Antitumoral Activity of Cecropia Pachystachya Leaves Extract in Vitro and in Vivo Model of Rat Glioma: Brain and Blood Effects.

The aim of this study was to investigate the antiglioma effect of Cecropia pachystachya Trécul (CEC) leaves extract against C6 and U87 glioblastoma (GB) cells and in a rat preclinical GB model. The CEC extract reduced in vitro cell viability and biomass. In vivo, the extract decreased the tumor volume approximately 62%, without inducing systemic toxicity. The deficit in locomotion and memory and an anxiolytic-like behaviors induced in the GB model were minimized by CEC. The extract decreased the levels of reactive oxygen species, nitrites and thiobarbituric acid reactive substances and increased the activity of antioxidant enzymes in platelets, sera and brains of GB animals. The activity of NTPDases, 5'-nucleotidase and adenosine deaminase (ADA) was evaluated in lymphocytes, platelets and serum. In platelets, ATP and AMP hydrolysis was reduced and hydrolysis of ADP and the activity of ADA were increased in the control, while in CEC-treated animals no alteration in the hydrolysis of ADP was detected. In serum, the reduction in ATP hydrolysis was reversed by CEC. In lymphocytes, the increase in the hydrolysis of ATP, ADP and in the activity of ADA observed in GB model was altered by CEC administration. The observed increase in IL-6 and decrease in IL-10 levels in the serum of GB animals was reversed by CEC. These results demonstrate that CEC extract is a potential complementary treatment to GB, decreasing the tumor size, while modulating aspects of redox and purinergic systems.

Alamandine: A promising treatment for fibrosis.

Angiotensin (Ang) II, the main active member of the renin angiotensin system (RAS), is essential for the maintenance of cardiovascular homeostasis. However, hyperactivation of the RAS causes fibrotic diseases. Ang II has pro-inflammatory actions, and moreover activates interstitial fibroblasts and/or dysregulates extracellular matrix degradation. The discovery of new RAS pathways has revealed the complexity of this system. Among the RAS peptides, alamandine (ALA, Ala1 Ang 1-7) has been identified in humans, rats, and mice, with protective actions in different pathological conditions. ALA has similar effects to its well-known congener, Ang-(1-7), as a vasodilator, anti-inflammatory, and antifibrotic. Its protective role against cardiovascular diseases is well-reviewed in the literature. However, the protective actions of ALA in fibrotic conditions have been little explored. Therefore, in this article, we review the ability of ALA to modulate the inflammatory process and collagen deposition, to serve as an antioxidant, and to mediate protection against functional disorders. In this scenario, we also explore ALA as a promising therapy for pulmonary fibrosis after COVID-19 infection.

Investigating the Effect of Inosine on Brain Purinergic Receptors and Neurotrophic and Neuroinflammatory Parameters in an Experimental Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative pathology characterized by progressive impairment of memory, associated with neurochemical alterations and limited therapy. The aim of this study was to evaluate the effects of inosine on memory, neuroinflammatory cytokines, neurotrophic factors, expression of purinergic receptors, and morphological changes in the hippocampus and cerebral cortex of the rats with AD induced by streptozotocin (STZ). Male rats were divided into four groups: I, control; II, STZ; III, STZ plus inosine (50 mg/kg); and IV, STZ plus inosine (100 mg/kg). The animals received intracerebroventricular injections of STZ or buffer. Three days after the surgical procedure, animals were treated with inosine (50 mg/kg or 100 mg/kg) for 25 days. Inosine was able to prevent memory deficits and decreased the immunoreactivity of the brain A2A adenosine receptor induced by STZ. Inosine also increased the levels of brain anti-inflammatory cytokines (IL-4 and IL-10) and the expression of brain-derived neurotrophic factor and its receptor. Changes induced by STZ in the molecular layer of the hippocampus were attenuated by treatment with inosine. Inosine also protected against the reduction of immunoreactivity for synaptophysin induced by STZ in CA3 hippocampus region. However, inosine did not prevent the increase in GFAP in animals exposed to STZ. In conclusion, our findings suggest that inosine has therapeutic potential for AD through the modulation of different brain mechanisms involved in neuroprotection.

Protective Effects of Inosine on Memory Consolidation in a Rat Model of Scopolamine-Induced Cognitive Impairment: Involvement of Cholinergic Signaling, Redox Status, and Ion Pump Activities.

This study investigated the effects of inosine on memory acquisition and consolidation, cholinesterases activities, redox status and Na+, K+-ATPase activity in a rat model of scopolamine-induced cognitive impairment. Adult male rats were divided into four groups: control (saline), scopolamine (1 mg/kg), scopolamine plus inosine (50 mg/kg), and scopolamine plus inosine (100 mg/kg). Inosine was pre-administered for 7 days, intraperitoneally. On day 8, scopolamine was administered pre (memory acquisition protocol) or post training (memory consolidation protocol) on inhibitory avoidance tasks. The animals were subjected to the step-down inhibitory avoidance task 24 hours after the training. Scopolamine induced impairment in the acquisition and consolidation phases; however, inosine was able to prevent only the impairment in memory consolidation. Also, scopolamine increased the activity of acetylcholinesterase and reduced the activity of Na+, K+-ATPase and the treatment with inosine protected against these alterations in consolidation protocol. In the animals treated with scopolamine, inosine improved the redox status by reducing the levels of reactive oxygen species and thiobarbituric acid reactive substances and restoring the activity of the antioxidant enzymes, superoxide dismutase and catalase. Our findings suggest that inosine may offer protection against scopolamine-induced memory consolidation impairment by modulating brain redox status, cholinergic signaling and ion pump activity. This compound may provide an interesting approach in pharmacotherapy and as a prophylactic against neurodegenerative mechanisms involved in Alzheimer's disease.

Effect of Melatonin on the Reduction of Hepatic Steatosis and Intestinal Leptin Expression in Zebrafish Exposed to Fructose.

Melatonin is a hormone related to circadian rhythms and has potential clinical applications. Our objectives were to verify the effect of melatonin on the liver of zebrafish exposed to fructose and evaluate the expression of appetite-related genes (leptin, ghrelin, and melanocortin receptor 4 [MC4R]). Animals were divided into three groups: control (CG, n = 25), fructose (FG, n = 25), and fructose+melatonin (FMG, n = 25). The study was carried out in 8 weeks. FG and FMG were exposed to 2% fructose and FMG treated with 1 µM of melatonin. Histological liver studies and gene expression analyses of Leptin, Ghrelin, and MC4R (liver and intestines) were performed. FG developed hepatic steatosis, which did not occur with CG and FMG. Genetic expression of hepatic leptin and MC4R did not show significant difference among the groups. Animals exposed to fructose (FG) presented an increased expression of intestinal leptin compared to those administered with melatonin. Animals exposed to fructose gained weight and developed an important hepatic steatosis, but melatonin reduced significantly the hepatic damage. Intestinal leptin showed increased expression in the group exposed to fructose.

Aluminum-Induced Alterations in Purinergic System Parameters of BV-2 Brain Microglial Cells.

Aluminum (Al) is ubiquitously present in the environment and known to be a neurotoxin for humans. The trivalent free Al anion (Al3+) can cross the blood-brain barrier (BBB), accumulate in the brain, and elicit harmful effects to the central nervous system (CNS) cells. Thus, evidence has suggested that Al increases the risk of developing neurodegenerative diseases, particularly Alzheimer's disease (AD). Purinergic signaling has been shown to play a role in several neurological conditions as it can modulate the functioning of several cell types, such as microglial cells, the main resident immune cells of the CNS. However, Al effects on microglial cells and the role of the purinergic system remain elusive. Based on this background, this study is aimed at assessing the modulation of Al on purinergic system parameters of microglial cells. An in vitro study was performed using brain microglial cells exposed to Al chloride (AlCl3) and lipopolysaccharide (LPS) for 96 h. The uptake of Al, metabolism of nucleotides (ATP, ADP, and AMP) and nucleoside (adenosine), and the gene expression and protein density of purinoceptors were investigated. The results showed that both Al and LPS increased the breakdown of adenosine, whereas they decreased nucleotide hydrolysis. Furthermore, the findings revealed that both Al and LPS triggered an increase in gene expression and protein density of P2X7R and A2AR receptors, whereas reduced the A1R receptor expression and density. Taken together, the results showed that Al and LPS altered the setup of the purinergic system of microglial cells. Thus, this study provides new insights into the involvement of the purinergic system in the mechanisms underlying Al toxicity in microglial cells.

Effect of QTC-4-MeOBnE Treatment on Memory, Neurodegeneration, and Neurogenesis in a Streptozotocin-Induced Mouse Model of Alzheimer's Disease.

Growing evidence suggests that drugs targeting neurogenesis and myelinization could be novel therapeutic targets against Alzheimer's disease (AD). Intracerebroventricular (icv) injection of streptozotocin (STZ) induces neurodegeneration through multiple mechanisms ultimately resulting in reduced adult neurogenesis. Previously, the multitarget compound QTC-4-MeOBnE (1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide) demonstrated beneficial effects in preclinical models of AD. Here we investigated its pharmacokinetics profile and the effect on memory impairments and neurodegeneration induced by STZ. Two icv injections of STZ resulted in significant cognitive and memory impairments, assessed by novel object recognition, Y-maze, social recognition, and step-down passive avoidance paradigms. These deficits were reversed in STZ-injected mice treated with QTC-4-MeOBnE. This effect was associated with reversion of neuronal loss in hippocampal dentate gyrus, reduced oxidative stress, and amelioration of synaptic function trough Na+/K+ ATPase and acetylcholinesterase activities. Furthermore, brains from QTC-4-MeOBnE-treated mice had a significant increase in adult neurogenesis and remyelination through Prox1/NeuroD1 and Wnt/ß-catenin pathways. Overall, our findings support the potential anti-AD effect of QTC-4-MeOBnE through multiple pathways, all of which have been involved in the onset and progression of the disease.

Potential Therapeutic Role of Purinergic Receptors in Cardiovascular Disease Mediated by SARS-CoV-2.

Novel coronavirus disease 2019 (COVID-19) causes pulmonary and cardiovascular disorders and has become a worldwide emergency. Myocardial injury can be caused by direct or indirect damage, particularly mediated by a cytokine storm, a disordered immune response that can cause myocarditis, abnormal coagulation, arrhythmia, acute coronary syndrome, and myocardial infarction. The present review focuses on the mechanisms of this viral infection, cardiac biomarkers, consequences, and the possible therapeutic role of purinergic and adenosinergic signalling systems. In particular, we focus on the interaction of the extracellular nucleotide adenosine triphosphate (ATP) with its receptors P2X1, P2X4, P2X7, P2Y1, and P2Y2 and of adenosine (Ado) with A2A and A3 receptors, as well as their roles in host immune responses. We suggest that receptors of purinergic signalling could be ideal candidates for pharmacological targeting to protect against myocardial injury caused by a cytokine storm in COVID-19, in order to reduce systemic inflammatory damage to cells and tissues, preventing the progression of the disease by modulating the immune response and improving patient quality of life.

Hypermethioninemia induces memory deficits and morphological changes in hippocampus of young rats: implications on pathogenesis.

The aim of this study was to investigate the effect of the chronic administration of methionine (Met) and/or its metabolite, methionine sulfoxide (MetO), on the behavior and neurochemical parameters of young rats. Rats were treated with saline (control), Met (0.2-0.4 g/kg), MetO (0.05-0.1 g/kg), and/or a combination of Met + MetO, subcutaneously twice a day from postnatal day 6 (P6) to P28. The results showed that Met, MetO, and Met + MetO impaired short-term and spatial memories (P < 0.05), reduced rearing and grooming (P < 0.05), but did not alter locomotor activity (P > 0.05). Acetylcholinesterase activity was increased in the cerebral cortex, hippocampus, and striatum following Met and/or MetO (P < 0.05) treatment, while Na+, K+-ATPase activity was reduced in the hippocampus (P < 0.05). There was an increase in the level of thiobarbituric acid reactive substances (TBARS) in the cerebral cortex in Met-, MetO-, and Met + MetO-treated rats (P < 0.05). Met and/or MetO treatment reduced superoxide dismutase, catalase, and glutathione peroxidase activity, total thiol content, and nitrite levels, and increased reactive oxygen species and TBARS levels in the hippocampus and striatum (P < 0.05). Hippocampal brain-derived neurotrophic factor was reduced by MetO and Met + MetO compared with the control group. The number of NeuN-positive cells was decreased in the CA3 in Met + MetO group and in the dentate gyrus in the Met, MetO, and Met + MetO groups compared to control group (P < 0.05). Taken together, these findings further increase our understanding of changes in the brain in hypermethioninemia by elucidating behavioral alterations, biological mechanisms, and the vulnerability of brain function to high concentrations of Met and MetO.

A multifunctional compound ebselen reverses memory impairment, apoptosis and oxidative stress in a mouse model of sporadic Alzheimer's disease.

Alzheimer 's disease (AD) is characterized by progressive cognitive decline including memory impairment, cortical dysfunction, and neuropsychiatric disturbances. The drug discovery to treat AD consists to develop compounds able to act in multiple molecular targets involved in the pathogenesis of the disease and the repositioning of old drugs for new application. This way, the intracerebroventricular (icv) injection of streptozotocin (STZ) has been used as a metabolic model of sporadic AD. The aim of the present study was to investigate whether ebselen (1-10 mg/kg), a multifunctional selenoorganic compound, ameliorates memory impairment, hippocampal oxidative stress, apoptosis and cell proliferation in a mouse model of sporadic AD induced by icv STZ (3 mg/kg, 1 µl/min). The administration of ebselen (10 mg/kg, i.p.) reversed memory impairment and hippocampal oxidative stress, by increasing the activities of antioxidant enzymes and the level of a non-enzymatic antioxidant defense, in Swiss mice administered with icv STZ. The anti-apoptotic property of ebselen was demonstrated by its effectiveness against the increase in the ratios of Bax/Bcl-2, cleaved PARP/PARP and the cleaved caspase-3 levels in the hippocampus of icv STZ mice. Although ebselen reversed memory impairment, it was ineffective against the reduction in the number of BrdU positive cells induced by icv STZ. In conclusion, the multifunctional selenoorganic compound ebselen was effective to reverse memory impairment, hippocampal oxidative stress and apoptosis in a mouse model of sporadic AD induced by icv STZ.

Caffeine and high intensity exercise: Impact on purinergic and cholinergic signalling in lymphocytes and on cytokine levels.

This study evaluated the effects of caffeine in combination with high-intensity interval training (HIIT) on sensitivity to glucocorticoids and proliferation of lymphocytes, IL-6 and IL-10 levels and NTPDase, adenosine deaminase (ADA) and acetylcholinesterase (AChE) activity in rat lymphocytes. The animals were divided into groups: control, caffeine 4 mg/kg, caffeine 8 mg/kg, HIIT, HIIT plus caffeine 4 mg/kg and HIIT plus caffeine 8 mg/kg. The rats were trained three times a week for 6 weeks for a total workload 23% of body weight at the end of the experiment. Caffeine was administered orally 30 min before the training session. When lymphocytes were stimulated with phytohaemagglutinin no changes were observed in proliferative response between trained and sedentary animals; however, when caffeine was associated with HIIT an increase in T lymphocyte proliferation and in the sensitivity of lymphocytes to glucocorticoids occurred. ATP and ADP hydrolysis was decreased in the lymphocytes of the animals only trained and caffeine treatment prevented alterations in ATP hydrolysis. HIIT caused an increase in the ADA and AChE activity in lymphocytes and this effect was more pronounced in rats trained and supplemented with caffeine. The level of IL-6 was increased while the level of IL-10 was decreased in trained animals (HIIT) and caffeine was capable of preventing this exercise effect. Our findings suggest that caffeine ingestion attenuates, as least in part, the immune and inflammatory alterations following a prolonged HIIT protocol.

The Impact of Purinergic System Enzymes on Noncommunicable, Neurological, and Degenerative Diseases.

Evidences show that purinergic signaling is involved in processes associated with health and disease, including noncommunicable, neurological, and degenerative diseases. These diseases strike from children to elderly and are generally characterized by progressive deterioration of cells, eventually leading to tissue or organ degeneration. These pathological conditions can be associated with disturbance in the signaling mediated by nucleotides and nucleosides of adenine, in expression or activity of extracellular ectonucleotidases and in activation of P2X and P2Y receptors. Among the best known of these diseases are atherosclerosis, hypertension, cancer, epilepsy, Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). The currently available treatments present limited effectiveness and are mostly palliative. This review aims to present the role of purinergic signaling highlighting the ectonucleotidases E-NTPDase, E-NPP, E-5'-nucleotidase, and adenosine deaminase in noncommunicable, neurological, and degenerative diseases associated with the cardiovascular and central nervous systems and cancer. In conclusion, changes in the activity of ectonucleotidases were verified in all reviewed diseases. Although the role of ectonucleotidases still remains to be further investigated, evidences reviewed here can contribute to a better understanding of the molecular mechanisms of highly complex diseases, which majorly impact on patients' quality of life.

Southern Brazilian native fruit shows neurochemical, metabolic and behavioral benefits in an animal model of metabolic syndrome.

In this work, we evaluated the effects of Psidium cattleianum (Red Type) (PcRT) fruit extract on metabolic, behavioral, and neurochemical parameters in rats fed with a highly palatable diet (HPD) consisted of sucrose (65% carbohydrates being 34% from condensed milk, 8% from sucrose and 23% from starch, 25% protein and 10% fat). Animals were divided into 4 groups: standard chow, standard chow + PcRT extract (200 mg/Kg/day by gavage), HPD, HPD + extract. The animals were treated for 150 days. Concerning chemical profiling, LC/PDA/MS/MS analysis revealed cyanidin-3-O-glucoside as the only anthocyanin in the PcRT extract. Our results showed that the animals exposed to HPD presented glucose intolerance, increased weight gain and visceral fat, as well as higher serum levels of glucose, triacylglycerol, total cholesterol, LDL-cholesterol and interleukin-6. These alterations were prevented by PcRT. In addition, HPD caused an increase in immobility time in a forced swimming test and the fruit extract prevented this alteration, indicating an antidepressant-like effect. PcRT treatment also prevented increased acetylcholinesterase activity in the prefrontal cortex caused by HPD consumption. Moreover, PcRT extract was able to restore Ca2+-ATPase activity in the prefrontal cortex, hippocampus, and striatum, as well as Na+,K+-ATPase activity in the prefrontal cortex and hippocampus. PcRT treatment decreased thiobarbituric acid-reactive substances, nitrite, and reactive oxygen species levels and prevented the reduction of superoxide dismutase activity in all cerebral structures of the HPD group. Additionally, HPD decreased catalase in the hippocampus and striatum. However, the extract prevented this change in the hippocampus. Our results showed that this berry extract has antihyperglycemic and antihyperlipidemic effects, and neuroprotective properties, proving to be a potential therapeutic agent for individuals with metabolic syndrome.

Anthocyanins as a potential pharmacological agent to manage memory deficit, oxidative stress and alterations in ion pump activity induced by experimental sporadic dementia of Alzheimer's type.

Anthocyanins (ANT) are polyphenolic flavonoids with antioxidant and neuroprotective properties. This study evaluated the effect of ANT treatment on cognitive performance and neurochemical parameters in an experimental model of sporadic dementia of Alzheimer's type (SDAT). Adult male rats were divided into four groups: control (1 ml/kg saline, once daily, by gavage), ANT (200 mg/kg, once daily, by gavage), streptozotocin (STZ, 3 mg/kg) and STZ plus ANT. STZ was administered via bilateral intracerebroventricular (ICV) injection (5 µl). ANT were administered after ICV injection for 25 days. Cognitive deficits (short-term memory and spatial memory), oxidative stress parameters, and acetylcholinesterase (AChE) and Na+-K+-ATPase activity in the cerebral cortex and hippocampus were evaluated. ANT treatment protected against the worsening of memory in STZ-induced SDAT. STZ promoted an increase in AChE and Na+-K+-ATPase total and isoform activity in both structures; ANT restored this change. STZ administration induced an increase in lipid peroxidation and decrease in the level of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), in the cerebral cortex; ANT significantly attenuated these effects. In the hippocampus, an increase in reactive oxygen species (ROS), nitrite and lipid peroxidation levels, and SOD activity and a decrease in CAT and GPx activity were seen after STZ injection. ANT protected against the changes in ROS and antioxidant enzyme levels. In conclusion, the present study showed that treatment with ANT attenuated memory deficits, protected against oxidative damage in the brain, and restored AChE and ion pump activity in an STZ-induced SDAT in rats.

α-Spinasterol: a COX inhibitor and a transient receptor potential vanilloid 1 antagonist presents an antinociceptive effect in clinically relevant models of pain in mice.

BACKGROUND AND PURPOSE: Postoperative pain is one of the most common manifestations of acute pain and is an important problem faced by patients after surgery. Moreover, neuronal trauma or chemotherapeutic treatment often causes neuropathic pain, which induces disabling and distressing symptoms. At present, treatments of both painful conditions are inadequate. α-Spinasterol, which is well characterized as a transient receptor potential vanilloid 1 antagonist, has anti-inflammatory, antioxidant and antinociceptive effects. Therefore, we investigated its antinociceptive potential on postoperative and neuropathic pain, as well as its effect on COX-1 and COX-2 activities. EXPERIMENTAL APPROACH: Nociceptive responses in a postoperative pain model (surgical incision-induced) or different neuropathic pain models (trauma or chemotherapy-induced) were investigated in mice. KEY RESULTS: Oral administration of α-spinasterol reduced postoperative pain, when given as a pre- (0.5 h before incision) or post-treatment (0.5 h after incision), and reduced cell infiltration in the injured tissue. α-Spinasterol also reduced the mechanical allodynia induced by partial sciatic nerve ligation and the mechanical and cold allodynia induced by paclitaxel. Moreover, α-spinasterol inhibited COX-1 and COX-2 enzyme activities without altering the body temperature of animals. Importantly, α-spinasterol did not alter spontaneous or forced locomotor activity. Furthermore, it did not cause gastric damage or liver and kidney changes, nor did it alter cell viability in the cerebral cortex and spinal cord slices of mice. CONCLUSION AND IMPLICATIONS: α-Spinasterol is an effective and safe COX inhibitor with antinociceptive effects in postoperative and neuropathic pain models. Therefore, it is an interesting prototype for the development of novel analgesic drugs.

Tabernaemontana catharinensis ethyl acetate fraction presents antinociceptive activity without causing toxicological effects in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Tabernaemontana catharinensis (Apocynaceae) is a medicinal plant used for the treatment of painful and inflammatory disorders. Here, we investigated the antinociceptive potential of the ethyl acetate fraction (Eta) from T. catharinensis leaves and assessed its toxic effects in mice to validate its popular use. MATERIALS AND METHODS: Adult male Swiss mice (30-35g) were used. The Eta antinociceptive effect (200-800mg/kg, oral route (p.o.)) was evaluated in the acetic acid, formalin, capsaicin and tail-immersion tests. Adverse effects were analyzed using rotarod and open-field tests, body temperature, biochemical analysis and gastric lesions assessment. To evaluate the acute (OECD 423) or sub-acute (OECD 407) toxicity of the Eta, it was administered orally at a single (2000mg/kg) or repeated doses (100-400mg/kg/day for 28 days), respectively. Mortality, behavioral changes, biochemical and hematological parameters were evaluated. The Eta effect on cellular viability also was evaluated. RESULTS: Eta (200-800mg/kg) inhibited the nociception caused by acetic acid (93.9±1.5%), formalin (86.2±10.8%) or capsaicin (75.4±3.3%) without inducing gastric lesions. Moreover, Eta neither altered the body temperature, biochemical parameters, nor forced or spontaneous locomotor activity of mice. The acute administration of the Eta (2000mg/kg) promoted a decrease in blood glucose levels and alanine aminotransferase activity. In the sub-acute toxicity study, Eta increased the aspartate aminotransferase activity (400mg/kg) and platelet distribution width (200mg/kg). Furthermore, Eta did not alter the cellular viability in cortical slices. CONCLUSIONS: Eta presents antinociceptive effects and mild toxicity in mice. These results support its traditional use as a potential analgesic.

Effect of vitamin D3 on behavioural and biochemical parameters in diabetes type 1-induced rats.

Diabetes is associated with long-term complications in the brain and reduced cognitive ability. Vitamin D3 (VD3 ) appears to be involved in the amelioration of hyperglycaemia in streptozotocin (STZ)-induced diabetic rats. Our aim was to analyse the potential of VD3 in avoiding brain damage through evaluation of acetylcholinesterase (AChE), Na(+) K(+) -adenosine triphosphatase (ATPase) and delta aminolevulinate dehydratase (δ-ALA-D) activities and thiobarbituric acid reactive substance (TBARS) levels from cerebral cortex, as well as memory in STZ-induced diabetic rats. Animals were divided into eight groups (n = 5): control/saline, control/metformin (Metf), control/VD3 , control/Metf + VD3 , diabetic/saline, diabetic/Metf, diabetic/VD3 and diabetic/Metf + VD3 . Thirty days after treatment, animals were submitted to contextual fear-conditioning and open-field behavioural tests, after which they were sacrificed and the cerebral cortex was dissected. Our results demonstrate a significant memory deficit, an increase in AChE activity and TBARS levels and a decrease in δ-ALA-D and Na(+) K(+) -ATPase activities in diabetic rats when compared with the controls. Treatment of diabetic rats with Metf and VD3 prevented the increase in AChE activity when compared with the diabetic/saline group. In treated diabetic rats, the decrease in Na(+) K(+) -ATPase was reverted when compared with non-treated rats, but the increase in δ-ALA-D activity was not. VD3 prevented diabetes-induced TBARS level and improved memory. Our results show that VD3 can avoid cognitive deficit through prevention of changes in important enzymes such as Na(+) K(+) -ATPase and AChE in cerebral cortex in type 1 diabetic rats.

Effects of chlorogenic acid, caffeine, and coffee on behavioral and biochemical parameters of diabetic rats.

Diabetes mellitus (DM) is associated with brain alterations that may contribute to cognitive dysfunctions. Chlorogenic acid (CGA) and caffeine (CA), abundant in coffee (CF), are natural compounds that have showed important actions in the brain. The present study aimed to evaluate the effect of CGA, CA, and CF on acetylcholinesterase (AChE), Na(+), K(+)-ATPase, aminolevulinate dehydratase (δ-ALA-D) activities and TBARS levels from cerebral cortex, as well as memory and anxiety in streptozotocin-induced diabetic rats. Animals were divided into eight groups (n = 5-10): control; control/CGA 5 mg/kg; control/CA 15 mg/kg; control/CF 0.5 g/kg; diabetic; diabetic/CGA 5 mg/kg; diabetic/CA 15 mg/kg; and diabetic/CF 0.5 g/kg. Our results demonstrated an increase in AChE activity and TBARS levels in cerebral cortex, while δ-ALA-D and Na(+), K(+)-ATPase activities were decreased in the diabetic rats when compared to control water group. Furthermore, a memory deficit and an increase in anxiety in diabetic rats were observed. The treatment with CGA and CA prevented the increase in AChE activity in diabetic rats when compared to the diabetic water group. CGA, CA, and CF intake partially prevented cerebral δ-ALA-D and Na(+), K(+)-ATPase activity decrease due to diabetes. Moreover, CGA prevented diabetes-induced TBARS production, improved memory, and decreased anxiety. In conclusion, among the compounds studied CGA proved to be a compound which acts better in the prevention of brain disorders promoted by DM.