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There is currently no efficacious intervention for preventing post-traumatic epilepsy (PTE). Preclinical studies support the potential use of anticholinergics for this condition. The purpose of this study was to evaluate the effects of biperiden as an intervention for preventing PTE. A randomized, double-blinded clinical trial was conducted at HC/FMUSP between 2018-2022. Adults with acute traumatic brain injury (TBI) were randomly assigned to receive biperiden or placebo, for 10 days. The primary outcome was the incidence of PTE while the secondary outcomes included the frequency of seizures, the frequency of any adverse events and mortality after 24 months. The study was powered at a planned enrolment of 132 patients. The trial began in January 2018 and was halted by researchers on March 2020 (and terminated in December 2022) in the face of the global COVID-19 pandemic. Overall, 123 participants were randomized and 112 contributed with data for modified mITT analysis, being that 61 (49.5%) participants completed the 24-month follow-up consult. Data analysis indicated lack of evidence of biperiden for either, the incidence of post-traumatic epilepsy (2.6, 95%CI, 0.65-10.57; p = 0.170) or the mortality rate (1.57, 95%CI, 0.73-3.38; p = 0.248). The frequency of late post-traumatic seizures was higher for biperiden group (2.03, 95%CI = 0.912-3.1597; p <0.001). The present study suggests that there was insufficient evidence regarding the effect of biperiden in preventing PTE after TBI, which underpins the need for larger studies. Clinical trial registration: ClinicalTrials.gov, identifier: NCT01048138.
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Non-human primates (NHPs) have played a crucial role in our understanding of epilepsy, given their striking similarities with humans. Through their use, we have gained a deeper understanding of the neurophysiology and pathophysiology of epileptic seizures, and they have proven invaluable allies in developing anti-seizure therapies. This review explores the history of NHPs as natural models of epilepsy, discusses the findings obtained after exposure to various chemoconvulsant drugs and focal electrical stimulation protocols that helped uncover important mechanisms related to epilepsy, examines diverse treatments to prevent and manage epilepsy, and addresses essential ethical issues in research. In this review, we aim to emphasize the important role of NHPs in epilepsy research and summarize the benefits and challenges associated with their use as models.
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Epilepsia , Primatas , Animais , Humanos , Modelos Animais de Doenças , Epilepsia/fisiopatologiaRESUMO
AIM: To explore associations of cerebrospinal fluid biomarkers of neurodegeneration and amyloidosis with caregiver burden, cognition and functionality in dementia with Lewy bodies (DLB) paired with late-onset Alzheimer's disease (AD) and healthy older people. METHODS: Consecutive outpatients with DLB were matched with outpatients with AD according to sex, cognitive scores and dementia stage, and with cognitively healthy controls according to age and sex to investigate associations of cerebrospinal fluid amyloid-ß (Aß42,Aß40,Aß38), tau, phospho-tau Thr181, ubiquitin, α-synuclein and neurofilament light with caregiver burden, functionality, reverse digit span, a clock drawing test, Mini-Mental State Examination (MMSE) and Severe MMSE, adjusted for sex, age, education, dementia duration and APOE-ε4 alleles. RESULTS: Overall, 27 patients with DLB (78.98 ± 9.0 years-old; eleven APOE-ε4 +) were paired with 27 patients with AD (81.50 ± 5.8 years-old; twelve APOE-ε4 +) and 27 controls (78.98 ± 8.7 years-old; four APOE-ε4 +); two-thirds were women. In AD, Aß42/Aß38 and Aß42 were lower, while tau/Aß42 and phospho-tau Thr181/Aß42 were higher; α-synuclein/Aß42 was lower in DLB and higher in AD. The following corrected associations remained significant: in DLB, instrumental functionality was inversely associated with tau/phospho-tau Thr181 and tau/Aß42, and reverse digit span associated with α-synuclein; in AD, instrumental functionality was inversely associated with neurofilament light, clock drawing test scores inversely associated with phospho-tau Thr181/Aß42 and α-synuclein/Aß42, and Severe MMSE inversely associated with tau/Aß42 and tau/phospho-tau Thr181. CONCLUSIONS: Cerebrospinal fluid phospho-tau Thr181 in DLB was similar to AD, but not Aß42. In associations with test scores, biomarker ratios were superior to isolated biomarkers, while worse functionality was associated with axonal degeneration only in AD.
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Doença de Alzheimer , Doença por Corpos de Lewy , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Masculino , Doença de Alzheimer/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/psicologia , Proteínas tau , Fragmentos de Peptídeos , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Apolipoproteínas E/genéticaRESUMO
Interest in the use of anticholinergics to prevent the development of epilepsy after traumatic brain injury (TBI) has grown since recent basic studies have shown their effectiveness in modifying the epileptogenic process. These studies demonstrated that treatment with anticholinergics, in the acute phase after brain injury, decreases seizure frequency, and severity, and the number of spontaneous recurrent seizures (SRS). Therefore, anticholinergics may reduce the risk of developing posttraumatic epilepsy (PTE). In this brief review, we summarize the role of the cholinergic system in epilepsy and the key findings from using anticholinergic drugs to prevent PTE in animal models and new clinical trial protocols. Furthermore, we discuss why treatment with anticholinergics is more likely to prevent PTE than treatment for other epilepsies.
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BACKGROUND: Behavioral features may reflect proteinopathies predicting pathophysiology in neurodegenerative diseases. OBJECTIVE: We aimed to investigate associations of cerebrospinal fluid biomarkers of amyloidogenesis and neurodegeneration with neuropsychiatric features in dementia with Lewy bodies (DLB) compared with late-onset Alzheimer's disease (AD) and cognitively healthy people. METHODS: Consecutive outpatients with DLB were paired with outpatients with AD according to sex, dementia stage, and cognitive scores, and with cognitively healthy controls according to sex and age to investigate associations of cerebrospinal fluid amyloid-ß (Aß)42, Aß40, Aß38, total tau, phospho-tau Thr181, α-synuclein, ubiquitin, and neurofilament light with neuropsychiatric features according to APOEÉ4 carrier status. RESULTS: Overall, 27 patients with DLB (78.48±9.0 years old, eleven APOEÉ4 carriers) were paired with 27 patients with AD (81.00±5.8 years old, twelve APOEÉ4 carriers) and 27 controls (78.48±8.7 years old, four APOEÉ4 carriers); two thirds were women. Behavioral burden was more intense in DLB. Biomarker ratios reflecting amyloidogenesis and neurodegeneration in DLB were more similar to those in AD when patients carried APOEÉ4 alleles. After corrections for false discovery rates, the following associations remained significant: in DLB, dysphoria was associated with tauopathy and indirect measures of amyloidogenesis, while in AD, agitation, and night-time behavior disturbances were associated with tauopathy, and delusions were associated with tauopathy and indirect measures of amyloidogenesis. CONCLUSION: Biomarker ratios were superior to Aß and tau biomarkers predicting neuropsychiatric symptoms when associations with isolated biomarkers were not significant. At the end, APOEÉ4 carrier status influenced amyloidogenesis and tau pathology in DLB and in AD, and axonal degeneration only in DLB.
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Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Cognição/fisiologia , Doença por Corpos de Lewy/psicologia , alfa-Sinucleína/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Diagnóstico Diferencial , Feminino , Humanos , Doença por Corpos de Lewy/líquido cefalorraquidiano , Masculino , Fragmentos de Peptídeos/líquido cefalorraquidiano , FosforilaçãoRESUMO
OBJECTIVE: Differential diagnosis between Parkinson's disease (PD) dementia and dementia with Lewy bodies (DLB) is difficult due to common features, whereas management decisions and research endpoints depend upon knowledge of dementia severity. We aimed to assess risk factors for age at dementia onset, as well as which neuropsychiatric features are associated with pharmacotherapy and signs and symptoms of Lewy body dementia. PATIENTS AND METHODS: Patients with PD dementia or DLB were evaluated for age at disease onset, education, sanitation, anthropometric measures, alcohol use, smoking, history of infections or head trauma with unconsciousness, family history of neurodegenerative diseases, functional independence, cognition, behavior, motor features, caregiver burden and pharmacotherapy. RESULTS: Fifty-one patients were recruited (37 with DLB, 14 with PD dementia). Cumulative alcohol use and married status were associated with earlier dementia onset, whereas history of treated systemic infections and cumulative family history of primary neurodegenerative diseases led to later dementia onset. The length of dementia was shorter only for severely impaired patients who used anti-depressants, but not for users of cholinesterase inhibitors, while no behavioral symptom was associated with dopaminergic therapy. Night-time behavior disturbances were inversely associated with sleep satisfaction, while caregiver burden was more affected by depression and motor features. Non-motor symptoms were more burdensome for patients with DLB, while in PD dementia anxiety and dysphoria occurred when motor features were less burdensome. CONCLUSIONS: PD dementia and DLB are two phenotypes of the same pathological entity, differing mostly by the occurrence of parkinsonian signs. Predictors of dementia onset differ from other neurodegenerative diseases.
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Doença por Corpos de Lewy/psicologia , Transtornos Mentais/psicologia , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas , Antidepressivos/uso terapêutico , Cuidadores , Efeitos Psicossociais da Doença , Estudos Transversais , Diagnóstico Diferencial , Escolaridade , Feminino , Humanos , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/tratamento farmacológico , Masculino , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Doenças Neurodegenerativas/epidemiologia , Doenças Neurodegenerativas/genética , Doença de Parkinson/diagnóstico , Doença de Parkinson/psicologia , Fatores de Risco , Fatores SocioeconômicosRESUMO
Temporal lobe epilepsy (TLE) is a chronic disease, characterized by severe and refractory seizures, triggered in the hippocampus and/or amygdala, disrupting the blood-brain barrier. This disruption can sustain, or aggravate, the epileptic condition. The aim of this study was to evaluate the activation of the kallikrein-kinin system in patients with TLE, as it relates to the maintenance of blood-brain barrier. Human hippocampal sclerotic tissues removed after surgery for seizure control, plasma, and serum were used in the following assays: immunostaining for white blood cells in the TLE hippocampus, C-reactive protein in serum, quantification of plasma kallikrein (PKal) and cathepsin B (CatB) activity in serum and plasma, quantification of C1-inhibitor, analysis of high-molecular-weight kininogen (H-kininogen) fragments, and activation of plasma prekallikrein for comparison with healthy controls. Infiltration of white blood cells in the sclerotic hippocampus and a significant increase in the neutrophil/lymphocyte ratio in the blood of TLE patients were observed. High levels of C-reactive protein (TLE = 1.4 ± 0.3 µg/mL), PKal (TLE = 5.4 ± 0.4 U/mL), and CatB (TLE = 4.9 ± 0.4 U/mL) were also evident in the serum of TLE patients comparing to controls. A strong linear correlation was observed between active CatB and PKal in the serum of TLE patients (r = 0.88). High levels of cleaved H-kininogen and free PKal, and low levels of C1-inhibitor (TLE = 188 ± 12 µg/mL) were observed in the serum of TLE patients. Our data demonstrated that the plasma kallikrein-kinin system is activated in patients with TLE. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
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Catepsina B/sangue , Epilepsia do Lobo Temporal/metabolismo , Inflamação/metabolismo , Sistema Calicreína-Cinina/fisiologia , Calicreínas/sangue , Adulto , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Neuroprotection is a desirable process in many neurological disorders, yet complex mechanisms involved in this field are not completely understood. The pilocarpine epilepsy model causes potent, seizure-induced excitotoxicity cell death and mitochondria impairment. The present study is aimed at investigating the role of UCP2, a ROS negative regulator, in the neuroprotection after cholinergic insult. Our data demonstrated that UCP2 expression was augmented in the rat hippocampus 3 days after status epilepticus (SE), reaching a peak on the fifth day, then returning to basal levels. Concomitantly, phospho-AKT expression levels were higher in the hippocampus during the early silent phase (5 days after SE). Additionally, it was demonstrated that the blockade of UCP2 by antisense oligonucleotides (ASO) in SE rats successfully diminished both UCP2 mRNA and protein contents. SE ASO rats presented increased mitochondrial proapoptotic factor expression, caspase-3 activity, inflammatory cytokine expression, and ROS formation. Moreover, ASO treatment diminished p-AKT expression and antioxidant enzyme activities after pilocarpine insult. In conclusion, the present results highlight the neuroprotective actions of UCP2, acting in the inhibition of apoptotic factors and oxidative stress, to increase neuron survival after SE onset.
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Estresse Oxidativo/fisiologia , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Proteína Desacopladora 2/metabolismo , Animais , Apoptose/fisiologia , Modelos Animais de Doenças , Masculino , Estresse Oxidativo/efeitos dos fármacos , Pilocarpina , Ratos , Ratos Wistar , Estado Epiléptico/patologiaRESUMO
Lifetime risk factors for cognitive and functional decline in Alzheimer's disease (AD) are not fully understood, and were prospectively evaluated in patients with low mean schooling from São Paulo, Brazil. Consecutive outpatients with late-onset AD were assessed for APOE haplotypes and the following potential baseline predictors: gender, schooling, age at dementia onset, lifetime urban living and sanitary conditions, occupational complexity, cognitive and physical activities, cerebrovascular risk factors (obesity, lifetime alcohol use and smoking, length of arterial hypertension, diabetes mellitus, and a dyslipidemic profile), use of a pacemaker, creatinine clearance, body mass index, waist circumference, head traumas with unconsciousness, treated systemic bacterial infections, amount of surgical procedures under general anesthesia, and family history of AD. Participants were followed from October 2010 to May 2017 for baseline risk factor associations with time since dementia onset for Clinical Dementia Rating and Mini-Mental State Examination score changes. For 227 patients (154 women, 119 APOE ε 4 carriers), later AD onset (mean 73.60±6.4 years-old, earlier for APOE ε 4/ε 4 carriers, p < 0.001) was the only variable hastening all endpoints, baseline creatinine clearance and lifetime alcohol use were hazardous for earlier cognitive and functional endpoints, women had earlier cognitive endpoints only, and schooling had a cumulative protective effect over later cognitive endpoints, particularly for carriers of APOE ε 4. Exclusively for carriers of APOE ε 4, head traumas with unconsciousness were hazardous for earlier cognitive endpoints, while lifetime sanitary conditions were protective regarding later cognitive endpoints. Functional and cognitive outcomes in AD represent probable interactions between effects of brain reserve and cerebral perfusion over neurodegeneration.
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Doença de Alzheimer/complicações , Transtornos Cognitivos/etiologia , Fatores de Risco , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Brasil/epidemiologia , Transtornos Cognitivos/epidemiologia , Escolaridade , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Avaliação de Resultados em Cuidados de Saúde , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de TempoRESUMO
Mesial temporal lobe epilepsy is a serious brain disorder in adults that is often preceded by an initial brain insult, such as status epilepticus (SE), that after a latent period leads to recurrent seizures. Post-SE models are widely used for studies on epileptogenic processes. Previous findings of our laboratory suggested that the Neotropical rodents Proechimys exhibit endogenous antiepileptogenic mechanisms in post-SE models. Strong body of research supports that SE triggers a rapid and dramatic upregulation of inflammatory mediators and vascular endothelial growth factor (VEGF). In this work we found that, in the epilepsy-resistant Proechimys, hippocampal and cortical levels of inflammatory cytokines (IL-1ß, IL-6, IL-10, TNF-α) and VEGF remained unchanged 24h after SE, strongly contrasting to the high levels of post-SE changes observed in Wistar rats. Furthermore, substantial differences in the brain baseline levels of these proteins were encountered between animal species studied. Since inflammatory cytokines and VEGF have been recognized as major orchestrators of the epileptogenic process, our results suggest their role in the antiepileptogenic mechanisms previously described in Proechimys.
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Córtex Cerebral/imunologia , Citocinas/metabolismo , Epilepsia do Lobo Temporal/imunologia , Inflamação/imunologia , Estado Epiléptico/imunologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/metabolismo , Hipocampo/imunologia , Hipocampo/metabolismo , Inflamação/metabolismo , Masculino , Agonistas Muscarínicos/farmacologia , Pilocarpina/farmacologia , Ratos , Ratos Wistar , Roedores , Estado Epiléptico/metabolismoRESUMO
Parkinson's disease is a neurodegenerative disorder where the main hallmark is the dopaminergic neuronal loss. Besides motor symptoms, PD also causes cognitive decline. Although current therapies focus on the restoration of dopamine levels in the striatum, prevention or disease-modifying therapies are urgently needed. Valproic acid (VA) is a wide spectrum antiepileptic drug, exerting many biochemical and physiological effects. It has been shown to inhibit histone deacetylase which seems to be associated with the drug neuroprotective action. The objectives were to study the neuroprotective properties of VA in a model of Parkinson's disease, consisting in the unilateral striatal injection of the neurotoxin 6-OHDA. For that, male Wistar rats (250 g) were divided into the groups: sham-operated (SO), untreated 6-OHDA-lesioned, and 6-OHDA-lesioned treated with VA (25 or 50 mg/kg). Oral treatments started 24 h after the stereotaxic surgery and continued daily for 2 weeks, when the animals were subjected to behavioral evaluations (apomorphine-induced rotations and open-field tests). Then, they were sacrificed and had their mesencephalon, striatum, and hippocampus dissected for neurochemical (DA and DOPAC determinations), histological (Fluoro-Jade staining), and immunohistochemistry evaluations (TH, OX-42, GFAP, TNF-alpha, and HDAC). The results showed that VA partly reversed behavioral and neurochemical alterations observed in the untreated 6-OHDA-lesioned rats. Besides, VA also decreased neuron degeneration in the striatum and reversed the TH depletion observed in the mesencephalon of the untreated 6-OHDA groups. This neurotoxin increased the OX-42 and GFAP immunoreactivities in the mesencephalon, indicating increased microglia and astrocyte reactivities, respectively, which were reversed by VA. In addition, the immunostainings for TNF-alpha and HDAC demonstrated in the untreated 6-OHDA-lesioned rats were also decreased after VA treatments. These results were observed not only in the CA1 and CA3 subfields of the hippocampus, but also in the temporal cortex. In conclusion, we showed that VA partly reversed the behavioral, neurochemical, histological, and immunohistochemical alterations observed in the untreated 6-OHDA-lesioned animals. These effects are probably related to the drug anti-inflammatory activity and strongly suggest that VA is a potential candidate to be included in translational studies for the treatment of neurodegenerative diseases as PD.
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During the epileptogenic process, several events may occur, such as an important activation of the immune system in the central nervous system. The response to seizure activity results in an inflammation in the brain as well as in the periphery. Moreover, CRP and cytokines may be able to interact with numerous ligands in response to cardiac injury caused by sympathetic stimulation in ictal and postictal states. Based on this, we measured the serum levels of C-reactive protein (CRP) and cytokines during acute, silent, and chronic phases of rats submitted to the pilocarpine model of epilepsy. We have also analyzed the effect of a chronic treatment of these rats with omega-3 fatty acid in CRP and cytokine levels, during an epileptic focus generation. C-reactive protein and cytokines such as IL-1ß, IL-6, and TNF-α presented high concentration in the blood of rats, even well after the occurrence of SE. We found reduced levels of CRP and all proinflammatory cytokines in the blood of animals with chronic seizures, treated with omega-3, when compared with those treated with vehicle solution. Taken together, our results strongly suggest that the omega-3 is an effective treatment to prevent SUDEP occurrence due to its capability to act as an anti-inflammatory compound, reducing the systemic inflammatory parameters altered by seizures.
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Biomarcadores/sangue , Epilepsia/sangue , Epilepsia/prevenção & controle , Ácidos Graxos Ômega-3/uso terapêutico , Inflamação/sangue , Animais , Comportamento Animal , Proteína C-Reativa/metabolismo , Convulsivantes , Citocinas/sangue , Epilepsia/induzido quimicamente , Masculino , Pilocarpina , Ratos , Ratos Wistar , Estado Epiléptico/sangue , Estado Epiléptico/induzido quimicamenteRESUMO
The kallikrein-kinin system (KKS) is an intricate endogenous pathway involved in several physiological and pathological cascades in the brain. Due to the pathological effects of kinins in blood vessels and tissues, their formation and degradation are tightly controlled. Their components have been related to several central nervous system diseases such as stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy and others. Bradykinin and its receptors (B1R and B2R) may have a role in the pathophysiology of certain central nervous system diseases. It has been suggested that kinin B1R is up-regulated in pathological conditions and has a neurodegenerative pattern, while kinin B2R is constitutive and can act as a neuroprotective factor in many neurological conditions. The renin angiotensin system (RAS) is an important blood pressure regulator and controls both sodium and water intake. AngII is a potent vasoconstrictor molecule and angiotensin converting enzyme is the major enzyme responsible for its release. AngII acts mainly on the AT1 receptor, with involvement in several systemic and neurological disorders. Brain RAS has been associated with physiological pathways, but is also associated with brain disorders. This review describes topics relating to the involvement of both systems in several forms of brain dysfunction and indicates components of the KKS and RAS that have been used as targets in several pharmacological approaches.
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OBJECTIVE: Thimet oligopeptidase (TOP) is a metalloprotease that has been associated with peptide processing in several nervous system structures, and its substrates include several peptides such as bradykinin, amyloid beta (Aß), and major histocompatibility complex (MHC) class I molecules. As shown previously by our research group, patients with temporal lobe epilepsy (TLE) have a high level of kinin receptors as well as kallikrein, a kinin-releasing enzyme, in the hippocampus. METHODS: In this study, we evaluated the expression, distribution, and activity of TOP in the hippocampus of patients with TLE and autopsy-control tissues, through reverse-transcription polymerase chain reaction (RT-PCR), enzymatic activity, Western blot, and immunohistochemistry. In addition, hippocampi of rats were analyzed using the pilocarpine-induced epilepsy model. Animals were grouped according to the epilepsy phases defined in the model as acute, silent, and chronic. RESULTS: Increased TOP mRNA expression, decreased protein levels and enzymatic activity were observed in tissues of patients, compared to control samples. In addition, decreased TOP distribution was also visualized by immunohistochemistry. Similar results were observed in tissues of rats during the acute phase of epilepsy model. However, increased TOP mRNA expression and no changes in immunoreactivity were found in the silent phase, whereas increased TOP mRNA expression and increased enzymatic activity were observed in the chronic phase. SIGNIFICANCE: The results show that these alterations could be related to a failure in the mechanisms involved in clearance of inflammatory peptides in the hippocampus, suggesting an accumulation of potentially harmful substances in nervous tissue such as Aß, bradykinin, and antigenic peptides. These accumulations could be related to hippocampal inflammation observed in TLE subjects.
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Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/patologia , Hipocampo/patologia , Metaloendopeptidases/genética , RNA Mensageiro/genética , Adulto , Animais , Lobectomia Temporal Anterior , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/cirurgia , Feminino , Regulação Enzimológica da Expressão Gênica/genética , Hipocampo/cirurgia , Humanos , Injeções Intraperitoneais , Masculino , Pessoa de Meia-Idade , Pilocarpina , Ratos , Esclerose , Lobo Temporal/patologia , Adulto JovemRESUMO
Several lines of evidences have shown the inversion association between coffee consumption and Parkinson's disease (PD) development. Caffeine is a methylxanthine known as a non-selective inhibitor of A2A and A1 adenosine receptors in the brain and shown to be a neuroprotective drug. The objectives were to study caffeine effects in a unilateral 6-OHDA model of PD in rats. Male rats were divided into the following groups: sham-operated (SO), striatal 6-OHDA-lesioned and 6-OHDA-lesioned and treated for 2 weeks with caffeine (10 and 20mg/kg, p.o.). Then, animals were subjected to behavioral (open field and apomorphine-induced rotations), neurochemical (striatal determinations of DA and DOPAC), histological (cresyl violet staining) and immunohistochemical (TH, TNF-α, IL-1ß and HDAC) evaluations. The results showed that while the 6-OHDA group presented a decreased locomotor activity and a high number of apomorphine-induced rotations, these behaviors were partially blocked by caffeine. Caffeine itself increased DA contents and reversed the decrease in striatal DA observed in the 6-OHDA-lesioned group. Furthermore, it improved the hippocampal neuronal viability and significantly increased TH immunoreactivity in the striatum of the 6-OHDA-lesioned group. In addition, caffeine treatment also decreased the number of immunopositive cells for HDAC and pro-inflammatory cytokines TNF-α and IL-1ß. All these effects points out to a neuroprotective effect of caffeine and its potential benefit in the prevention and treatment of PD.
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Cafeína/farmacologia , Citocinas/metabolismo , Histona Desacetilases/metabolismo , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Adrenérgicos/toxicidade , Animais , Apomorfina/farmacologia , Encéfalo/metabolismo , Cafeína/uso terapêutico , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Oxidopamina/toxicidade , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , Ratos , Ratos Wistar , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
AIM: To evaluate changes in neurotransmission induced by a psychoactive beverage ayahuasca in the hippocampus and amygdala of naive rats. METHODS: The level of monoamines, their main metabolites and amino acid neurotransmitters concentrations were quantified using high performance liquid chromatography (HPLC). Four groups of rats were employed: saline-treated and rats receiving 250, 500 and 800 mg/kg of ayahuasca infusion (gavage). Animals were killed 40 min after drug ingestion and the structures stored at -80â °C until HPLC assay. The data from all groups were compared using Analysis of variance and Scheffé as post test and P < 0.05 was accepted as significant. RESULTS: The results showed decreased concentrations of glycine (GLY) (0.13 ± 0.03 vs 0.29 ± 0.07, P < 0.001) and γ-aminobutyric acid (GABA) (1.07 ± 0.14 vs 1.73 ± 0.25, P < 0.001) in the amygdala of rats that received 500 of ayahuasca. Animals that ingested 800 mg/kg of ayahuasca also showed a reduction of GLY level (0.11 ± 0.01 vs 0.29 ± 0.07, P < 0.001) and GABA (0.98 ± 0.06 vs 1.73 ± 0.25, P < 0.001). In the hippocampus, increased GABA levels were found in rats that received all ayahuasca doses: 250 mg/kg (1.29 ± 0.19 vs 0.84 ± 0.21, P < 0.05); 500 mg/kg (2.23 ± 038 vs 084 ± 0.21, P < 0.05) and 800 mg/kg (1.98 ± 0.92 vs 0.84 ± 0.21, P < 0.05). In addition, an increased utilization rate of all monoamines was found in the amygdala after ayahuasca administration in doses: 250 mg/kg (noradrenaline: 0.16 ± 0.02 vs 0.36 ± 0.06, P < 0.01; dopamine: 0.39 ± 0.012 vs 2.39 ± 0.84, P < 0.001; serotonin: 1.02 ± 0.22 vs 4.04 ± 0.91, P < 0.001), 500 mg/kg (noradrenaline: 0.08 ± 0.02 vs 0.36 ± 0.06, P < 0.001; dopamine: 0.33 ± 0.19 vs 2.39 ± 0.84, P < 0.001; serotonin: 0.59 ± 0.08 vs 4.04 ± 0.91, P < 0.001) and 800 mg/kg (noradrenaline: 0.16 ± 0.04 vs 0.36 ± 0.06, P < 0.001; dopamine: 0.84 ± 0.65 vs 2.39 ± 0.84, P < 0.05; serotonin: 0.36 ± 0.02 vs 4.04 ± 0.91, P < 0.001). CONCLUSION: Our data suggest increased release of inhibitory amino acids by the hippocampus and an increased utilization rate of monoamines by the amygdala after different doses of ayahuasca ingestion.
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We previously showed that patients with temporal lobe epilepsy (TLE) present an increased expression of angiotensin II (AngII) AT1 and AT2 receptors in the hippocampus, supporting the idea of an upregulation of renin-angiotensin system (RAS) in this disease. This study aimed to verify the relationship between the RAS and TLE during epileptogenesis. Levels of the peptides angiotensin I (AngI), angiotensin II (AngII) and angiotensin 1-7 (Ang 1-7), were detected by HPLC assay. Angiotensin AT1 and AT2 receptors, Mas mRNA receptors and angiotensin converting enzyme (ACE), tonin and neutral endopeptidase (NEP) mRNA were also quantified at the hippocampus of Wistar rats by real time PCR, during acute (n=10), silent (n=10) and chronic (n=10) phases of pilocarpine-induced epilepsy. We observed an increased peptide level of Ang1-7 into acute and silent phases, decreasing importantly (p≤0.05) in the chronic phase, suggesting that AngI may be converted into Ang 1-7 by NEP, which is present in high levels in these periods. Our results also showed increased peptide level of AngII in the chronic phase of this model. In contraposition, the ACE expression is reduced in all periods. These data suggest that angiotensinogen or AngI may be cleaved to AngII by tonin, which showed increased expression in all phases. We found changes in AT1, AT2 and Mas mRNA receptors levels suggesting that Ang1-7 could act at Mas receptor during the silent period. Herein, we demonstrated for the first time, changes in angiotensin-related peptides, their receptors as well as the releasing enzymes in the hippocampus of rats during pilocarpine-induced epilepsy.
Assuntos
Epilepsia do Lobo Temporal/metabolismo , Hipocampo/efeitos dos fármacos , Pilocarpina/toxicidade , Sistema Renina-Angiotensina , Animais , Sequência de Bases , Primers do DNA , Epilepsia do Lobo Temporal/induzido quimicamente , Hipocampo/metabolismo , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo RealRESUMO
There is a great deal of evidence showing the capacity of physical exercise to enhance cognitive function, reduce anxiety and depression, and protect the brain against neurodegenerative disorders. Although the effects of exercise are well documented in the mature brain, the influence of exercise in the developing brain has been poorly explored. Therefore, we investigated the morphological and functional hippocampal changes in adult rats submitted to daily treadmill exercise during the adolescent period. Male Wistar rats aged 21 postnatal days old (P21) were divided into two groups: exercise and control. Animals in the exercise group were submitted to daily exercise on the treadmill between P21 and P60. Running time and speed gradually increased over this period, reaching a maximum of 18 m/min for 60 min. After the aerobic exercise program (P60), histological and behavioral (water maze) analyses were performed. The results show that early-life exercise increased mossy fibers density and hippocampal expression of brain-derived neurotrophic factor and its receptor tropomyosin-related kinase B, improved spatial learning and memory, and enhanced capacity to evoke spatial memories in later stages (when measured at P96). It is important to point out that while physical exercise induces hippocampal plasticity, degenerative effects could appear in undue conditions of physical or psychological stress. In this regard, we also showed that the exercise protocol used here did not induce inflammatory response and degenerating neurons in the hippocampal formation of developing rats. Our findings demonstrate that physical exercise during postnatal development results in positive changes for the hippocampal formation, both in structure and function.
Assuntos
Hipocampo/citologia , Hipocampo/fisiologia , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Western Blotting , Contagem de Células , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Imuno-Histoquímica , Masculino , Aprendizagem em Labirinto/fisiologia , Fibras Musgosas Hipocampais/fisiologia , Ratos , Ratos Wistar , Comportamento Espacial/fisiologiaRESUMO
Malnutrition during the earliest stages of life may result in innumerable brain problems. Moreover, this condition could increase the chances of developing neurological diseases, such as epilepsy. We analyzed the effects of early-life malnutrition on susceptibility to epileptic seizures induced by the pilocarpine model of epilepsy. Wistar rat pups were kept on a starvation regimen from day 1 to day 21 after birth. At day 60, 16 animals (8 = well-nourished; 8 = malnourished) were exposed to the pilocarpine experimental model of epilepsy. Age-matched well-nourished (n = 8) and malnourished (n = 8) rats were used as controls. Animals were video-monitored over 9 weeks. The following behavioral parameters were evaluated: first seizure threshold (acute period of the pilocarpine model); status epilepticus (SE) latency; first spontaneous seizure latency (silent period), and spontaneous seizure frequency during the chronic phase. The cell and mossy fiber sprouting (MFS) density were evaluated in the hippocampal formation. Our results showed that the malnourished animals required a lower pilocarpine dose in order to develop SE (200 mg/kg), lower latency to reach SE, less time for the first spontaneous seizure and higher seizure frequency, when compared to well-nourished pilocarpine rats. Histopathological findings revealed a significant cell density reduction in the CA1 region and intense MFS among the malnourished animals. Our data indicate that early malnutrition greatly influences susceptibility to seizures and behavioral manifestations in adult life. These findings suggest that malnutrition in infancy reduces the threshold for epilepsy and promotes alterations in the brain that persist into adult life.
Assuntos
Epilepsia do Lobo Temporal/etiologia , Epilepsia do Lobo Temporal/patologia , Hipocampo/patologia , Desnutrição/complicações , Desnutrição/patologia , Animais , Animais Recém-Nascidos , Convulsivantes/toxicidade , Modelos Animais de Doenças , Humanos , Transtornos da Nutrição do Lactente/complicações , Transtornos da Nutrição do Lactente/patologia , Recém-Nascido , Fibras Musgosas Hipocampais/patologia , Pilocarpina/toxicidade , Ratos , Ratos WistarRESUMO
OBJECTIVE: The goal of this study was to verify the effects of treatment with melatonin and N-acetylserotonin on the pilocarpine-induced epilepsy model. METHODS: The animals were divided into four groups: (1) animals treated with saline (Saline); (2) animals that received pilocarpine and exhibited SE (SE); (3) animals that exhibited SE and were treated with N-acetylserotonin (30 minutes and 1, 2, 4, 6, 12, 24, 36, and 48 hours) after SE onset (SE+NAS); (4) animals that exhibited SE and were treated with melatonin at the same time the SE+NAS group (SE+MEL). Behavioral (latency to first seizure, frequency of seizures, and mortality) and histological (Nissl and neo-Timm) parameters were analyzed. RESULTS: The animals treated with melatonin (SE+MEL) had a decreased number of spontaneous seizures during the chronic period (P<0.05), a reduction in mossy fiber sprouting, and less cell damage than the SE group. Animals treated with N-acetylserotonin did not exhibit any kind of significant change. CONCLUSION: Melatonin exerts an important neuroprotective effect by attenuating SE-induced postlesion and promoting a decrease in the number of seizures in epileptic rats. This suggests, for the first time, that melatonin could be used co-therapeutically in treatment of patients exhibiting SE to minimize associated injuries in these situations.