Byrsonima sericea Ethanol Extract Protected PC12 Cells from the Oxidative Stress and Apoptosis Induced by 6-Hydroxydopamine.

Parkinson's disease is characterized by the progressive loss of dopaminergic neurons in the nigrostriatal pathway and oxidative stress is one of the main mechanisms that lead to neuronal death in this disease. Previous studies have shown antioxidant activity from the leaves of Byrsonima sericea, a plant of the Malpighiaceae family. This study aimed to evaluate the cytoprotective activity of the B. sericea ethanolic extract (BSEE) against the cytotoxicity induced by 6-hydroxydopamine (6-OHDA) in PC12 cells, an in vitro model of parkinsonism. The identification of phenolic compounds in the extract by HPLC-DAD revealed the presence of geraniin, rutin, isoquercetin, kaempferol 3-O-ß-rutinoside, and quercetin. The BSEE (75-300 µg/mL) protected PC12 cells from toxicity induced by 6-OHDA (25 µg/mL), protected cell membrane integrity and showed antioxidant activity. BSEE was able to decrease nitrite levels, glutathione depletion, and protect cells from 6-OHDA-induced apoptosis. Thus, we suggest that the BSEE can be explored as a possible cytoprotective agent for Parkinson's disease due to its high antioxidant capacity and anti-apoptotic action.

Blackberry extract prevents lipopolysaccharide-induced depressive-like behavior in female mice: implications for redox status, inflammation, and brain enzymes.

ABSTRACTThis study evaluated the effects of Rubus sp. extract on behavioral and neurochemical parameters in female mice submitted to experimental model of depression induced by lipopolysaccharide (LPS). The results indicated that Rubus sp. extract protected against depressive-like behavior induced by LPS. Moreover, the administration of Rubus sp. extract was effective in preventing the increase in reactive species and nitrites levels, as well as the decrease in catalase activity induced by LPS in the cerebral cortex. In the serum, the Rubus sp. extract was effective in preventing the decrease in catalase activity induced by LPS. Treatment with Rubus sp. extract attenuated the increase in acetylcholinesterase activity induced by LPS in the cerebral cortex. Finally, blackberry extract also downregulated IL-1ß levels in cerebral cortex. In conclusion, our findings demonstrated that treatment with Rubus sp. exerted antidepressant, antioxidant, anticholinesterase and anti-inflammatory effects in a model of depressive - like behavior induced by LPS in female mice. This highlights Rubus sp. as a potential therapeutic agent for individuals with major depressive disorder.

Blueberry Extract Modulates Brain Enzymes Activities and Reduces Neuroinflammation: Promising Effect on Lipopolysaccharide-Induced Depressive-Like Behavior.

Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders with high rates of prevalence and mortality. MDD is pathophysiologically complex, and treatment options are limited. Blueberries are rich in polyphenols and have neuroprotective potential. The aim of this study was to investigate the effects of blueberry extract on neuroinflammatory and neuroplasticity parameters, as well as Na+/K+-ATPase, monoamine oxidase-A (MAO-A), and acetylcholinesterase (AChE) activities in the cerebral cortex and hippocampus of mice subject to lipopolysaccharide (LPS)-induced depressive-like behavior. We also analyzed the interaction between anthocyanins and indoleamine 2 3-dioxygenase (IDO). Male Swiss mice (60-day-old) received vehicle, fluoxetine (20 mg/kg), or blueberry extract (100 or 200 mg/kg) intragastrically for 7 days before intraperitoneal LPS (0.83 mg/kg) injection. Twenty-four hours after LPS administration, the mice were subjected to behavioral tests. Both fluoxetine and blueberry extract (200 mg/kg) decreased the immobility time in the forced swim test, without affecting locomotor activity. Fluoxetine attenuated the decrease of Na+/K+-ATPase in the cerebral cortex, while blueberry extract promoted this same effect in the hippocampus. Additionally, fluoxetine and blueberry extract attenuated the decrease in the activity of MAO-A in the hippocampus. Blueberry extract (200 mg/kg) also prevented LPS-induced increase in AChE activity in the hippocampus as well as LPS upregulation of relative mRNA expression of tumor necrosis factor alpha, interleukin (IL)-1ß, and IL-10 in the cerebral cortex. Molecular docking analysis revealed binding sites for malvidin 3-galactoside (- 7.8 kcal/mol) and malvidin 3-glucoside (- 7.9 kcal/mol) residues with IDO. Taken together, these results indicate that blueberry extract improved depression-like behavior and attenuated the neurochemical and molecular changes in the brains of mice challenged with LPS.

Chemical hypermethioninemia in young mice: oxidative damage and reduction of antioxidant enzyme activity in brain, kidney, and liver.

High levels of methionine (Met) and its metabolites, such as methionine sulfoxide (MetO), found in hypermethioninemia, can be detrimental to the body; however, the underlying mechanisms are still uncertain. Using a recently standardized protocol, the aim of this study was to investigate the effects of chronic administration of Met and/or MetO on parameters of oxidative damage in the total brain, liver, and kidney of young mice. Swiss male mice were subcutaneously injected with Met and MetO at concentrations of 0.35-1.2 g/kg body weight and 0.09-0.3 g/kg body weight, respectively, from the 10th-38th day post-birth, while the control group was treated with saline solution. Results showed that Met and/or MetO caused an increase in reactive oxygen species (ROS) and lipoperoxidation, along with a reduction of superoxide dismutase (SOD) and catalase (CAT) activities in the brain. In the liver, Met and/or MetO enhanced ROS and nitrite levels, and reduced SOD, CAT, and delta aminolevulinic dehydratase activities. The effects on the kidney were an increase in ROS production and SOD activity, and a reduction in thiol content and CAT activity. These data demonstrated the contribution of redox imbalance to the systemic changes found in patients with hypermethioninemia. In conclusion, our findings may help future studies to better understand the pathophysiological mechanisms of hypermethioninemia as well as contribute to the search for new therapeutic agents for this pathology.

Therapeutic potential of blackberry extract in the preventing memory deficits and neurochemical alterations in the cerebral cortex, hippocampus and cerebellum of a rat model with amnesia.

The blackberry (Rubus sp.) is a popular fruit that has a high concentration of phenolic compounds. Pharmacological investigations have demonstrated the important biological activities of the blackberry extract, such as neuroprotective actions. This study aimed to evaluate the effects of blackberry extract on memory and neurochemical parameters in rats subjected to scopolamine (SCO)-induced amnesia. Male rats were divided into five groups: I, control (saline); II, SCO; III, SCO + Rubus sp. (100 mg/kg); IV, SCO + Rubus sp. (200 mg/kg); and V, SCO + donepezil (5 mg/kg). Blackberry extract and donepezil were orally administered for 10 days. On day 11, group I received saline, and groups II, III, IV, and V received SCO (1 mg/kg) intraperitoneally after object recognition behavioral training. Twenty-four hours after the training session, animals were subjected to an object recognition test. Finally, the animals were euthanized, and the cerebral cortex, hippocampus, and cerebellum were collected to evaluate the oxidative stress and acetylcholinesterase (AChE) activity. Rubus sp. extract prevented memory impairment induced by SCO in a manner similar to that of donepezil. Additionally, Rubus sp. extract and donepezil prevented the increase in AChE activity induced by SCO in all the evaluated brain structures. SCO induced oxidative damage in the cerebral cortex, hippocampus, and cerebellum, which was prevented by Rubus sp. and donepezil. Our results suggest that the antioxidant and anticholinesterase activities of Rubus sp. are associated with memory improvement; hence, it can potentially be used for the treatment of neurodegenerative diseases.

LPS-induced impairment of Na+/K+-ATPase activity: ameliorative effect of tannic acid in mice.

Acetylcholine is an excitatory neurotransmitter that modulates synaptic plasticity and communication, and it is essential for learning and memory processes. This neurotransmitter is hydrolyzed by acetylcholinesterase (AChE), which plays other cellular roles in processes such as inflammation and oxidative stress. Ion pumps, such as Na+/K+-ATPase and Ca2+-ATPase, are highly expressed channels that derive energy for their functions from ATP hydrolysis. Impairment of the cholinergic system and ion pumps is associated with neuropsychiatric diseases. Major depressive disorder (MDD) is an example of a complex disease with high morbidity and a heterogenous etiology. Polyphenols have been investigated for their therapeutic effects, and tannic acid (TA) has been reported to show neuroprotective and antidepressant-like activities. Animal models of depression-like behavior, such as lipopolysaccharide (LPS)-induced models of depression, are useful for investigating the pathophysiology of MDD. In this context, effects of TA were evaluated in an LPS-induced mouse model of depression-like behavior. Animals received TA for 7 days, and on the last day of treatment, LPS (830 µg/kg) was administered intraperitoneally. In vitro exposure of healthy brain to TA decreased the AChE activity. Additionally, this enzyme activity was decreased in cerebral cortex of LPS-treated mice. LPS injection increased the activity of Ca2+-ATPase in the cerebral cortex but decreased the enzyme activity in the hippocampus. LPS administration decreased Na+/K+-ATPase activity in the cerebral cortex, hippocampus, and striatum; however, TA administration prevented these changes. In conclusion, tannins may affect Na+/K+-ATPase and Ca2+-ATPase activities, which is interesting in the context of MDD.

Neuroprotective Effect of Chlorogenic Acid in an Animal Model of Sporadic Alzheimer's Disease Induced by Streptozotocin.

Alzheimer's Disease is a degenerative neurological condition which leads to a decline in memory and cognitive function. Chlorogenic Acid (CGA) presents properties including neuroprotective, antioxidant and anti-inflammatory. The aim of this study was to examine the impact of CGA on cognitive impairments, neuroinflammation and neuronal damage in mice submitted to an experimental model of Sporadic Alzheimer Disease (SAD) induced by intracerebroventricular administration of streptozotocin (ICV-STZ). Male Swiss mice received bilateral ICV-STZ injections (3 mg/Kg) on days 1 and 3. The treatment with CGA (5 mg/Kg, orally) or vehicle (water, orally), was initiated and continued for 26 days, starting 2 h after the second induction procedure. At first, there was no change in serum glucose levels after SAD induction. ICV-STZ induces impairments in aversive, recognition, and spatial memory, while CGA treatment significantly alleviated these memory deficits. Furthermore, locomotor activity, working memory, and anxiety-related activities remained unaffected by the treatments. CGA treatment protects against ICV-STZ-induced increase in the nitrite/nitrate and TBARS levels. ICV-STZ induced a reduction in viable cells, depletion of BDNF, and triggered astrogliosis and microgliosis in the cortex and hippocampus. Treatment with CGA preserves viable cell count in the prefrontal cortex, CA1, and CA3 regions of the hippocampus. Additionally, it prevented BDNF depletion in the prefrontal cortex and hippocampus (CA1, CA3, and DG regions), and mitigated astrogliosis and microgliosis in the prefrontal cortex and hippocampus (CA1, CA3, and DG regions). These findings indicate the neuroprotective effects of CGA, underscoring their potential as therapeutic agents or adjuncts in the treatment of SAD.

Senolytics prevent age-associated changes in female mice brain.

PURPOSE: Considering that the combination of dasatinib and quercetin (D + Q) demonstrated a neuroprotective action, as well as that females experience a decline in hormonal levels during aging and this is linked to increased susceptibility to Alzheimer's disease, in this study we evaluated the effect of D + Q on inflammatory and oxidative stress markers and on acetylcholinesterase and Na+, K+-ATPase activities in brain of female mice. METHODS: Female C57BL/6 mice were divided in Control and D (5 mg/kg) + Q (50 mg/kg) treated. Treatment was administered via gavage for three consecutive days every two weeks starting at 30 days of age. The animals were euthanized at 6 months of age and at 14 months of age. RESULTS: Results indicate an increase in reactive species (RS), thiol content and lipid peroxidation followed by a reduction in nitrite levels and superoxide dismutase, catalase and glutathione S-transferase activity in the brain of control animals with age. D+Q protected against age-associated increase in RS and catalase activity reduction. Acetylcholinesterase activity was increased, while Na+, K+-ATPase activity was reduced at 14 months of age and D+Q prevented this reduction. CONCLUSION: These data demonstrate that D+Q can protect against age-associated neurochemical alterations in the female brain.

Impact of gallic acid on tumor suppression: Modulation of redox homeostasis and purinergic response in in vitro and a preclinical glioblastoma model.

Glioblastoma (GBM) is the deadliest primary brain tumor in adults due to the high rate of relapse with current treatment. Therefore, the search for therapeutic alternatives is urgent. Gallic acid (GA), a potent natural antioxidant, has antitumor and modulatory actions on purinergic signaling. In this study, we investigated the cytotoxic effects of GA on the rat GBM (C6) cell line and on astrocyte culture and analyzed its role in regulating oxidative stress and purinergic enzymes involved in GBM proliferation. Cells were exposed to GA from 50 to 400 µM for 24 and/or 48 h. Next, the effect of GA was evaluated in the preclinical model of GBM. Wistar rats were treated with 50 or 100 mg/kg of GA for 15 days, and cerebral and systemic redox status and degradation of adenine nucleotides and nucleosides in circulating platelets, lymphocytes, and serum were evaluated. Our results demonstrated that GA has selective anti-glioma activity in vitro, without inducing cytotoxicity in astrocyte. Furthermore, GA prevented oxidative stress and changes in the hydrolysis of nucleotides in GBM cells. The anti-glioma effect was also observed in vivo, as GA reduced tumor volume by 90%. Interestingly, GA decreased the oxidative damage induced by a tumor in the brain, serum, and platelets, and, also prevented changes in the degradation of nucleotides and nucleosides in lymphocytes, platelets, and serum. These results indicate, for the first time, the therapeutic potential of GA in a preclinical model of GBM, whose effects may be related to its role in redox and purinergic modulation.