Assessment of suberoylanilide hydroxamic acid on a Alzheimer's disease model induced by ß-amyloid(1-42) in aged female mice: Neuromodulatory and epigenetic effect.

Alzheimer's disease (AD) is a neurodegenerative disease that affects several elderly people per years. AD is a pathology of multifactorial etiology, resulting from multiple environmental and genetic determinants. However, there is no effective pharmacological alternative for the treatment of this illness. In this sense, the purpose of current study was to characterize the mechanisms by which Aß1-42 injection via intracerebroventricular induces neurobehavioral changes in a time-course curve. In addition, suberoylanilide hydroxamic acid (SAHA) inhibitor of histone deacetylase (HDAC) was used to investigate the involvement of epigenetic modifications Aß1-42-caused in aged female mice. In general manner, Aß1-42 injection induced a major neurochemical disturbance in hippocampus and prefrontal cortex of animals and a serious impairment of memory. Overall, SAHA treatment attenuated neurobehavioral changes caused by Aß1-42 injection in aged female mice. The subchronic effects presented of SAHA were through modulation of HDAC activity, regulation of brain-derived neurotrophic factor (BDNF) levels and expression of BDNF mRNA, accompanied by unlocking cAMP/PKA/pCREB pathway in hippocampus and prefrontal cortex of animals.

Surface-functionalized curcumin-loaded polymeric nanocapsules could block apomorphine-induced behavioral changes in rats.

BACKGROUND: Surface functionalization enhances the properties and characteristics of polymeric nanocapsules (NCs) mainly due to the surface charge, surfactants, and polymer coating type. Curcumin (CUR) is a bioactive compound with several proven pharmacological properties and low bioavailability. This study aimed to develop anionic (poly-ɛ-caprolactone; PCL) and cationic (Eudragit® RS100 (EUD)) NCs prepared with sorbitan monostearate (Span 60®) or sorbitan monooleate (Span 80®), coated with d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and optimized using 23 factorial analysis. Subsequently, the biological activity was evaluated. METHODS: A two-level, three-factor design (polymer, Span type, and TPGS concentration) was used. The biological effects of CUR-loaded TPGS-coated cationic and anionic NCs were assessed in apomorphine-induced stereotyped behavior in rats. RESULTS: The type of polymer (anionic or cationic) and Span® had a factorial influence on the physical and chemical characteristics of NCs according to the changes in TPGS concentrations. Both cationic and anionic CUR-NCs could block apomorphine-induced behavioral changes. CONCLUSIONS: The CUR-loaded TPGS-coated NCs proved to be a promising brain delivery system.

Involvement of Indoleamine-2,3-Dioxygenase and Kynurenine Pathway in Experimental Autoimmune Encephalomyelitis in Mice.

The experimental autoimmune encephalomyelitis (EAE) is a model that mimics multiple sclerosis in rodents. Evidence has suggested that the activation of indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme in the kynurenine pathway (KP), plays a crucial role in inflammation-related diseases. The present study aimed to investigate the involvement of the inflammatory process and KP components in a model of EAE in mice. To identify the role of KP in EAE pathogenesis, mice received IDO inhibitor (INCB024360) at a dose of 200 mg/kg (per oral) for 25 days. We demonstrated that IDO inhibitor mitigated the clinical signs of EAE, in parallel with the reduction of cytokine levels (brain, spinal cord, spleen and lymph node) and ionized calcium-binding adaptor protein-1 (Iba-1) gene expression in the central nervous system of EAE mice. Besides, IDO inhibitor causes a significant decrease in the levels of tryptophan, kynurenine and neurotoxic metabolites of KP, such as 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) in the prefrontal cortex, hippocampus, spinal cord, spleen and lymph node of EAE mice. The mRNA expression and enzyme activity of IDO and kynurenine 3-monooxygenase (KMO) were also reduced by IDO inhibitor. These findings indicate that the inflammatory process concomitant with the activation of IDO/KP is involved in the pathogenic mechanisms of EAE. The modulation of KP is a promising target for novel pharmacological treatment of MS.

Curcumin-loaded poly(ϵ-caprolactone) lipid-core nanocapsules: Evaluation of fetal and maternal toxicity.

This study was designed to examine fetal and maternal toxicity of curcumin (CURC) loaded lipid-core nanocapsules (LNC) prepared with poly(ϵ-caprolactone) as a polymer, administered during the organogenesis period. Free CURC and CURC loaded-LNC (C-LNC) (2 mg/kg), blank LNC (B-LNC) and saline (CONTROL) were administered per oral route from the 7° to 13° gestational day (GD). Dams were evaluated daily for body weight gain, clinical signs, water and food intake. On 20° GD, dams were euthanized, organs were weighed and blood was collected for biochemical determinations. Fetal biometrics and external morphological anomalies were assessed. Also, were performed histopathological analysis of placenta and measurement of cytokines levels in placental and fetal liver tissues. All groups did not cause changes in dams during the pregnancy. Furthermore, treatments did not cause external morphological changes and delayed fetal development. Still, for histopathological analysis of placental tissue, treatments did not cause alterations in evaluated parameters. For cytokines levels, CURC and C-LNC caused a decrease in placental levels of TNF-α. Therefore, we have demonstrated that C-LNC did not cause toxicological effects (mother and fetus), in the same manner as pattern bioactive compound, proving to be a promising nutraceutical delivery system for maternal supplementation with CURC.

The challenge of using nanotherapy during pregnancy: Technological aspects and biomedical implications.

During the period of pregnancy, several processes and physiological adaptations occur in the body and metabolism of pregnant woman. These physiological adaptations in pregnant woman end up leading to a suppression in immune system favoring obstetric complications to the mother, fetus and placental tissue. An effective pharmacological therapy for these complications is still a challenge, since some drugs during pregnancy can have deleterious and teratogenic effects. An emerging alternative to pharmacological therapy during pregnancy is drugs encapsulated in nanoparticles (NP), recent area called nano-obstetrics. NP have the advantage of drug targeting and reduction of side effects. Then, maternal, placental or fetal uptake can be expected, depending on the characteristics of NP. Inorganic NP, crossing placental barrier effectively, but have several nanotoxicological effects. While organic NP appear to have a better targeting capacity and have few toxicological effects, but the studies are still scarce. Thus, in this review, were examined questions related to use and impact of physicochemical aspects of inorganic and organic NP during pregnancy.

Curcumin-loaded lipid-core nanocapsules attenuates the immune challenge LPS-induced in rats: Neuroinflammatory and behavioral response in sickness behavior.

The purpose of current study was to evaluate the effect of curcumin (CUR) loaded lipid-core nanocapsules (CUR-LNC) treatment on neuroinflammatory and behavioral alterations in a model of sickness behavior induced by lipopolysaccharide (LPS) in rats. Rats were treated with CUR-LNC and CUR daily for 14 days. After the last treatments, sickness behavior was induced with LPS. Sickness behavior LPS-induced was confirmed by behavioral tests, an increase in levels of proinflammatory cytokines, decrease in levels of IL-10, overexpression of IDO-1 and IDO-2. In conclusion, CUR-LNC treatment attenuated the neuroinflammatory and behavioral changes caused in sickness behavior model.

Chrysin loaded lipid-core nanocapsules ameliorates neurobehavioral alterations induced by ß-amyloid1-42 in aged female mice.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a clinically and progressive loss of cognitive function, neuropsychiatric and behavioral disorders. Some studies showed that chrysin has antioxidant and anti-inflammatory properties. However, your bioavailability is relatively low. Therefore, the present study was designed to investigate the effects of chrysin loaded lipid-core nanocapsules (LNCs) on neurochemical and behavioral changes in a model of AD induced by ß-amyloid1-42 (Aß1-42) peptide in aged female mice. For this purpose, aged female mice received free chrysin (FC) (5 mg/kg, per oral, p.o.) or chrysin loaded LNCs (C1-LNC and C5-LNC) (1 or 5 mg/kg, p.o.) for 14 days after Aß1-42 administration (400 pmol, i.c.v.). Aß1-42 induced significant impairments on memory and learning (morris water maze task, object recognition and step-down-type passive avoidance), also caused oxidative stress, reduced the levels of brain-derived neurotrophic factor (BDNF), increased neuroinflammation in prefrontal cortex and hippocampus of aged animals. Thus, C1-LNC and C5-LNC displayed significant effect against Aß1-42, via attenuation of oxidative stress and neuroinflammation, modulation of neurochemical and behavioral changes in a model of AD. These results point to chrysin loaded LNCs (mainly C5-LNC) can be a promising biomedical tool and a new therapeutic approach for treatment and prevention of AD.

Neuroprotective effects of curcumin lipid-core nanocapsules in a model Alzheimer's disease induced by ß-amyloid 1-42 peptide in aged female mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of dementia, representing about 60-70% of cases. Curcumin is a natural compound extracted from Curcuma longa Linn, widely used in cooking, presenting several biological activities, including neuroprotection. However, it has low solubility and consequently its bioavailability is limited. In recent years, researchers have focused their attention on delivery systems based on nanotechnology because of their promising potential and advantages over conventional approaches. This study investigated the neuroprotective effects of curcumin loaded lipid-core nanocapsules (LNC) in a model of Alzheimer's disease (AD) induced by intracerebroventricular injections of ß-amyloid1-42 (Aß1-42) peptide in aged female mice, and compared these effects with those from free curcumin. Aged female mice received curcumin, free (50 mg/kg, p.o.) or loaded nanocapsules (10 or 1 mg/kg, p.o.) for 14 days after Aß1-42 administration. Aß1-42 induced significant cognitive deficit (Morris Water Maze test), as well as caused increased the levels of inflammatory cytokines in prefrontal cortex, hippocampus and serum of mice. LNC displayed significant neuroprotection against Aß1-42-induced behavioral and neurochemical changes in a model of AD. These results provide insights into the neuroprotective actions of curcumin and its nanoencapsulation as a promising approach for application as an neuroprotective agent in the prevention of AD.

Neurochemical factors associated with the antidepressant-like effect of flavonoid chrysin in chronically stressed mice.

Chrysin is a flavonoid which is found in bee propolis, honey and various plants. Antidepressant-like effect of chrysin in chronically stressed mice was previously demonstrated by our group. Conversely, neurochemical factors associated with this effect require further investigations. Thus, we investigated the possible involvement of pro-inflammatory cytokines, kynurenine pathway (KP), 5-hydroxytryptamine (5-HT) metabolism and caspases activities in the effect of chrysin in mice exposed to unpredictable chronic stress (UCS). UCS applied for 28 days induced a depressive-like behavior, characterized by decrease in the time of grooming in the splash test and by increase in the immobility time in the tail suspension test. Oral treatment with chrysin (5 or 20mg/kg, 28 days), similarly to fluoxetine (10mg/kg, positive control), culminated in the prevention of these alterations. UCS elevated plasma levels of corticotropin-releasing hormone and adrenocorticotropic hormone, as well the tumor necrosis factor-α, interleukin-1ß, interleukin-6 and kynurenine levels in the prefrontal cortex (PFC) and hippocampus (HP). UCS induced the decrease in the 5-HT levels in the HP and the increase in the indoleamine-2,3-dioxygenase, caspase 3 and 9 activities in the PFC and HP. Treatment with chrysin, similarly to fluoxetine, promoted the attenuation of these alterations occasioned by UCS. These results corroborated with the antidepressant potential of chrysin in the treatment of psychiatric diseases. Furthermore, this work indicated the association of pro-inflammatory cytokines synthesis, KP, 5-HT metabolism and caspases activities with the action exercised by chrysin in mice exposed to UCS.

Hesperidin reverses cognitive and depressive disturbances induced by olfactory bulbectomy in mice by modulating hippocampal neurotrophins and cytokine levels and acetylcholinesterase activity.

Depression is a serious mental disorder that is becoming more common. To better treat patients suffering from this illness, elucidation of the underlying psychopathological and neurobiological mechanisms of depression is needed. Based on the evidence, we sought to investigate the effects of hesperidin in a model of depression induced by olfactory bulbectomy (OB). C57BL/6 mice were treated with hesperidin (50mg/kg) and imipramine (10mg/kg, positive control) after OB induction. The brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) levels and acetylcholinesterase activity were analyzed in the hippocampus of the mice. The behavioral parameters were also verified in the model of depression induced by OB. This study demonstrated that OB increased the pro-inflammatory cytokines levels and acetylcholinesterase activity in the hippocampus, exploratory activity in the open field test and immobility in the forced swimming test in mice. In addition, OB decreased the BDNF and NGF levels in the hippocampus, grooming time in the splash test and memory consolidation in the Morris water maze task. Treatment with hesperidin, similar to imipramine, was effective in preventing these behavioral and neurochemical alterations. We suggest that the main targets of hesperidin are pro-inflammatory cytokine modulation, helping to maintain brain plasticity and acetylcholinesterase activity regulation, which are closely linked with antidepressant-like action, as shown by behavior tests. This study demonstrated that there is a pharmacological effect of hesperidin in alterations induced by OB in mice, indicating that hesperidin could be useful as a treatment for depression.

Indoleamine-2,3-dioxygenase mediates neurobehavioral alterations induced by an intracerebroventricular injection of amyloid-ß1-42 peptide in mice.

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by a progressive cognitive decline along with various neuropsychiatric symptoms, including depression and anxiety. Increasing evidence has been proposed the activation of the tryptophan-degrading indoleamine-2,3-dyoxigenase (IDO), the rate-limiting enzyme of kynurerine pathway (KP), as a pathogenic factor of amyloid-beta (Aß)-related inflammation in AD. In the current study, the effects of an intracerebroventricular (i.c.v.) injection of Aß1-42 peptide (400pmol/mice; 3µl/site) on the regulation of KP biomarkers (IDO activity, tryptophan and kynurerine levels) and the impact of Aß1-42 on neurotrophic factors levels were investigated as potential mechanisms linking neuroinflammation to cognitive/emotional disturbances in mice. Our results demonstrated that Aß1-42 induced memory impairment in the object recognition test. Aß1-42 also induced emotional alterations, such as depressive and anxiety-like behaviors, as evaluated in the tail suspension and elevated-plus maze tests, respectively. We observed an increase in levels of proinflammatory cytokines in the Aß1-42-treated mice, which led to an increase in IDO activity in the prefrontal cortex (PFC) and the hippocampus (HC). The IDO activation subsequently increased kynurerine production and the kynurenine/tryptophan ratio and decreased the levels of neurotrophic factors in the PFC and HC, which contributed to Aß-associated behavioral disturbances. The inhibition of IDO activation by IDO inhibitor 1-methyltryptophan (1-MT), prevented the development of behavioral and neurochemical alterations. These data demonstrate that brain IDO activation plays a key role in mediating the memory and emotional disturbances in an experimental model based on Aß-induced neuroinflammation.

Evidence for the Involvement of Potassium Channel Inhibition in the Antidepressant-Like Effects of Hesperidin in the Tail Suspension Test in Mice.

The administration of hesperidin elicits an antidepressant-like effect in mice by a mechanism dependent on an interaction with the L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, whose stimulation is associated with the activation of potassium (K(+)) channels. Thus, this study investigated the involvement of different types of K(+) channels in the antidepressant-like effect of hesperidin in the mice tail suspension test (TST). The intracerebroventricular administration of tetraethylammonium (TEA, a nonspecific blocker of K(+) channels), glibenclamide (an ATP-sensitive K(+) channel blocker), charybdotoxin (a large- and intermediate-conductance calcium-activated K(+) channel blocker) or apamin (a small-conductance calcium-activated K(+) channel blocker) combined with a subeffective dose of hesperidin (0.01 mg/kg, intraperitoneally [i.p.]) was able to produce a synergistic antidepressant-like effect in the mice TST. Moreover, the antidepressant-like effect elicited by an effective dose of hesperidin (0.3 mg/kg, i.p.) in TST was abolished by the treatment of mice with pharmacological compounds K(+) channel openers (cromakalim and minoxidil). Results showed that the antidepressant-like effect of hesperidin in TST may involve, at least in part, the modulation of neuronal excitability through inhibition of K(+) channels and may act through a mechanism dependent on the inhibition of L-arginine-NO pathway.