Worst spasticity in patients post-stroke associated with MNSOD ALA16VAL polymorphism and interleukin-1ß.

The MnSOD Ala16Val single nucleotide polymorphism (SNP) has shown to be associated to risk factors of several metabolic and vascular diseases. However, little is known about interaction between MnSOD Ala16Val SNP in stroke, a frequent neurologic disease that involves clinic manifestations such as motor deficits and spasticity. In this sense, we decided to investigate the relationship between MnSOD Ala16Val SNP with spasticity in stroke and also its influence on interleukin levels, BDNF, and glycolipid parameters. Eighty post-stroke subjects and 80 healthy controls were investigated. We showed a higher spasticity, levels of total cholesterol, LDL, IL-1ß, IL-6, and INF-γ in VV post-stroke group. Interesting, we found a correlation between IL-1ß levels and spasticity in VV post-stroke. Triglycerides, glucose levels and caspases (1 and 3) activation were significantly higher, as well as BDNF levels were lower in VV and AV post-stroke. DNA damage was higher in post-stroke group. Thus, we can suggest that the V allele has a worse glycolipid profile, which would facilitate changes in neurovascular homeostasis. These events associated with an increase in inflammatory markers and a reduction in BDNF can contribute with the stroke and a worse clinical evolution in relation to spasticity in patients with VV genotype.

Relationship between seizure type, metabolic profile, and inflammatory markers in blood samples of patients with epilepsy.

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. 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. 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). This study supports evidence that the levels of inflammatory, glycolipid, and oxidative factors are higher in epilepsy patients, especially those with generalized epilepsy.

Characteristics of Post-Ictal Headaches in Patients with Epilepsy: a Longitudinal Study.

OBJECTIVES: This study aimed to investigate the clinical predictors of post-ictal headache (PIH) in patients with epilepsy in a tertiary center in Brazil. METHODS: 302 individuals with adult-onset epilepsy were followed for 9.8 years in our Hospital. Structured questionnaires about headaches were applied. The presence of PIH was the primary outcome. We used multilevel linear modeling in our data analysis. RESULTS: From the total, 46.3% had post-ictal headaches. Tension-type post-ictal headache was present in 55% (N = 77) of the subjects, migrainous in 32.1% (N = 45), and both types in 12.8% (N = 18). Family history of migraine (Odds ratio: 1.696; 95% CI: 1.372 to 2.096), diagnosis of drug-resistant epilepsy (Odds ratio: 1.169; 95% CI: 1.135 to 2.146), months since last visit (Odds ratio: 1.464; 95% CI: 1.243 to 2.888), and generalized seizure onset type of epilepsy (Odds ratio: 1.527; 95% CI: 1.114 to 1.668), were significant determinants of PIH on multilevel linear modeling. DISCUSSION: PIH are associated with drug-resistant epilepsy, generalized seizures, and family history of migraine. The rates of pos-ictal headaches could be influenced by the use of antiepileptic drugs.

MnSOD Ala16Val polymorphism in cognitive dysfunction in patients with epilepsy: A relationship with oxidative and inflammatory markers.

OBJECTIVE: The objective of the study was to evaluate the neurocognitive profile and its relation with Ala16ValMnSOD polymorphism in epilepsy and if these clinical parameters are linked to oxidative stress and inflammatory markers. METHODS: Patients with epilepsy (n = 31) and healthy subjects (n = 42) were recruited. A neuropsychological evaluation was performed in both groups through a battery of cognitive tests. Oxidative stress, inflammatory markers, apoptotic factors, and deoxyribonucleic acid (DNA) damage were measured in blood samples. RESULTS: Statistical analyses showed the association of MnSOD Ala16Val polymorphism with cognitive impairment, including praxis, perception, attention, language, executive functions, long-term semantic memory, short-term visual memory, and total memory in patients with epilepsy and Valine-Valine (VV) genotype compared with the control group. Compared with the controls and patients with epilepsy, Alanine-Alanine (AA), and Alanine-Valine (AV) genotype, the patients with epilepsy and VV genotype exhibited higher levels of tumor necrosis factor alpha (TNF-α), interleukin 1ß (IL-1ß), interleukin 6 (IL-6), activation of caspases 1 and 3 (CASP-1 and -3), and DNA damage. Our findings also showed higher carbonyl protein and thiobarbituric acid reactive substances (TBARS) levels as well as an increased superoxide dismutase (SOD) and acetylcholinesterase (AChE) activities in patients with epilepsy and VV genotype. CONCLUSION: This study supports the evidence of a distinct neuropsychological profile in patients with epilepsy, especially those with the VV genotype. Furthermore, our results suggest that oxidative and inflammatory pathways may be associated with genetic polymorphism and cognitive dysfunction in patients with epilepsy.

Apoptotic Markers Are Increased in Epilepsy Patients: A Relation with Manganese Superoxide Dismutase Ala16Val Polymorphism and Seizure Type through IL-1ß and IL-6 Pathways.

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-1ß, IL-6, caspase-1, and caspase-3 levels were increased in the epilepsy group (VV genotype). Furthermore, an important correlation between IL-1ß 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-1ß 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.

Course and prognosis of adult-onset epilepsy in Brazil: A cohort study.

BACKGROUND: Most of the epilepsy longitudinal studies have analyzed children. However, in endemic regions, such as Brazil, neurocysticercosis accounts for many adult-onset epilepsy cases. So, the main objective of this study was to identify the clinical predictors associated with drug-resistant adult-onset epilepsy in Brazil during a long-term follow-up. METHODS: We followed 302 individuals with adult-onset epilepsy for 9.8 years in our University Hospital. Structured questionnaires about drug-resistant epilepsy were applied. The presence of drug-resistant epilepsy was the primary outcome. We used multilevel linear modeling in our data analysis. RESULTS: Overall 47 (15.6%) individuals presented drug-resistant epilepsy and the etiology was structural in 70.2% of them, while infectious etiology was present in 8.5% of this group. Infectious etiology occurred in 25.9% (n = 66) of the patients from the nondrug-resistant group. Those with developmental delay were two times more likely to present seizures. Structural epilepsy etiology was associated with an increased chance of relapsing. Poor school performance and abnormal electroencephalogram were also associated with an increased chance of seizures. CONCLUSION: The course of epilepsy was favorable in the majority of our patients, and drug-resistant epilepsy rates were similar to those found in other studies, although we evaluated older individuals with higher levels of infectious etiology. Also, we found that neurocysticercosis was associated with well-controlled epilepsy, while structural epilepsy was directly related to the occurrence of seizures. We also hypothesized that the smaller size of lesions found in neurocysticercosis could contribute to better treatment response.

Involvement of MnSOD Ala16Val polymorphism in epilepsy: A relationship with seizure type, inflammation, and metabolic syndrome.

The MnSOD Ala16Val single nucleotide polymorphism (SNP) has shown to be associated to inflammatory pathways and many metabolic disorders, such as obesity and dyslipidemia. Metabolic syndrome (MetS) is an emergent problem among patients with epilepsy. However, little is known about interaction between MnSOD Ala16Val SNP and metabolic comorbities in epilepsy. Thus, we investigated the relationship between MnSOD Ala16Val SNP with epilepsy and its influence on MetS, inflammation, apoptosis and DNA damage parameters. Ninety subjects were evaluated (47 epilepsy patients and 43 healthy controls) by questionnaires and laboratorial exams. Levels of inflammatory, apoptotic and DNA damage markers, as well as MnSOD polymorphism were assessed. An increased proportion of VV genotype in epilepsy group when compared to control group was observed. Tumor Necrosis Factor-α (TNF-α), Acetylcholinesterase, caspase-8, and Picogreen levels were increased in VV epilepsy group. An important correlation between TNF-α vs caspase-8, and Cholesterol vs. Triglycerides was observed in the epilepsy group with VV genotype. Our findings suggest that the MnSOD Ala16Val SNP might have an important role in epilepsy, mainly in patients with generalized seizures and particularly with VV genotype. The metabolic parameters also presented significant results in epilepsy group with VV genotype, which applying attention in view of further consequences and disorders that could be developed.

Delayed creatine supplementation counteracts reduction of GABAergic function and protects against seizures susceptibility after traumatic brain injury in rats.

Traumatic brain injury (TBI) is a devastating disease frequently followed by behavioral disabilities including post-traumatic epilepsy (PTE). Although reasonable progress in understanding its pathophysiology has been made, treatment of PTE is still limited. Several studies have shown the neuroprotective effect of creatine in different models of brain pathology, but its effects on PTE is not elucidated. Thus, we decided to investigate the impact of delayed and chronic creatine supplementation on susceptibility to epileptic seizures evoked by pentylenetetrazol (PTZ) after TBI. Our experimental data revealed that 4 weeks of creatine supplementation (300 mg/kg, p.o.) initiated 1 week after fluid percussion injury (FPI) notably increased the latency to first myoclonic and tonic-clonic seizures, decreased the time spent in tonic-clonic seizure, seizure intensity, epileptiform discharges and spindle oscillations induced by a sub-convulsant dose of PTZ (35 mg/kg, i.p.). Interestingly, this protective effect persists for 1 week even when creatine supplementation is discontinued. The anticonvulsant effect of creatine was associated with its ability to reduce cell loss including the number of parvalbumin positive (PARV+) cells in CA3 region of the hippocampus. Furthermore, creatine supplementation also protected against the reduction of GAD67 levels, GAD activity and specific [3H]flunitrazepam binding in the hippocampus. These findings showed that chronic creatine supplementation may play a neuroprotective role on brain excitability by controlling the GABAergic function after TBI, providing a possible new strategy for the treatment of PTE.

Depressive, inflammatory, and metabolic factors associated with cognitive impairment in patients with epilepsy.

PURPOSE: The purpose of this study was to examine the cognitive function and depressive traits most frequently associated with the clinical assessment of patients with epilepsy and if these clinical parameters are linked to glycolipid levels and inflammatory and apoptotic markers. METHODS: Patients with epilepsy (n = 32) and healthy subjects (n = 41) were recruited to participate in this study. Neuropsychological evaluation was performed in both groups through a battery of cognitive tests. Inflammatory markers, apoptotic factors, and deoxyribonucleic acid (DNA) damage were measured in blood samples. Additionally, the metabolic markers total cholesterol (CHO), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), and glucose (GLU) levels were analyzed. RESULTS: Statistical analyses showed that patients with epilepsy presented decreased scores in memory, attention, language, and executive function tests compared with the control group. Analysis revealed that there was negative correlation in epilepsy for seizure duration vs. oral language (R = -0.4484, p < 0.05) and seizure duration vs. problem solving (executive functions) (R = -0.3995, p < 0.05). This was also observed when comparing depression with temporal-spatial orientation (TSO) (R = -0.39, p < 0.05). Furthermore, we observed a higher depression score in patients with epilepsy than in the healthy ones. Statistical analyses showed higher acetylcholinesterase (AChE) (p < 0.05), interleukin 1ß (IL-1ß, p < 0.001), and tumor necrosis factor-alpha (TNF-α) (p < 0.001) levels compared with those in the control group. Moreover, patients with epilepsy had significantly higher serum levels of caspase 3 (CASP 3) (p < 0.001) and Picogreen (p < 0.001) compared with the control subjects. Regarding the metabolic markers, higher glycolipid levels were observed in the patients with epilepsy (CHO < 0.05*, LDL < 0.0001*, TG < 0.05*, GLU p < 0.05). High-density lipoprotein levels were not significant. The patients with epilepsy had significant correlation when comparing total language with TNF-α (R = -0.4, p < 0.05), praxes with CASP 3 (R = -0.52, p < 0.01), total CHO with total language (R = -0.48, p < 0.05), TG with semantic memory (R = -0.54, p < 0.05), TG with prospective memory (R = -0.2165, p < 0.02), TG with total memory (R = -0.53, p < 0.02), and GLU with total attention (R = -0.62, p < 0.002). CONCLUSION: This study supports the evidence of a distinct neuropsychological profile between patients with epilepsy and healthy subjects. Furthermore, our findings suggest that inflammatory pathway, glycolipid profile, and depressive factors may be associated with cognitive dysfunction in patients with epilepsy.

ALA16VAL-MnSOD gene polymorphism and stroke: Association with dyslipidemia and glucose levels.

Stroke risk has been associated to the progression of carotid plaques due to high glucose levels and lipid accumulation, which are greatly associated to cerebral injury, brain oxidative stress, and apoptosis. The ALA16VAL-MnSOD gene single nucleotide polymorphism (SNP) has shown to modulate risk factors of several metabolic and vascular diseases, such as blood glucose (GLU) and lipid levels. However, the association of these factors in stroke patients has not been studied to date. Thus, we evaluated the influence of the Ala16Val-MnSOD SNP on lipid profile, GLU levels, oxidative and DNA damage of 44 patients in a late phase of stroke (>6months). The statistical analysis showed a greater proportion of VV carries in stroke patients. The results also indicated that stroke patients had higher cholesterol (CHO) and GLU levels when compared to healthy counterparts. Interestingly, V allele carriers with stroke showed higher levels of CHO and GLU when compared to AA stroke and healthy counterparts. Our findings suggest that oxidative stress markers are still increased even after 6 months of cerebral injury. Furthermore, we propose that the Ala16Val-MnSOD SNPs may contribute to hypercholesterolemia and higher GLU levels, increasing the risk to neurovascular events that may lead to stroke.

Iron and Oxidative Stress in Parkinson's Disease: An Observational Study of Injury Biomarkers.

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.

Apoptotic markers and DNA damage are related to late phase of stroke: Involvement of dyslipidemia and inflammation.

Oxidative stress and brain inflammation are thought to contribute to the pathophysiology of cerebral injury in acute stroke, leading to apoptosis and cell death. Lipid accumulation may lead to progression of carotid plaques and inflammation, contributing to increased acute stroke risk. However, little is known about these events and markers in the late stroke (>6 months) and if dyslipidemia could contribute to disease's pathophysiology in a later phase. In this case-control study, we recruited patients in the late stroke phase (n=40) and health subjects (control group; n = 40). Dichlorodihydrofluorescein (DCFH), nitrite/nitrate (NOx), Tumor necrosis factor-alpha (TNF-α), Acetylcholinesterase (AChE), Caspase 8 (CASP 8), Caspase 3 (CASP 3) and Picogreen (PG) were measured in periphery blood samples. Furthermore, a correlation among all measured markers (DCFH, NOx, TNF-α, AChE, CASP 8, CASP 3 and PG) was realized. The marker levels were also compared to triglycerides (TG), total (CHO), LDL and HDL cholesterol levels and medications used. Statistical analyses showed that stroke patients presented an increase of DCFH, NOx, TNF-α and AChE levels when compared to control subjects. In addition, we observed that stroke patients had significantly higher CASP 8, CASP 3 and PG levels than control group. A significant correlation between TNF-α with CASP 8 (r = 0.4) and CASP 3 (r = 0.4) levels was observed, but not with oxidative/nitrosative markers. Moreover, we observed that stroke patients with dyslipidemia had significantly higher TNF-α, CASP 8 and CASP 3 levels than stroke without dyslipidemia and control groups. Our findings suggest that oxidative and inflammatory markers may be still increased and lead to caspase activation and DNA damage even after 6 months to cerebral injury. Furthermore, it is plausible to propose that dyslipidemia may contribute to worsen proinflammatory state in a later phase of stroke and an increased risk to new neurovascular events.