus after AMPH treatment. AMPH impaired short- (1 h) and long- (24 h) term memory in the HVF group. AMPH exposure was able to reduce hippocampal BDNF- mRNA expression, which was increased in FO. While HVF was related to higher trans FA (TFA) incorporation in hippocampus, FO was associated with increased percentage of n-3 polyunsaturated FA (PUFA) together with lower n-6/n-3 PUFA ratio. Interestingly, our data showed a positive correlation between brain-derived neurotrophic factor (BDNF) mRNA and short- and long-term memory (r(2) = 0.53; P = 0.000/r(2) = 0.32; P = 0.011, respectively), as well as a negative correlation between PC and DAT levels (r(2) = 0.23; P = 0.015). Our findings confirm that provision of n-3 or TFA during development over two generations is able to change the neuronal membrane lipid composition, protecting or impairing the hippocampus, respectively, thus affecting neurothrophic factor expression such as BDNF mRNA. In this context, chronic consumption of trans fats over two generations can facilitate the development of mania-like behavior, so leading to memory impairment and emotionality, which are related to neuropsychiatric conditions.

Asunto(s)

Trastorno Bipolar/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/metabolismo , Efectos Tardíos de la Exposición Prenatal , ARN Mensajero/metabolismo , Ácidos Grasos trans/toxicidad , Animales , Trastorno Bipolar/psicología , Modelos Animales de Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Femenino , Aceites de Pescado/toxicidad , Lactancia , Masculino , Trastornos de la Memoria/metabolismo , Embarazo , Ratas Wistar , Reconocimiento en Psicología/fisiología , Aceite de Soja/toxicidad , Productos Vegetales/toxicidad

RESUMEN

OBJECTIVE: The present study describes the isolation of linalool from the essential oil of Lippia alba (Mill.) N. E. Brown, and its anesthetic effect in silver catfish (Rhamdia quelen) in comparison with essential oil. The potentiation of depressant effects of linalool with a benzodiazepine (BDZ) and the involvement of GABAergic system in its antagonism by flumazenil were also evaluated. STUDY DESIGN: Prospective experimental study. ANIMALS: Juvenile silver catfish unknown sex weighing mean 9.24 ± 2.83 g (n = 6 for each experimental group per experiment). METHODS: Column chromatography was used for the isolation of S-(+)-linalool. Fish (n = 6 for each concentration) were transferred to aquaria with linalool (30, 60, and 180 µL L(-1)) or EO of L. alba (50, 100, and 300 µL L(-1)) to determine the induction time for anesthesia. After induction, the animals were transferred to anesthetic-free aquaria to assess their recovery time. To observe the potentiation, fish were exposed to linalool (30, 60, and 180 µL L(-1)) in the presence or absence of BDZ (diazepam 150 µm). In another experiment, fish exposed to linalool (30 and 180 µL L(-1) or BDZ were transferred to an anesthetic-free aquaria containing flumazenil (5 µm) or water to assess recovery time. RESULTS: Linalool had a similar sedation profile to the essential oil at a proportional concentration in silver catfish. However, the anesthesia profile was different. Potentiation of linalool effect occurred only when tested at low concentration. Fish exposed to BDZ showed faster anesthesia recovery in water with flumazenil, but the same did not occur with linalool. CONCLUSIONS AND CLINICAL RELEVANCE: The use of linalool as a sedative and anesthetic for silver catfish was effective at 30 and 180 µL L(-1), respectively. The mechanism of action seems not to involve the benzodiazepine site of the GABAergic system.

Asunto(s)

Anestesia/veterinaria , Bagres , Hipnóticos y Sedantes/farmacología , Lippia/química , Monoterpenos/farmacología , Monoterpenos Acíclicos , Anestesia/métodos , Anestésicos/aislamiento & purificación , Anestésicos/farmacología , Animales , Sistema Nervioso Central/efectos de los fármacos , Diazepam/farmacología , Flumazenil/farmacología , Hipnóticos y Sedantes/aislamiento & purificación , Monoterpenos/aislamiento & purificación , Aceites de Plantas/aislamiento & purificación , Aceites de Plantas/farmacología

RESUMEN

The current Western diet often provides considerable amounts of saturated and trans fatty acids (TFA), whose incorporation into neuronal membranes has been implicated in changes of brain neurochemical functions. Such influence has caused concerns due to precipitation of neuropsychiatric disorders, whose data are still unclear. Here we evaluated the influence of different fats on preference parameters for amphetamine (AMPH): adolescent rats were orally supplemented with soybean oil (SO, rich in n-6 FA, which was considered an isocaloric control group), fish oil (FO, rich in n-3 FA) and hydrogenated vegetable fat (HVF, rich in saturated and trans FA) from weaning, which were born of dams supplemented with the same fat from pregnancy and lactation. AMPH preference, anxiety-like symptoms and locomotor index were evaluated in conditioned place preference (CPP), elevated plus maze (EPM) and open-field (OF), respectively, while brain oxidative status was determined in cortex, striatum and hippocampus. HVF increased AMPH-CPP and was associated with withdrawal signs, as observed by increased anxiety-like symptoms. Moreover, SO and FO were not associated with AMPH preference, but only FO-supplemented rats did not show any anxiety-like symptoms or increased locomotion. FO supplementation was related to lower oxidative damages to proteins and increased CAT activity in striatum and hippocampus, as well as increased GSH levels in blood, while HVF was related to increased oxidative status. In conclusion, our study showed the harmful influence of TFA on AMPH-CPP and drug craving symptoms, which can be related to dopaminergic neurotransmission.

Asunto(s)

Anfetamina/farmacología , Conducta Animal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos trans/farmacología , Animales , Condicionamiento Clásico , Femenino , Ratas , Ratas Wistar

RESUMEN

In this study we evaluated the influence of neonatal tactile stimulation (TS) on behavioral and biochemical effects related to a low dose of diazepam (DZP) in adult rats. Male pups of Wistar rats were handled (TS) daily from PND1 to PND21 for 10 min, while unhandled (UH) rats were not touched. In adulthood, half the animals of each group received a single administration of diazepam (0.25mg/kg body weight i.p.) or vehicle and then were submitted to behavioral and biochemical evaluations. In the TS group, DZP administration reduced anxiety-like symptoms in different behavioral paradigms (elevated plus maze, EPM; staircase and open-field and defensive burying) and increased exploratory behavior. These findings show that neonatal TS increased DZP pharmacological responses in adulthood compared to neonatally UH animals, as observed by reduced anxiety-like symptoms and lower levels of plasma cortisol. TS also changed plasma levels of antioxidant defenses such as vitamin C and glutathione peroxidase, whose increase may be involved in lower oxidative damages to proteins in cortex, subthalamic region and hippocampus of these animals. Here we are showing for the first time that neonatal TS is able to change responsiveness to benzodiazepine drugs in adulthood and provides better pharmacological responses in novel situations of stress.

Asunto(s)

Ansiolíticos/farmacología , Ansiedad/fisiopatología , Diazepam/farmacología , Estimulación Física/métodos , Tacto/fisiología , Animales , Animales Recién Nacidos , Ansiedad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Masculino , Ratas , Ratas Wistar , Estrés Psicológico/tratamiento farmacológico

RESUMEN

Acute reserpine and subchronic haloperidol are animal models of extrapyramidal disorders often used to study parkinsonism, akinesia and tardive dyskinesia. In humans, these usually irreversible and disabling extrapyramidal disorders are developed by typical antipsychotic treatment, whose pathophysiology has been related to oxidative damages development. So far, there is no treatment to prevent these problems of the psychiatric clinic, and therefore further studies are needed. Here we used the animal models of extrapyramidal disorders cited above, which were performed in two distinct experiments: orofacial dyskinesia (OD)/catalepsy induced by acute reserpine and subchronic haloperidol after (experiment 1) and before (experiment 2) oral treatment with pecan shell aqueous extract (AE), a natural and promissory antioxidant. When administered previously (exp.1), the AE prevented OD and catalepsy induced by both reserpine and haloperidol. When reserpine and haloperidol were administered before the extract (exp.2), the animals developed OD and catalepsy all the same. However, the orofacial parameter (but not catalepsy) in both animal models was reversed after 7 and 14 days of AE treatment. These results indicate that, acute reserpine and subchronic haloperidol administrations induced similar motor disorders, although through different mechanisms, and therefore are important animal models to study the physiopathology of extrapyramidal disorders. Comparatively, the pecan shell AE was able to both prevent and reverse OD but only to prevent catalepsy. These results reinforce the role of oxidative stress and validate the two animal models used here. Our findings also favor the idea of prevention of extrapyramidal disorders, rather than their reversal.

Asunto(s)

Enfermedades de los Ganglios Basales/tratamiento farmacológico , Enfermedades de los Ganglios Basales/prevención & control , Carya/química , Modelos Animales de Enfermedad , Nueces/química , Fitoterapia , Extractos Vegetales/uso terapéutico , Animales , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Haloperidol , Masculino , Trastornos del Movimiento/tratamiento farmacológico , Extractos Vegetales/farmacología , Ratas , Ratas Wistar , Reserpina

RESUMEN

In the last decades, foods rich in omega-3 (ω-3) fatty acids (FA) have been replaced by omega-6 (ω-6) and trans FA, which are found in processed foods. The influence of ω-6 (soybean oil--SO), trans (hydrogenated vegetable fat--HVF) and ω-3 (fish oil--FO) fatty acids on locomotor and oxidative stress (OS) parameters were studied in an animal model of mania. Rats orally fed with SO, HVF and FO for 8 weeks received daily injections of amphetamine (AMPH--4 mg/kg/mL-ip) for the last week of oral supplementation. HVF induced hyperactivity, increased the protein carbonyl levels in the cortex and decreased the mitochondrial viability in cortex and striatum. AMPH-treatment increased the locomotion and decreased the mitochondrial viability in all groups, but its neurotoxicity was higher in the HVF group. Similarly, AMPH administration increased the protein carbonyl levels in striatum and cortex of HVF-supplemented rats. AMPH reduced the vitamin-C plasmatic levels of SO and HVF-fed rats, whereas no change was observed in the FO group. Our findings suggest that trans fatty acids increased the oxidative damage per se and exacerbated the AMPH-induced effects. The impact of trans fatty acids consumption on neuronal diseases and its consequences in brain functions must be further evaluated.

Asunto(s)

Anfetaminas/farmacología , Trastorno Bipolar/inducido químicamente , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-6/farmacología , Anfetaminas/administración & dosificación , Anfetaminas/efectos adversos , Animales , Ácido Ascórbico/sangre , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Sinergismo Farmacológico , Ácidos Grasos Omega-3/efectos adversos , Ácidos Grasos Omega-6/efectos adversos , Locomoción/efectos de los fármacos , Ratas

RESUMEN

Haloperidol is an antipsychotic drug associated with the development of movement disorders. We evaluated the effect of its nanoencapsulation on its pharmacological activity and motor side effects. Haloperidol-loaded polysorbate-coated nanocapsules (H-NC) showed nanometric size, negative zeta potential and low polydispersity indices and high encapsulation efficiency (>95%). Rats received a single dose of H-NC (0.2mg/kg ip) and four doses of D,L-amphetamine, AMPH (8.0mg/kg ip), injected every 3h (0, 3, 6 and 9h). The AMPH-induced stereotyped movements were quantified in the intervals of 15 min after each of four doses of AMPH, demonstrating greater pharmacological efficacy of the H-NC over free haloperidol (FH). The acute motor side effects were evaluated 1h after a single dose of H-NC or its free solution (0.2mg/kg ip). The group treated with H-NC presented lower extrapyramidal effects (catalepsy and oral dyskinesia) than those treated with FH. In the last experimental set, rats sub-chronically treated with a daily dose of H-NC (0.2mg/kg ip) for 28 days showed a lower incidence of extrapyramidal effects than those treated with the free drug (0.2mg/kg ip). Our findings showed the potential of using H-NC in the development of a nanomedicine aimed at increasing the efficacy of this antipsychotic drug and reducing its side effects.

Asunto(s)

Antipsicóticos/toxicidad , Antipsicóticos/uso terapéutico , Discinesia Inducida por Medicamentos/etiología , Haloperidol/toxicidad , Haloperidol/uso terapéutico , Conducta Estereotipada/efectos de los fármacos , Anfetamina , Animales , Antipsicóticos/administración & dosificación , Antipsicóticos/química , Fenómenos Químicos , Modelos Animales de Enfermedad , Haloperidol/administración & dosificación , Haloperidol/química , Masculino , Nanocápsulas , Polisorbatos , Ratas , Ratas Wistar , Esquizofrenia/tratamiento farmacológico