Neuroprotective role of resveratrol mediated by purinergic signalling in cerebral cortex of mice infected by Toxoplasma gondii.

The central nervous system of the intermediate host plays a central role in lifelong persistence of Toxoplasma gondii as well as the pathogenesis of congenital toxoplasmosis and reactivated infection in immunocompromised individuals. The purinergic system has been implicated in a wide range of immunological pathways for controlling intracellular responses to pathogens, including T. gondii. In the present study, we investigated the effect of resveratrol (RSV) on ectonucleotidases, adenosine deaminase (ADA), and purinergic receptors during chronic infection by T. gondii. For this study, Swiss mice were divided into control (CTL), resveratrol (RSV), infected (INF), and INF+RSV groups. The animals were orally infected with the VEG strain and treated with RSV (100 mg/kg, orally). Ectonucleotidase activities, P2X7, P2Y1, A1, and A2A purinergic receptor density, ROS, and thiobarbituric acid reactive substances levels were measured in the cerebral cortex of mice. T. gondii infection increased NTPDase and reduced ADA activities. Treatment with RSV also affected enzymes hydrolysing extracellular nucleotides and nucleosides. Finally, RSV affected P1 and P2 purinergic receptor expression during T. gondii infection. Overall, RSV-mediated beneficial changes in purinergic signalling and oxidative stress, possibly improving cerebral cortex homeostasis in T. gondii infection.

Physical exercise prevents alterations in purinergic system and oxidative status in lipopolysaccharide-induced sepsis in rats.

Sepsis is a generalized infection that involves alterations in inflammatory parameters, oxidant status, and purinergic signaling in many tissues. Physical exercise has emerged as a tool to prevent this disease because of its anti-inflammatory and antioxidant properties. Thus, in this study, we investigated the effects of physical exercise on preventing alterations in purinergic system components, oxidative stress, and inflammatory parameters in lipopolysaccharide (LPS)-induced sepsis in rats. Male Wistar rats were divided into four groups: control, exercise (EX), LPS, and EX+LPS. The resisted physical exercise was performed for 12 weeks on a ladder with 1 m height. After 72 hours of the last exercise session, the animals received 2.5 mg/kg of LPS for induction of sepsis, and after 24 hours, lungs and blood samples were collected for analysis. The results showed that the exercise protocol used was able to prevent, in septic animals: (1) the increase in body temperature; (2) the increase of lipid peroxidation and reactive species levels in the lung, (3) the increase in adenosine triphosphate levels in serum; (4) the change in the activity of the enzymes ectonucleotidases in lymphocytes, partially; (5) the change in the density of purinergic enzymes and receptors in the lung, and (6) the increase of IL-6 and IL-1ß gene expression. Our results revealed the involvement of purinergic signaling and oxidative damage in the mechanisms by which exercise prevents sepsis aggravations. Therefore, the regular practice of physical exercise is encouraged as a better way to prepare the body against sepsis complications.

Hypothyroidism Enhanced Ectonucleotidases and Acetylcholinesterase Activities in Rat Synaptosomes can be Prevented by the Naturally Occurring Polyphenol Quercetin.

Thyroid hormones have an influence on the functioning of the central nervous system. Furthermore, the cholinergic and purinergic systems also are extensively involved in brain function. In this context, quercetin is a polyphenol with antioxidant and neuroprotective properties. This study investigated the effects of (MMI)-induced hypothyroidism on the NTPDase, 5'-nucleotidase, adenosine deaminase (ADA), and acetylcholinesterase (AChE) activities in synaptosomes of rats and whether the quercetin can prevent it. MMI at a concentration of 20 mg/100 mL was administered for 90 days in the drinking water. The animals were divided into six groups: control/water (CT/W), control/quercetin 10 mg/kg, control/quercetin 25 mg/kg, methimazole/water (MMI/W), methimazole/quercetin 10 mg/kg (MMI/Q10), and methimazole/quercetin 25 mg/kg (MMI/Q25). On the 30th day, hormonal dosing was performed to confirm hypothyroidism, and the animals were subsequently treated with 10 or 25 mg/kg quercetin for 60 days. NTPDase activity was not altered in the MMI/W group. However, treatment with quercetin decreased ATP and ADP hydrolysis in the MMI/Q10 and MMI/Q25 groups. 5'-nucleotidase activity increased in the MMI/W group, but treatments with 10 or 25 mg/kg quercetin decreased 5'-nucleotidase activity. ADA activity decreased in the CT/25 and MMI/Q25 groups. Furthermore, AChE activity was reduced in all groups with hypothyroidism. In vitro tests also demonstrated that quercetin per se decreased NTPDase, 5'-nucleotidase, and AChE activities. This study demonstrated changes in the 5'-nucleotidase and AChE activities indicating that purinergic and cholinergic neurotransmission are altered in this condition. In addition, quercetin can alter these parameters and may be a promising natural compound with important neuroprotective actions in hypothyroidism.

Evaluation of mediators of oxidative stress and inflammation in patients with acute appendicitis.

CONTEXT: This study aims to explore the potential of new inflammatory markers for improving the challenging diagnosis of acute appendicitis (AA). METHODS: Levels of IL-1, IL-6, IL-8, IL-10, CRP, INF-γ, and TNF-α in serum were measured in 73 patients with AA. Oxidative stress and antioxidant enzymes were analyzed. RESULTS: Serum levels of interleukins, TNF-α, and INF-γ were significantly elevated in patients with appendicitis (p < 0.0001), except for IL-10, which presented decreased levels. There were no significant differences in SOD (p = 0.29), CAT (p = 0.19), or TBARS levels (p = 0.18), whereas protein carbonyls presented significant increase (p < 0.0001). CONCLUSION: Evaluating these biomarkers could aid in diagnosing AA.

Rosmarinic acid prevents lipid peroxidation and increase in acetylcholinesterase activity in brain of streptozotocin-induced diabetic rats.

We investigated the efficacy of rosmarinic acid (RA) in preventing lipid peroxidation and increased activity of acetylcholinesterase (AChE) in the brain of streptozotocin-induced diabetic rats. The animals were divided into six groups (n = 8): control, ethanol, RA 10 mg/kg, diabetic, diabetic/ethanol and diabetic/RA 10 mg/kg. After 21 days of treatment with RA, the cerebral structures (striatum, cortex and hippocampus) were removed for experimental assays. The results demonstrated that the treatment with RA (10 mg/kg) significantly reduced the level of lipid peroxidation in hippocampus (28%), cortex (38%) and striatum (47%) of diabetic rats when compared with the control. In addition, it was found that hyperglycaemia caused significant increased in the activity of AChE in hippocampus (58%), cortex (46%) and striatum (30%) in comparison with the control. On the other hand, the treatment with RA reversed this effect to the level of control after 3 weeks. In conclusion, the present findings showed that treatment with RA prevents the lipid peroxidation and consequently the increase in AChE activity in diabetic rats, demonstrating that this compound can modulate cholinergic neurotransmission and prevent damage oxidative in brain in the diabetic state. Thus, we can suggest that RA could be a promising compound in the complementary therapy in diabetes.

Purinergic signaling influences the neuroinflammatory outcomes of a testosterone-derived synthetic in female rats: Resistance training protective effects on brain health.

Physical exercise is recognized as a non-pharmacological approach to treat and protect against several neuroinflammatory conditions and thus to prevent brain disorders. However, the interest in ergogenic resources by athletes and bodybuilding practitioners is widespread and on the rise. These substances shorten the process of performance gain and improve aesthetics, having led to the prominent use and abuse of hormones in the past years. Recent evidence has shown that the purinergic system, composed of adenine nucleotides, nucleosides, enzymes, and receptors, participates in a wide range of processes within the brain, such as neuroinflammation, neuromodulation, and cellular communication. Here, we investigated the effects of the anabolic androgenic steroid (AAS) testosterone (TES) at a dose of 70 mg/kg/week in female rats and the neuroprotective effect of resistance exercise related to the purinergic system and oxidative stress parameters. Our findings showed a decrease in ATP and ADO hydrolysis in treated and trained animals. Furthermore, there was an increase in the density of purinoceptors (P2X7 and A2A) and inflammatory markers (IBA-1, NRLP3, CASP-1, IL-1ß, and IL-6) in the cerebral cortex of animals that received AAS. On the other hand, exercise reversed neuroinflammatory parameters such as IBA-1, NLRP3, CASP-1, and IL-1ß and improved antioxidant response and anti-inflammatory IL-10 cytokine levels. Overall, this study shows that the use of TES without indication or prescription disrupts brain homeostasis, as demonstrated by the increase in neuroinflammation, and that the practice of exercise can protect brain health.

Vitamin D3 mitigates type 2 diabetes induced by a high carbohydrate-high fat diet in rats: Role of the purinergic system.

This study evaluated the effect of vitamin D3 (VIT D3) supplementation on the enzymatic activities and density of ectonucleoside triphosphate diphosphohydrolase (E-NTPDase), ecto-5-nucleotidase (E-5'-NT), adenosine deaminase (ADA), as well as the density of P2 × 7R, P2Y12R, A1R, A2AR receptors, IL-1ß, and oxidative parameters in type 2 diabetic rats. Forty male Wistar rats were fed a high carbohydrate-high fat diet (HCHFD) and received an intraperitoneal injection containing a single dose of streptozotocin (STZ, 35 mg/kg). Animals were divided into four groups: 1) control; 2) control/VIT D3 12 µg/kg; 3) diabetic; and 4) diabetic/VIT D3 12 µg/kg. Results show that VIT D3 reduced blood glucose, ATP hydrolysis, ADA activity, P2Y12R density (platelets), as well as ATP, ADP, and AMP hydrolysis and ADA activity (synaptosomes). Moreover, VIT D3 increased insulin levels and AMP hydrolysis (platelets) and improved antioxidant defense. Therefore, we suggest that VIT D3 treatment modulates hyperglycemia-induced changes via purinergic enzymes and receptor expression, consequently attenuating insulin homeostasis dysregulation in the diabetic state.

Caffeic acid attenuates neuroinflammation and cognitive impairment in streptozotocin-induced diabetic rats: Pivotal role of the cholinergic and purinergic signaling pathways.

The present study evaluated the effect of caffeic acid (CA) on behavioral learning and memory tasks in the diabetic state. We also evaluated the effect of this phenolic acid on the enzymatic activities of acetylcholinesterase, ecto-nucleoside triphosphate diphosphohydrolase, ecto-5-nucleotidase and adenosine deaminase as well as on the density of M1R, α7nAChR, P2×7R, A1R, A2AR, and inflammatory parameters in the cortex and hippocampus of diabetic rats. Diabetes was induced by a single intraperitoneal dose of streptozotocin (55 mg/kg). The animals were divided into six groups: control/vehicle; control/CA 10 and 50 mg/kg; diabetic/vehicle; diabetic/CA 10 and 50 mg/kg, treated by gavage. The results showed that CA improved learning and memory deficits in diabetic rats. Also, CA reversed the increase in acetylcholinesterase and adenosine deaminase activities and reduced ATP and ADP hydrolysis. Moreover, CA increased the density of M1R, α7nAChR, and A1R receptors and reversed the increase in P2×7R and A2AR density in both evaluated structures. In addition, CA treatment attenuated the increase in NLRP3, caspase 1, and interleukin 1ß density in the diabetic state; moreover, it increased the density of interleukin-10 in the diabetic/CA 10 mg/kg group. The results indicated that CA treatment positively modified the activities of cholinergic and purinergic enzymes and the density of receptors, and improved the inflammatory parameters of diabetic animals. Thus, the outcomes suggest that this phenolic acid could improve the cognitive deficit linked to cholinergic and purinergic signaling in the diabetic state.

Resistance physical exercise alleviates lipopolysaccharide-triggered neuroinflammation in cortex and hippocampus of rats via purinergic signaling.

Resistance physical exercise has neuroprotective and anti-inflammatory effects on many known diseases and, therefore, it has been increasingly explored. The way in which this type of exercise exerts these actions is still under investigation. In this study, we aimed to analyze the enzymes and components of the purinergic system involved in the inflammatory process triggered by the P2X7R. Rats were divided into four groups: control, exercise (EX), lipopolysaccharide (LPS), and EX + LPS. The animals in the exercise groups were subjected to a 12-week ladder-climbing resistance physical exercise and received LPS after the last session for sepsis induction. Enzymes activities (NTPDase, 5'-nucleotidase, and adenosine deaminase), purinoceptors' density (P2X7R, A1, and A2A), and the levels of inflammatory indicators (pyrin domain-containing protein 3 (NLRP3), Caspase-1, interleukin (IL)- 6, IL-1B, and tumor necrosis factor (TNF) -α) were measured in the cortex and hippocampus of the animals. The results show that exercise prevented (in the both structures) the increase of: 1) nucleoside-triphosphatase (NTPDase) and 5'-nucleotidase activities; 2) P2X7R density; 3) NLRP3 and Caspase-1; and 4) IL-6, IL-1ß, and TNF-α It is suggested that the purinergic system and the inflammatory pathway of P2X7R are of fundamental importance and influence the effects of resistance physical exercise on LPS-induced inflammation. Thus, the modulation of the P2X7R by resistance physical exercise offers new avenues for the management of inflammatory-related illnesses.

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.

Assessment of sexual behavior and neuromodulation of Cyperus esculentus L. and Tetracarpidium conophorum Müll. Arg dietary supplementation regulating the purinergic system in the cerebral cortex of L-NAME-challenged rats.

This study examined the behavioral responses, purinergic receptor densities, ectonucleotidases (E-NTPDase), adenosine deaminase (ADA) activity, and nitric oxide (NO) levels along with the parameters of oxidative stress-related to erectile function in the cerebral cortex (CC) of L-NAME-challenged rats pretreated with tigernut (TN) and walnut (WN) dietary supplementation. Wistar rats (male) of 70 total animals (250-300 g) were used in this research and hence separated into seven groups (n = 10): Group I: normal control-fed basal diet; Group II: positive control-fed basal diet/L-NAME/Sildenafil citrate (5 mg kg-1  day-1 ); Group III: ED-induced (placed on a basal diet/L-NAME); Group IV: diet supplemented with processed TN (20%)/L-NAME; Group V: diet supplemented with raw TN (20%)/L-NAME; Group VI: diet supplemented with processed WN (20%)/L-NAME; and Group VII placed on a diet supplemented with raw WN (20%)/L-NAME. The rats were pretreated for 2 weeks before the L-NAME (40 mg kg-1  day-1 ) challenge on their respective diet. L-NAME brought about a decrease in the sexual behaviors evaluated while the effect was significantly reversed by supplemented diets containing TN and WN. L-NAME increased the levels of reactive oxygen species and malondialdehyde, E-NTPDase as well as ADA activities, and caused the level of NO in the CC as well as the purinoreceptor densities to be downregulated. Treatments with enriched diets, however, greatly reverse these effects. The behavioral responses and neuromodulatory capacity of the nuts displayed on the CC can, therefore, further support their aphrodisiac property. PRACTICAL APPLICATIONS: The results revealed the ability of tigernut (TN; Cyperus esculentus L.) and walnut (WN; Tetracarpidium conophorum Müll. Arg.) to enhance behavioral responses; modulate purinergic receptor densities, E-NTPDase, and ADA activities; increase NO levels; and prevent oxidative stress related to erectile function in the CC of L-NAME-challenged Wistar rats. The results show that these nuts are useful feeds for both animal and human nutrition.

Diabetes and hypertension: Pivotal involvement of purinergic signaling.

Diabetes mellitus (DM) and hypertension are highly prevalent worldwide health problems and frequently associated with severe clinical complications, such as diabetic cardiomyopathy, nephropathy, retinopathy, neuropathy, stroke, and cardiac arrhythmia, among others. Despite all existing research results and reasonable speculations, knowledge about the role of purinergic system in individuals with DM and hypertension remains restricted. Purinergic signaling accounts for a complex network of receptors and extracellular enzymes responsible for the recognition and degradation of extracellular nucleotides and adenosine. The main components of this system that will be presented in this review are: P1 and P2 receptors and the enzymatic cascade composed by CD39 (NTPDase; with ATP and ADP as a substrate), CD73 (5'-nucleotidase; with AMP as a substrate), and adenosine deaminase (ADA; with adenosine as a substrate). The purinergic system has recently emerged as a central player in several physiopathological conditions, particularly those linked to inflammatory responses such as diabetes and hypertension. Therefore, the present review focuses on changes in both purinergic P1 and P2 receptor expression as well as the activities of CD39, CD73, and ADA in diabetes and hypertension conditions. It can be postulated that the manipulation of the purinergic axis at different levels can prevent or exacerbate the insurgency and evolution of diabetes and hypertension working as a compensatory mechanism.

Neuroprotection elicited by resveratrol in a rat model of hypothyroidism: Possible involvement of cholinergic signaling and redox status.

Both the cholinergic pathway and oxidative stress are important mechanisms involved in the pathogenesis of hypothyroidism, a condition characterized by low levels of thyroid hormone that predispose the patient to brain dysfunction. Phenolic compounds have numerous health benefits, including antioxidant activity. This study evaluates the preventive effects of resveratrol in the cholinergic system and redox status in rats with methimazole-induced hypothyroidism. Hypothyroidism increases acetylcholinesterase (AChE) activity and density in the cerebral cortex and hippocampus and decreases the α7 and M1 receptor densities in the hippocampus. Hypothyroidism also increases cellular levels of reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS), but reduces total thiol content, and catalase and superoxide dismutase activities in the serum. In the cerebral cortex and hippocampus, hypothyroidism increases the levels of ROS and nitrites. In this study, resveratrol (50 mg/kg) treatment prevents the observed increase in AChE in the cerebral cortex, and increases the protein levels of NeuN, a marker of mature neurons. Resveratrol also prevents changes in serum ROS levels and brain structure, as well as the levels of TBARS, total thiol content, and serum catalase enzyme activity. These collective findings suggest that resveratrol has a high antioxidant capacity and can restore hypothyroidism-triggered alterations related to neurotransmission. Thus, it is a promising agent for the prevention of brain damage resulting from hypothyroidism.

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.

Lingonberry Extract Provides Neuroprotection by Regulating the Purinergic System and Reducing Oxidative Stress in Diabetic Rats.

SCOPE: Beneficial effects produced by polyphenolic compounds are used in the treatment of various diseases, including diabetes. Thus it is relevant to investigate the protective effect of lingonberry extract (LB) on the activities of nucleoside triphosphate diphosphohydrolase (NTPDase), 5'-nucleotidase (5'-NT), and adenosine deaminase (ADA); the density of A1, A2A, and P2×7 receptors; production of reactive species (RS); and the levels of thiobarbituric acid reactive substances (TBARS) in the cerebral cortex of streptozotocin-induced diabetic rats. METHODS AND RESULTS: Animals were divided into five groups (n = 10): control/saline; control/LB 50 mg kg-1 ; diabetic/saline; diabetic/LB 25 mg kg-1 ; and diabetic/LB 50 mg kg-1 ; and treated for 30 days. Our results demonstrate that the treatment with LB increased NTPDase activity in the diabetic/LB 50 group compared to diabetic/saline group. Western blot analysis showed that LB restored the density of purinergic receptors to the approximate values of the control/saline group. An increase in the levels of RS and TBARS was observed in the diabetic/saline group compared with the control/saline group, and treatment with LB can prevent this increase. CONCLUSION: This study showed that LB could reverse the modifications found in the diabetic state, suggesting that lingonberry may be a coadjuvant in the treatment of diabetes.

Effects of gallic acid on delta - aminolevulinic dehydratase activity and in the biochemical, histological and oxidative stress parameters in the liver and kidney of diabetic rats.

Diabetes mellitus (DM) is characterised by hyperglycaemia associated with the increase of oxidative stress. Gallic acid has potent antioxidant properties. The aim of this study was to evaluate the effect of gallic acid on the biochemical, histological and oxidative stress parameters in the liver and kidney of diabetic rats. Male rats were divided in groups: control, gallic acid, diabetic and diabetic plus gallic acid. DM was induced in the animals by intraperitoneal injection of streptozotocin (65mg/kg). Gallic acid (30mg/kg) was administered orally for 21days. Our results showed an increase in reactive species levels and lipid peroxidation, and a decrease in activity of the enzymes superoxide dismutase and delta-aminolevulinic acid dehydratase in the liver and kidney of the diabetic animals (P<0.05). Gallic acid treatment showed protective effects in these parameters evaluated, and also prevented a decrease in the activity of catalase and glutathione S-transferase, and vitamin C levels in the liver of diabetic rats. In addition, gallic acid reduced the number of nuclei and increased the area of the core in hepatic tissue, and increased the glomerular area in renal tissue. These results indicate that gallic acid can protect against oxidative stress-induced damage in the diabetic state.

Protective effect of rosmarinic acid against oxidative stress biomarkers in liver and kidney of strepotozotocin-induced diabetic rats.

In the present study, we investigated the efficiency of rosmarinic acid (RA) in preventing the alteration of oxidative parameters in the liver and kidney of diabetic rats induced by streptozotocin (STZ). The animals were divided into six groups (n = 8): control, ethanol, RA 10 mg/kg, diabetic, diabetic/ethanol, and diabetic/RA 10 mg/kg. After 3 weeks of treatment, we found that TBARS levels in liver and kidney were significantly increased in the diabetic/saline group and the administration of RA prevented this increase in the liver and kidney (P < 0.05). Diabetes caused a significant decrease in the activity of superoxide dismutase (SOD) and catalase (CAT) in the diabetes/saline group (P < 0.05). However, the treatment with 10 mg/kg RA (antioxidant) prevented this alteration in SOD and CAT activity in the diabetic RA group (P < 0.05). In addition, RA reverses the decrease in ascorbic acid and non-protein-thiol (NPSH) levels in diabetic rats. The treatment with RA also prevented the decrease in the Delta-aminolevulinic acid dehydratase (ALA-D) activity in the liver and kidney of diabetic rats. Furthermore, RA did not have any effect on glycemic levels. These results indicate that RA effectively reduced the oxidative stress induced by STZ, suggesting that RA is a potential candidate for the prevention and treatment of pathological conditions in diabetic models.