Parkinson's disease (PD) is characterized by progressive motor impairment attributed to progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta. In addition to an ...accumulation of iron, there is also an increased production of reactive oxygen/nitrogen species (ROS/RNS) and inflammatory markers. These observations suggest that iron dyshomeostasis may be playing a key role in neurodegeneration. However, the mechanisms underlying this metal-associated oxidative stress and neuronal damage have not been fully elucidated. To determine peripheral levels of iron, ferritin, and transferrin in PD patients and its possible relation with oxidative/nitrosative parameters, whilst attempting to identify a profile of peripheral biomarkers in this neurological condition. Forty PD patients and 46 controls were recruited to compare serum levels of iron, ferritin, transferrin, oxidative stress markers (superoxide dismutase (SOD), catalase (CAT), nitrosative stress marker (NOx), thiobarbituric acid reactive substances (TBARS), non-protein thiols (NPSH), advanced oxidation protein products (AOPP), ferric reducing ability of plasma (FRAP) and vitamin C) as well as inflammatory markers (NTPDases, ecto-5'-nucleotidase, adenosine deaminase (ADA), ischemic-modified albumin (IMA) and myeloperoxidase). Iron levels were lower in PD patients, whereas there was no difference in ferritin and transferrin. Oxidative stress (TBARS and AOPP) and inflammatory markers (NTPDases, IMA, and myeloperoxidase) were significantly higher in PD, while antioxidants FRAP, vitamin C, and non-protein thiols were significantly lower in PD. The enzymes SOD, CAT, and ecto-5'-nucleotidase were not different among the groups, although NOx and ADA levels were significantly higher in the controls. Our data corroborate the idea that ROS/RNS production and neuroinflammation may dysregulate iron homeostasis and collaborate to reduce the periphery levels of this ion, contributing to alterations observed in the pathophysiology of PD.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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•Status epilepticus is a neurological life-threatening condition.•Beta-caryophyllene is a CB2R agonist with broad therapeutic potential.•Beta-caryophyllene attenuates short-term ...seizure recurrence after status epilepticus.•Beta-caryophyllene protects against blood-brain-barrier breakdown.•Seizure recurrence correlates positively with blood-brain-barrier breakdown.
Status epilepticus (SE) is a neurological life-threatening condition, resulting from the failure of the mechanisms responsible for seizure termination. SE is often pharmacoresistant and associated with significant morbidity and mortality. Hence, ceasing or attenuating SE and its consequences is of fundamental importance. Beta-caryophyllene is a functional CB2 receptor agonist and exhibit a good safety profile. Besides, it displays beneficial effects in several experimental conditions, including neuroprotective activity. In the present study we aimed to investigate the effects of beta-caryophyllene on pilocarpine-induced SE.
Wistar rats were submitted to pilocarpine-induced SE and monitored for 24 h by video and EEG for short-term recurrence of seizure activity (i.e. seizures occurring within 24 h after termination of SE). Rats received beta-caryophyllene (100 mg/kg, ip) at 1, 8- and 16-hours after SE. Twenty-four hours after SE we evaluated sensorimotor response, neuronal damage (fluoro jade C staining) and serum albumin infiltration into brain parenchyma.
Beta-caryophyllene-treated animals presented fewer short-term recurrent seizures than vehicle-treated counterparts, suggesting an anticonvulsant effect after SE. Behavioral recovery from SE and the number of fluoro jade C positive cells in the hippocampus and thalamus were not modified by beta-caryophyllene. Treatment with beta-caryophyllene attenuated the SE-induced increase of albumin immunoreactivity in the hippocampus, indicating a protective effect against blood-brain-barrier breakdown.
Given the inherent difficulties in the treatment of SE and its consequences, present results suggest that beta-caryophyllene deserve further investigation as an adjuvant therapeutic strategy for SE.
Several studies demonstrated the toxicity of aspartame (ASP) and aflatoxin B1 (AFB1) in preclinical models. Although the majority of these reports assessed the toxic effects of each substance ...separately, their concomitant exposure and hazardous consequences are scarce. Importantly, the deleterious effects at the central nervous system caused by ASP and AFB1 co‐exposure are rarely addressed. We evaluated if concomitant exposure to AFB1 and ASP would cause behavioral impairment and alteration in oxidative status of the brain in male rats. Animals received once a day for 14 days AFB1 (250 µg/kg, intragastric gavage i.g.), ASP (75 mg/kg, i.g.), or both substances (association). On day 14, they were subjected to behavioral evaluation, and biochemical and molecular parameters of oxidative status were measured in the cerebral cortex and hippocampus. In the open field test, AFB1 and combination treatments modified the motor, exploratory, and grooming behavior. In the splash test, all treatments caused a reduction in grooming time compared to the control group. An increase in thiobarbituric acid‐reactive substances content induced by AFB1 and combination treatments was observed. The antioxidant defenses (vitamin C, nonprotein sulfhydryl, and ferric reducing antioxidant power) were impaired in all groups compared to control. Regarding molecular evaluation, mitochondrial superoxide dismutase‐2 immunoreactivity decreased after AFB1 or ASP exposition in the hippocampus. Thus, co‐exposure to ASP and AFB1 was potentially more toxic because it aggravated behavioral impairments and oxidative status disbalance in comparison to the groups that received only ASP or AFB1. Therefore, our data suggest that those substances caused a disruption in brain homeostasis.
The MnSOD Ala16Val single nucleotide polymorphism (SNP) has been associated with different diseases. However, there are scarcely studies relating this SNP in epilepsy, a neurologic disease that ...involves some interacting pathways, such as apoptotic and inflammatory factors. In this sense, we decided to investigate the relationship of MnSOD Ala16Val SNP with apoptotic markers in epilepsy and its relation with inflammatory pathway and seizure type. Ninety subjects were evaluated (47 epilepsies; 43 controls) by questionnaires and laboratorial exams. We observed a higher percentage of VV genotype in the epilepsy group when compared to the control group. IL-1β, IL-6, caspase-1, and caspase-3 levels were increased in the epilepsy group (VV genotype). Furthermore, an important correlation between IL-1β vs. caspase-1 and IL-6 vs. caspase-3 was observed in the epilepsy group (VV genotype). The epilepsy group which presented generalized seizures also demonstrated a positive correlation between IL-1β vs. CASP1 and IL-6 vs. CASP3. Thus, it is a plausible propose that epilepsy patients with VV genotype and generalized seizures present a worse inflammatory and apoptotic status. Our findings suggest that the knowledge of MnSOD Ala16Val polymorphism existence is important to evaluate molecular mechanisms associated to seizure and improve the treatment of these patients.
•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.
Objective: We investigated the metabolic profile, reactive species production, and inflammatory parameters in patients with epilepsy. Furthermore, we investigated whether there is any relationship ...between these parameters and seizure type.
Methods: Patients with epilepsy (n=43) and healthy subjects (control group; n=41) were recruited to participate in the study. Initially, the participants were submitted to a clinical questionnaire and patients with epilepsy were classified according to seizure type. Metabolic markers and inflammatory and oxidative factors were also measured in specific blood samples. We compared these results with data from the control subjects.
Results: Statistical analyses showed that patients with epilepsy presented with higher levels of glycolipid, oxidative stress, and inflammatory parameters compared to the control subjects. Interestingly, patients with generalized seizures presented with higher MnSOD activity and metabolic parameters (total cholesterol, low‐density lipoprotein, glucose and triglyceride levels) compared to the partial seizure and control groups. Furthermore, patients with generalized epilepsy demonstrated a significant correlation between TNF‐α and caspase 8 (p<0.05), caspase 3 (p<0.05), and Picogreen (p<0.001).
Significance: This study supports evidence that the levels of inflammatory, glycolipid, and oxidative factors are higher in epilepsy patients, especially those with generalized epilepsy.
The manganese-dependent superoxide dismutase (MnSOD) Ala16Val single nucleotide polymorphism (SNP) has shown to be associated to risk factors of vascular diseases. Brain-Derived Neurotrophic Factor ...(BDNF) plays an essential role in the plasticity and neuronal regeneration of the brain after vascular injuries. However, little is known about interaction between MnSOD Ala16Val SNP on stroke, a frequent neurologic disease that involves various interacting pathways, such as vascular dysfunctions, inflammation, and neurotrophic factors. In this sense, the objective of this study was to investigate the relationship between MnSOD Ala16Val SNP with BDNF levels on stroke and also its influence on nitrosative stress, inflammatory, apoptotic, and DNA damage parameters. For this, 88 subjects were investigated, 44 subjects poststroke and 44 healthy controls. Questionnaires were applied to clinical characteristics and after laboratorial exams were collected. We analyzed levels of oxidative/nitrosative stress, inflammatory, apoptotic, and DNA damage markers. We showed a higher proportion of VV genotype in poststroke as compared to healthy subjects. Nitrite/nitrate, Tumor Necrosis Factor-α, Caspase 3 (CASP 3) and 8 (CASP 8) activation, Acethylcholinesterase (AChE), and Picogreen levels were higher in VV poststroke group, as well as BDNF and ACh levels were lower in VV and AV poststroke. We may suggest that V allele carries a worse outcome profile after stroke, relating to nitrosative stress, inflammatory, and apoptotic response. These events associated to a BDNF reduction, probably, contribute to the appearance or reincidence of stroke.
Epilepsy is characterized by a predisposition to generate recurrent and spontaneous seizures; it affects millions of people worldwide. Status epilepticus (SE) is a severe type of seizure. In this ...context, screening potential treatments is very important. In the present study, we evaluated the beneficial effects of rosmarinic acid (RA) in pilocarpine-induced in vitro and in vivo models of epileptiform activity. Using an in vitro model in combined entorhinal cortex-hippocampal from Wistar rats we evaluated the effects of RA (10 µg/mL) on the lactate release and a glucose fluorescent analogue, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NDBG), after incubation in high potassium aCSF supplemented or not with pilocarpine. In the in vivo model,
was induced in male C57BL/6 mice by pilocarpine. At 1, 24, and 48 h after the end of
mice were treated with RA (30 mg/kg/v.o.). We evaluated the neuromotor impairment by neuroscore tests and protein carbonyl levels in the cerebral cortex. In both in vitro models, RA was able to decrease the stimulated lactate release, while no effect on 2-NBDG uptake was found. RA has beneficial effects in models of epileptiform activity in vivo and in vitro. We found that RA treatment attenuated
-induced neuromotor impairment at the 48 h timepoint. Moreover, post-
treatment with RA decreased levels of protein carbonyls in the cerebral cortex of mice when compared to their vehicle-treated counterparts. Importantly, RA was effective in a model of
which is relevant for the human condition. The present data add to the literature on the biological effects of RA, which could be a good candidate for add-on therapy in epilepsy.
Summary Cyclooxygenases (COXs) are rate-limiting enzymes in the metabolic pathways in which arachidonic acid is converted to prostaglandins. COX-2 is the isoform induced at injury/inflammation sites ...and expressed constitutively in a few tissues, such as the central nervous system, and plays a role in neurodegenerative diseases associated with increased excitatory activity. However, the role of COX-2 and its main product, prostaglandin E2 (PGE2 ), in the convulsive states is not fully established. In this study we showed that the selective COX-2 inhibitor, celecoxib (at the dose of 2 mg/kg, but not at the doses of 0.2 or 20 mg/kg, p.o.), protects against the seizures induced by pentylenetetrazol (PTZ, 60 mg/kg, i.p.). The role of PGE2 in the convulsions induced by PTZ was further investigated by administering anti-PGE2 antibodies (4 μg/2 μl, i.c.v.), and assessing electroencephalographic changes induced by PTZ (PTZ, 60 mg/kg, i.p.). Anti-PGE2 antibodies attenuated PTZ-induced seizures in rats. In addition, combining PGE2 (100 ng/2 μl, i.c.v.) with a subconvulsant dose of PTZ (20 mg/kg, i.p.) caused seizures, further supporting a role for this prostaglandin in the convulsions induced by PTZ. Finally, we showed that the anticonvulsant action of celecoxib (2 mg/kg, p.o.) was reversed by the intracerebroventricular administration of PGE2 (10 ng/2 μl, i.c.v.). These data constitute strong converging pharmacological evidence supporting a facilitatory role for the COX-2/PGE2 pathway in the seizures induced by PTZ. However, whether selective COX-2 inhibitors are safer anti-inflammatory drugs for epileptic patients than nonspecific inhibitors remains to be determined.
Dysfunction of basal ganglia neurons is a characteristic of glutaric acidemia type I (GA-I), an autosomal recessive inherited neurometabolic disease characterized by deficiency of glutaryl-CoA ...dehydrogenase (GCDH) and accumulation of glutaric acid (GA). The affected patients present clinical manifestations such as motor dysfunction and memory impairment followed by extensive striatal neurodegeneration. Knowing that there is relevant striatal dysfunction in GA-I, the purpose of the present study was to verify the performance of young rats chronically injected with GA in working and procedural memory test, and whether
N
-acetylcysteine (NAC) would protect against impairment induced by GA. Rat pups were injected with GA (5 μmol g body weight
−1
, subcutaneously; twice per day; from the 5th to the 28th day of life) and were supplemented with NAC (150 mg/kg/day; intragastric gavage; for the same period). We found that GA injection caused delay procedural learning; increase of cytokine concentration, oxidative markers, and caspase levels; decrease of antioxidant defenses; and alteration of acetylcholinesterase (AChE) activity. Interestingly, we found an increase in glial cell immunoreactivity and decrease in the immunoreactivity of nuclear factor-erythroid 2-related factor 2 (Nrf2), nicotinic acetylcholine receptor subunit alpha 7 (α7nAChR), and neuronal nuclei (NeuN) in the striatum. Indeed, NAC administration improved the cognitive performance, ROS production, neuroinflammation, and caspase activation induced by GA. NAC did not prevent neuronal death, however protected against alterations induced by GA on Iba-1 and GFAP immunoreactivities and AChE activity. Then, this study suggests possible therapeutic strategies that could help in GA-I treatment and the importance of the striatum in the learning tasks.
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