•Apocynin protects against object recognition memory deficit induced by mLFPI.•Apocynin reduces IL-1β, TNF-α NOx contents increased by mLFPI.•Apocynin reduces the oxidative damage and Na+, K+, ATPase ...inhibition induced by mLFPI.•Apocynin reduces the cortical lesion induced by mLFPI.
Traumatic brain injury (TBI) is a devastating disease that commonly causes persistent mental disturbances and cognitive deficits. Although studies have indicated that overproduction of free radicals, especially superoxide (O2-) derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a common underlying mechanism of pathophysiology of TBI, little information is available regarding the role of apocynin, an NADPH oxidase inhibitor, in neurological consequences of TBI. Therefore, the present study evaluated the therapeutic potential of apocynin for treatment of inflammatory and oxidative damage, in addition to determining its action on neuromotor and memory impairments caused by moderate fluid percussion injury in mice (mLFPI). Statistical analysis revealed that apocynin (5mg/kg), when injected subcutaneously (s.c.) 30min and 24h after injury, had no effect on neuromotor deficit and brain edema, however it provided protection against mLFPI-induced object recognition memory impairment 7days after neuronal injury. The same treatment protected against mLFPI-induced IL-1β, TNF-α, nitric oxide metabolite content (NOx) 3 and 24h after neuronal injury. Moreover, apocynin treatment reduced oxidative damage (protein carbonyl, lipoperoxidation) and was effective against mLFPI-induced Na+, K+-ATPase activity inhibition. The present results were accompanied by effective reduction in lesion volume when analyzed 7days after neuronal injury. These data suggest that superoxide (O2-) derived from NADPH oxidase can contribute significantly to cognitive impairment, and that the post injury treatment with specific NADPH oxidase inhibitors, such as apocynin, may provide a new therapeutic approach to the control of neurological disabilities induced by TBI.
Traumatic brain injury (TBI) is a devastating condition that often triggers a sequel of neurological disorders that can last throughout lifespan. From a metabolic viewpoint, the compromising of the ...energy metabolism of the brain has produced evidence linking the severity of brain injury to the extent of disturbances in the cerebral metabolism. The cerebral metabolic crisis, however, displays that regional heterogeneity varies temporally post-injury. It is important to note that energy generation and mitochondrial function are closely related and interconnected with delayed secondary manifestations of brain injury, including early neuromotor dysfunction, cognitive impairment, and post-traumatic epilepsy (PTE). Given the extent of post-traumatic changes in neuronal function and the possibility of amplifying secondary cascades, different therapies designed to minimize damage and retain/restore cellular function after TBI are currently being studied. One of the possible strategies may be the inclusion of ergogenic compounds, which is a class of supplements that typically includes ingredients used by athletes to enhance their performance. The combination of these compounds offers specific physiological advantages, which include enhanced energy availability/metabolism and improved buffering capacity. However, the literature on their effects in certain biological systems and neurological diseases, such as TBI, has yet to be determined. Thus, the present review aims to discuss the role of ergogenic compounds popularly used in secondary damage induced by this neurological injury. In this narrative review, we also discuss how the results from animal studies can be applied to TBI clinical settings.
Traumatic brain injury (TBI) is a public health problem characterized by a combination of immediate mechanical dysfunction of the brain tissue, and secondary damage. Based on the hypothesis that ...selected targets, such as Na+ K+-ATPase are involved in the secondary damage after TBI and modulation of this enzyme activity by triterpene 3β, 6β, 16β-trihidroxilup-20 (29)-ene (TTHL) supports the ethnomedical applications of this plant, we decided to investigate whether previous TTHL treatment interrupts the progression of pathophysiology induced by TBI. Statistical analyses revealed that percussion fluid injury (FPI) increased Na+,K+-ATPase activity in all isoform (α1 and α2/3) 15 min after neuronal injury. The FPI protocol inhibited Na+,K+-ATPase activity total and α1 isoform, increased 3HMK-801 binding but did not alter Dichloro-dihydro-fluorescein diacetate (DCFH-DA) oxidation, carbonylated proteins and free –SH groups 60 min after injury. The increase of immunoreactivity of protein PKC and state of phosphorylation of at Ser16 of Na+,K+-ATPase 60 min after FPI suggest the involvement of PKC on Na+,K+-ATPase activity oscillations characterized by inhibition of total and α1 isoform. Our experimental data also revealed that natural product rich in compounds such as triterpenes (TTHL; 30 mg/kg) attenuates 3HMK-801 binding increase, phosphorylation of the PKC and the Na+,K+-ATPase alpha 1 subunit (Ser16) induced by FPI. The previous TTHL treatment had not effect on motor disability but protected against spatial memory deficit, BDNF, TrKB expression decrease, protein carbonylation and hippocampal cell death 7 days after FPI. These data suggest that TTHL-induced reduction on initial damage limits the long-term secondary degeneration and supports neural repair or behavioral compensation after neuronal injury.
Abstract The methylmalonic acidemia is an inborn error of metabolism (IEM) characterized by methylmalonic acid (MMA) accumulation in body fluids and tissues, causing neurological dysfunction, ...mitochondrial failure and oxidative stress. Although neurological evidence demonstrate that infection and/or inflammation mediators facilitate metabolic crises in patients, the involvement of neuroinflammatory processes in the neuropathology of this organic acidemia is not yet established. In this experimental study, we used newborn Wistar rats to induce a model of chronic acidemia via subcutaneous injections of methylmalonate (MMA, from 5th to 28th day of life, twice a day, ranged from 0.72 to 1.67 μmol/g as a function of animal age). In the following days (29th–31st) animal behavior was assessed in the object exploration test and elevated plus maze. It was performed differential cell and the number of neutrophils counting and interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) levels in the blood, as well as levels of IL-1β, TNF-α, inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in the cerebral cortex were measured. Behavioral tests showed that animals injected chronically with MMA have a reduction in the recognition index (R.I.) when the objects were arranged in a new configuration space, but do not exhibit anxiety-like behaviors. The blood of MMA-treated animals showed a decrease in the number of polymorphonuclear and neutrophils, and an increase in mononuclear and other cell types, as well as an increase of IL-1β and TNF-α levels. Concomitantly, MMA increased levels of IL-1β, TNF-α, and expression of iNOS and 3-NT in the cerebral cortex of rats. The overall results indicate that chronic administration of MMA increased pro-inflammatory markers in the cerebral cortex, reduced immune system defenses in blood, and coincide with the behavioral changes found in young rats. This leads to speculate that, through mechanisms not yet elucidated, the neuroinflammatory processes during critical periods of development may contribute to the progression of cognitive impairment in patients with methylmalonic acidemia.
Hyperammonemia is a common finding in children with methylmalonic acidemia. However, its contribution to methylmalonate-induced excitotoxicty is poorly understood. The aim of this study was to ...evaluate the mechanisms by which ammonia influences in the neurotoxicity induced by methylmalonate (MMA) in mice. The effects of ammonium chloride (NH₄Cl 3, 6, and 12 mmol/kg; s.c.) on electroencephalographic (EEG) and behavioral convulsions induced by MMA (0.3, 0.66, and 1 µmol/2 µL, i.c.v.) were observed in mice. After, ammonia, TNF-α, IL1β, IL-6, nitrite/nitrate (NOx) levels, mitochondrial potential (ΔΨ), reactive oxygen species (ROS) generation, Methyl-Tetrazolium (MTT) reduction, succinate dehydrogenase (SDH), and Na⁺, K⁺-ATPase activity levels were measured in the cerebral cortex. The binding of ³Hflunitrazepam, release of glutamate-GABA; glutamate decarboxylase (GAD) and glutamine synthetase (GS) activity and neuronal damage opening of blood brain barrier (BBB) permeability and cellular death volume were also measured. EEG recordings showed that an intermediate dose of NH₄Cl (6 mmol/kg) increased the duration of convulsive episodes induced by MMA (0.66 μmol/2 μL i.c.v). NH₄Cl (6 mmol/kg) administration also induced neuronal ammonia and NOx increase, as well as mitochondrial ROS generation throughout oxidation of 2,7-dichlorofluorescein diacetate (DCFH-DA) to DCF-RS, followed by GS and GAD inhibition. The NH₄Cl plus MMA administration did not alter cytokine levels, plasma fluorescein extravasation, or neuronal damage. However, it potentiated DCF-RS levels, decreased the ΔΨ potential, reduced MTT, inhibited SDH activity, and increased Na⁺, K⁺-ATPase activity. NH₄Cl also altered the GABA cycle characterized by GS and GAD activity inhibition, ³Hflunitrazepam binding, and GABA release after MMA injection. On the basis of our findings, the changes in ROS and reactive nitrogen species (RNS) levels elicited by ammonia alter the glycine/glutamate (GABA) cycle and contribute to MMA-induced excitability.
A growing body of evidence indicates that creatine (Cr) exerts beneficial effects on a variety of pathologies where energy metabolism and oxidative stress play an etiological role. However, the ...benefits of Cr treatment for epileptics are still shrouded in controversy. In the present study, we found that acute Cr treatment (300 mg/kg, p.o.) prevented the increase in electroencephalographic wave amplitude typically elicited by PTZ (30, 45 or 60 mg/kg, i.p.). Cr treatment also increased the latency periods of first myoclonic jerks, lengthened the latency periods of the generalized tonic–clonic seizures and reduced the time spent in the generalized tonic–clonic seizures induced by PTZ (60 mg/kg). Administration of PTZ (all doses) decreased Na
+
, K
+
-ATPase activity as well as adenosine triphosphate (ATP) and adenosine diphosphate levels in the cerebral cortex, but Cr treatment prevented these effects. Cr administration also prevented increases in xanthine oxidase activity, adenosine monophosphate levels, adenosine levels, inosine levels and uric acid levels that normally occur after PTZ treatment (60 mg/kg, i.p.). We also showed that Cr treatment increased the total Cr (Cr + PCr) content, creatine kinase activity and the mitochondrial membrane potential (ΔΨ) in the cerebral cortex. In addition, Cr prevented PTZ-induced mitochondrial dysfunction characterized by decreasing ΔΨ, increasing thiobarbituric acid-reactive substance levels and increasing protein carbonylation. These experimental findings reinforce the idea that mitochondrial dysfunction plays a critical role in models of epileptic seizures and suggest that buffering brain energy levels through Cr treatment may be a promising therapeutic approach for the treatment of this neurological disease.
Rationale
There are evidences indicating the role of kinins in pathophysiology of traumatic brain injury, but little is known about their action on memory deficits.
Objectives
Our aim was to ...establish the role of bradykinin receptors B
1
(B
1
R) and B
2
(B
2
R) on the behavioral, biochemical, and histologic features elicited by moderate lateral fluid percussion injury (mLFPI) in mice.
Methods
The role of kinin B
1
and B
2
receptors in brain damage, neuromotor, and cognitive deficits induced by mLFPI, was evaluated by means of subcutaneous injection of B
2
R antagonist (HOE-140; 1 or 10 nmol/kg) or B
1
R antagonist (des-Arg9-Leu8-bradykinin (DAL-Bk; 1 or 10 nmol/kg) 30 min and 24 h after brain injury. Brain damage was evaluated in the cortex, being considered as lesion volume, inflammatory, and oxidative damage. The open field and elevated plus maze tests were performed to exclude the nonspecific effects on object recognition memory test.
Results
Our data revealed that HOE-140 (10 nmol/kg) protected against memory impairment. This treatment attenuated the brain edema, interleukin-1β, tumor necrosis factor-α, and nitric oxide metabolites content elicited by mLFPI. Accordingly, HOE-140 administration protected against the increase of nicotinamide adenine dinucleotide phosphate oxidase activity, thiobarbituric-acid-reactive species, protein carbonylation generation, and Na
+
K
+
ATPase inhibition induced by trauma. Histologic analysis showed that HOE-140 reduced lesion volume when analyzed 7 days after brain injury.
Conclusions
This study suggests the involvement of the B
2
receptor in memory deficits and brain damage caused by mLFPI in mice.
Administration of the compound triterpene 3β, 6β, 16β-trihidroxilup-20(29)-ene (TTHL) resulted in antinociceptive activity in several pain models in mice. Because pain and epilepsy have common ...mechanisms, and several anticonvulsants are clinically used to treat painful disorders, we investigated the anticonvulsant potential of TTHL. Behavioral and electrographic recordings revealed that pretreatment with TTHL (30 mg/kg; i.g.) increased the latencies to the first clonic seizure to the tonic–clonic and reduced the duration of the generalized seizures induced by the GABAA receptor antagonist PTZ (80 g; i.p.). The TTHL pretreatment also protected against PTZ-induced deleterious effects, as characterized by protein carbonylation, lipid peroxidation, 3H glutamate uptake and the inhibition of Na+,K+-ATPase (subunits α1 and α2/α3). Although TTHL did not exhibit DPPH, ABTS radical scavenging activity per se and does not alter the binding of 3Hflunitrazepam to the benzodiazepinic site of the GABAA receptor, this compound was effective in preventing behavioral and EEG seizures, as well as the inhibition of Na+,K+-ATPase induced by ouabain. These results suggest that the protection against PTZ-induced seizures elicited by TTHL is due to Na+,K+-ATPase activity maintenance. In fact, experiments in homogenates of the cerebral cortex revealed that PTZ (10 mM) reduced Na+,K+-ATPase activity and that previous incubation with TTHL (10 μM) protected against this inhibition. Collectively, these data indicate that the protection exerted by TTHL in this model of convulsion is not related to antioxidant activity or GABAergic activity. However, these results demonstrated that the effective protection of Na+,K+-ATPase elicited by this compound protects against the damage due to neuronal excitability and oxidation that is induced by PTZ.
In the present study we revealed that previous administration of TTHL protected against the seizures induced by the GABAA receptor antagonist PTZ ▪. TTHL pretreatment also protected against PTZ-induced deleterious effects, characterized here by reactive oxygen species (ROS), 3H glutamate uptake and Na+,K+-ATPase inhibition (subunits α1 and α2/α3) ▪. Although TTHL has no antioxidant activity per se and not alter the 3Hflunitrazepam binding to benzodiazepinic site of GABAA receptors and Glutamate, ▪ this triterpene protected against the seizures induced by Na+,K+-ATPase inhibitor (ouabain). These results suggest that effective protection of selected targets as Na+,K+-ATPase ▪ elicited by this triterpene protects against neuronal excitability and oxidative damage elicited by PTZ. Display omitted
► TTHL protects against pentylenetetrazol-induced electroencephalography seizures. ► Na+,K+-ATPase maintenance elicited by TTHL protects against toxicity induced by PTZ. ► TTHL has no antioxidant activity per se and not alter the 3Hflunitrazepam binding. ► TTHL attenuates EEG seizures induced by Na+,K+-ATPase inhibitor (ouabain). ► Anticonvulsant action elicited by TTHL involves Na+,K+-ATPase activity maintenance.
Rationale There are evidences indicating the role of kinins in pathophysiology of traumatic brain injury, but little is known about their action on memory deficits. Objectives Our aim was to ...establish the role of bradykinin receptors B.sub.1(B.sub.1R) and B.sub.2(B.sub.2R) on the behavioral, biochemical, and histologic features elicited by moderate lateral fluid percussion injury (mLFPI) in mice. Methods The role of kinin B.sub.1 and B.sub.2 receptors in brain damage, neuromotor, and cognitive deficits induced by mLFPI, was evaluated by means of subcutaneous injection of B.sub.2R antagonist (HOE-140; 1 or 10 nmol/kg) or B.sub.1R-antagonist (des-Arg9-Leu8-bradykinin (DAL-Bk; 1 or 10 nmol/kg) 30 min and 24 h after brain injury. Brain damage was evaluated in the cortex, being considered as lesion volume, inflammatory, and oxidative damage. The open field and elevated plus maze tests were performed to exclude the nonspecific effects on object recognition memory test. Results Our data revealed that HOE-140 (10 nmol/kg) protected against memory impairment. This treatment attenuated the brain edema, interleukin-1|3, tumor necrosis factor-a, and nitric oxide metabolites content elicited by mLFPI. Accordingly, HOE-140 administration protected against the increase of nicotinamide adenine dinucleotide phosphate oxidase activity, thiobarbituric-acid-reactive species, protein carbonylation generation, and Na.sup.+ K.sup.+ ATPase inhibition induced by trauma. Histologic analysis showed that HOE-140 reduced lesion volume when analyzed 7 days after brain injury. Conclusions This study suggests the involvement of the B.sub.2 receptor in memory deficits and brain damage caused by mLFPI in mice. Keywords Traumatic brain injury * Bradykinin * Inflammation * Object recognition task * Oxidative stress
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