RESUMO
Positive influence of yerba mate (Ilex paraguariensis) on human health issues has been attributed to its frequent consumption in South American countries and is assumed to be due to its high content of antioxidant compounds, including chlorogenic acid (CGA); however, hard evidence about its positive effects under chronic stress conditions is still required. In this study, the effects of yerba mate extracts (IpE), and its main compound chlorogenic acid (CGA), on behavioral and morphological endpoints of brain damage induced by chronic restraint stress (CRS) to rats were evaluated and compared. CRS sessions were performed during 21 days. IpE (200 mg/mL, p.o.) or CGA (2 mg/mL, p.o.) were administered daily 30 min before stress. Behavioral tests comprised motor skills and anxiety-like activity. Histological (H&E) and histochemical changes were explored in three brain regions: cortex (Cx), hippocampus (Hp), and striatum (S). Rats subjected to CRS exhibited hypoactive patterns of locomotor activity. Rats receiving IpE before CRS preserved the basal locomotor activity. Stressed animals also augmented the anxiety-like activity, whereas IpE normalized exploratory behavior. Stressed animals presented cell damage in all regions. Morphological damage was more effectively prevented by IpE than CGA. Stressed animals also augmented the expression/localization pattern of the tumor necrosis factor alpha in the striatum and the expression of the glial fibrillary acidic protein in the hippocampus (stratum moleculare) and cortex, whereas IpE and CGA reduced the expression of these molecules. In turn, CGA exhibited only moderate protective effects on all markers analyzed. Our findings support a protective role of IpE against CRS, which may be related to the antioxidant and anti-inflammatory properties of its compounds. Since CGA was unable to prevent all the alterations induced by CRS, it is concluded that the protective properties of the whole extract of Ilex paraguariensis are the result of the combined effects of all its natural antioxidant compounds, and not only of the properties of CGA.
Assuntos
Encéfalo/metabolismo , Ácido Clorogênico/uso terapêutico , Ilex paraguariensis , Extratos Vegetais/uso terapêutico , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Animais , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Ácido Clorogênico/farmacologia , Masculino , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Restrição Física , Estresse Psicológico/patologiaRESUMO
The endocannabinoid system (ECS) actively participates in several physiological processes within the central nervous system. Among such, its involvement in the downregulation of the N-methyl-D-aspartate receptor (NMDAr) through a modulatory input at the cannabinoid receptors (CBr) has been established. After its production via the kynurenine pathway (KP), quinolinic acid (QUIN) can act as an excitotoxin through the selective overactivation of NMDAr, thus participating in the onset and development of neurological disorders. In this work, we evaluated whether the pharmacological inhibition of fatty acid amide hydrolase (FAAH) by URB597, and the consequent increase in the endogenous levels of anandamide, can prevent the excitotoxic damage induced by QUIN. URB597 (0.3 mg/kg/day × 7 days, administered before, during and after the striatal lesion) exerted protective effects on the QUIN-induced motor (asymmetric behavior) and biochemical (lipid peroxidation and protein carbonylation) alterations in rats. URB597 also preserved the structural integrity of the striatum and prevented the neuronal loss (assessed as microtubule-associated protein-2 and glutamate decarboxylase localization) induced by QUIN (1 µL intrastriatal, 240 nmol/µL), while modified the early localization patterns of CBr1 (CB1) and NMDAr subunit 1 (NR1). Altogether, these findings support the concept that the pharmacological manipulation of the endocannabinoid system plays a neuroprotective role against excitotoxic insults in the central nervous system.
Assuntos
Amidoidrolases/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Ácido Quinolínico/farmacologia , Receptor CB1 de Canabinoide/efeitos dos fármacos , Animais , Ácidos Araquidônicos/farmacologia , Corpo Estriado/lesões , Endocanabinoides/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Alcamidas Poli-Insaturadas/farmacologia , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismoRESUMO
Levetiracetam (LVT) is a relatively novel antiepileptic drug (AED) known to act through binding with the synaptic vesicular 2A (SV2A) protein, thus modulating the presynaptic neurotransmitter release. The tryptophan metabolite quinolinic acid (QUIN) acts as an excitotoxin when its brain concentrations reach toxic levels under pathological conditions. Since increased neuronal excitability induced by QUIN recruits degenerative events in the brain, and novel AED is also expected to exert neuroprotective effects in their pharmacological profiles, in this work the effect of LVT (54 mg/kg, i.p., administered for seven consecutive days) was tested as a pretreatment against the toxicity evoked by the bilateral intrastriatal injection of QUIN (60 nmol/µl) to adult rats. QUIN increased the striatal levels of peroxidized lipids and carbonylated proteins as indexes of oxidative damage 24 h after its infusion. In addition, in synaptosomal fractions isolated from QUIN-lesioned rats 24 h after the toxin infusion, γ-aminobutyric acid (GABA) release was decreased, whereas glutamate (Glu) release was increased. QUIN also decreased motor activity and augmented the rate of cell damage at 7 days post-lesion. All these alterations were significantly prevented by pretreatment of rats with LVT. The results of this study show a neuroprotective role and antioxidant action of LVT against the brain damage induced by excitotoxic events.
Assuntos
Anticonvulsivantes/farmacologia , Corpo Estriado/efeitos dos fármacos , Levetiracetam/farmacologia , Neostriado/efeitos dos fármacos , Animais , Lesões Encefálicas/tratamento farmacológico , Masculino , Fármacos Neuroprotetores , Ácido Quinolínico/toxicidade , Ratos Wistar , Transmissão Sináptica/efeitos dos fármacosRESUMO
Waltheria americana is a plant used in Mexican traditional medicine to treat some nervous system disorders. The aims of the present study were to isolate and determine the neuropharmacological and neurprotective activities of metabolites produced by a cell suspension culture of Waltheria americana. Submerged cultivation of W. americana cells provided biomass. A methanol-soluble extract (WAsc) was obtained from biomass. WAsc was fractionated yielding the chromatographic fractions 4WAsc-H2O and WAsc-CH2Cl2. For the determination of anticonvulsant activity in vivo, seizures were induced in mice by pentylenetetrazol (PTZ). Neuropharmacological activities (release of gamma amino butyric acid (GABA) and neuroprotection) of chromatographic fractions were determined by in vitro histological analysis of brain sections of mice post mortem. Fraction 4WAsc-H2O (containing saccharides) did not produce neuronal damage, neurodegeneration, interstitial tissue edema, astrocytic activation, nor cell death. Pretreatment of animals with 4WAsc-H2O and WAsc-CH2Cl2 from W. americana cell suspensions induced an increase in: GABA release, seizure latency, survival time, neuroprotection, and a decrease in the degree of severity of tonic/tonic-clonic convulsions, preventing PTZ-induced death of up to 100% of animals of study. Bioactive compounds produced in suspension cell culture of W. americana produce neuroprotective and neuropharmacological activities associated with the GABAergic neurotransmission system.
Assuntos
Malvaceae/química , Metaboloma , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Biomassa , Córtex Cerebral/patologia , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Pentilenotetrazol , Extratos Vegetais/uso terapêutico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/patologia , Solubilidade , Suspensões , Ácido gama-Aminobutírico/metabolismoRESUMO
The endocannabinoid system (ECS), and agonists acting on cannabinoid receptors (CBr), are known to regulate several physiological events in the brain, including modulatory actions on excitatory events probably through N-methyl-D-aspartate receptor (NMDAr) activity. Actually, CBr agonists can be neuroprotective. The synthetic CBr agonist WIN55,212-2 acts mainly on CB1 receptor. In turn, the mitochondrial toxin 3-nitropropionic acid (3-NP) produces striatal alterations in rats similar to those observed in the brain of Huntington's disease patients. Herein, the effects of WIN55,212-2 were tested on different endpoints of the 3-NP-induced toxicity in rat brain synaptosomes and striatal tissue. Motor activity was also evaluated. The 3-NP (1 mM)-induced mitochondrial dysfunction and lipid peroxidation was attenuated by WIN55,212-2 (1 µM) in synaptosomal fractions. The intrastriatal bilateral injection of 3-NP (500 nmol/µL) to rats increased lipid peroxidation and locomotor activity, augmented the rate of cell damage, and decreased the striatal density of neuronal cells. These alterations were accompanied by transcriptional changes in the NMDA (NR1 subunit) content. The administration of WIN55212-2 (1 mg/kg, i.p.) to rats for six consecutive days, before the 3-NP injection, exerted preventive effects on all alterations elicited by the toxin. The prevention of the 3-NP-induced NR1 transcriptional alterations by the CBr agonist together with the increase of CB1 content suggest an early reduction of the excitotoxic process via CBr activation. Our results demonstrate a protective role of WIN55,212-2 on the 3-NP-induced striatal neurotoxicity that could be partially related to the ECS stimulation and induction of NMDAr hypofunction, representing an effective therapeutic strategy at the experimental level for further studies.
RESUMO
BACKGROUND: URB597 is a compound largely linked to the inhibition of fatty acid amide hydrolase (FAAH), an enzyme responsible for the metabolic degradation of the endocannabinoid anandamide (AEA). Despite this pharmacological property accounts for its modulatory profile demonstrated in some neurotoxic paradigms, the possible protective properties of this agent have been poorly investigated, and deserve exploration in different neurotoxic models. In this study, we explored the effects of URB597 on oxidative damage to lipids and other major endpoints of toxicity in two neurotoxic models in vivo in rats (the first one produced by the mitochondrial neurotoxin 3-nitropropionic acid [3-NP], and the other generated by the striatal injection of the pro-oxidant toxin 6-hydroxidopamine [6-OHDA]) in order to provide further supporting evidence of its modulatory profile. METHODS: Male Wistar adult rats were treated for 5 or 7 consecutive days with URB597 (0.3mg/kg, i.p.) and simultaneously exposed to three injections of 3-NP (30mg/kg, i.p.) or a single intrastriatal infusion of 6-OHDA (0.02mg/2µl), respectively. Twenty four hours after all treatments were administered, lipid peroxidation was measured in the striatum of 3-NP-treated rats, and in the midbrain of 6-OHDA-treated rats. Motor skills and histological assessment in the striatum were also evaluated in 3-NP-treated rats 6 and 7days after the last drug administration, respectively; whereas apomorphine-induced circling behavior and tyrosine hydroxylase immunolocalization in the striatum and substantia nigra were investigated 21 and 22days after the last drug infusion, respectively. RESULTS: URB597 prevented the oxidative damage to lipids induced by 3-NP in the striatum, and this effect could account for the attenuation of motor deficits in this model. Attenuation of motor disturbances induced by URB597 in both models was associated with the morphological preservation of the striatum in the 3-NP model and the partial preservation of tyrosine hydroxylase in the 6-OHDA model in the SNpc and striatum. CONCLUSION: The modulatory actions exerted by URB597 in both toxic models support its potential against toxic conditions implying motor and neurochemical alterations linked to energy depletion, excitotoxicity and oxidative stress. Although most of these effects could be attributable to its action on FAAH and further AEA accumulation, in light of our present findings other properties are suggested.
Assuntos
Benzamidas/uso terapêutico , Carbamatos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Amidoidrolases/antagonistas & inibidores , Animais , Apomorfina , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Injeções , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Destreza Motora/efeitos dos fármacos , Neostriado , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/psicologia , Nitrocompostos , Oxidopamina , Propionatos , Ratos , Ratos WistarRESUMO
Alzheimer Disease (AD) is a neurodegenerative disorder and the most common form of dementia. Histopathologically is characterized by the presence of two major hallmarks, the intracellular neurofibrillary tangles (NFTs) and extracellular neuritic plaques (NPs) surrounded by activated astrocytes and microglia. NFTs consist of paired helical filaments of truncated tau protein that is abnormally hyperphosphorylated. The main component in the NP is the amyloid-ß peptide (Aß), a small fragment of 40-42 amino acids with a molecular weight of 4 kD. It has been proposed that the amyloid aggregates and microglia activation are able to favor the neurodegenerative process observed in AD patients. However, the role of inflammation in AD is controversial, because in early stages the inflammation could have a beneficial role in the pathology, since it has been thought that the microglia and astrocytes activated could be involved in Aß clearance. Nevertheless the chronic activation of the microglia has been related with an increase of Aß and possibly with tau phosphorylation. Studies in AD brains have shown an upregulation of complement molecules, pro-inflammatory cytokines, acute phase reactants and other inflammatory mediators that could contribute with the neurodegenerative process. Clinical trials and animal models with non-steroidal anti-inflammatory drugs (NSAIDs) indicate that these drugs may decrease the risk of developing AD and apparently reduce Aß deposition. Finally, further studies are needed to determine whether treatment with anti-inflammatory strategies, may decrease the neurodegenerative process that affects these patients.
RESUMO
Epilepsy affects 1 and 2 percent of the worldwide population, while temporal lobe epilepsy (TLE) covers 40 percent of all epilepsy cases. Controversy in defining epilepsy as a neurodegenerative disease exists because, no there is enough evidence to show seizures and status epilepticus (SE) as cause for irreversible neuronal damage. Epileptogenic insult at the beginning of the disease produces an acute and delayed neuronal death, resulting in gliosis, but also triggers compensatory processes such as angiogenesis, cell proliferation and reorganization of extracellular matrix as receptors, channels and drug transporter proteins. In neurogenesis and axonal regrowth, the age of onset is crucial for the formation of abnormal neurons and aberrant circuits as a result of seizures; approximately 30 percent begin in the temporal lobe. These disturbances continue in parallel or sequentially during the course of epilepsy, which implies a great challenge in the search of new treatments...
La epilepsia es una enfermedad que afecta entre el 1 al 2 por ciento de la población mundial, siendo la epilepsia del lóbulo temporal (ELT) la que abarca el 40 por ciento de todos los casos de epilepsia. La controversia en definir a la epilepsia como una enfermedad neurodegenerativa, se debe a que no hay pruebas suficientes que demuestren como las convulsiones y el estado de mal epiléptico (SE) provocan un daño neuronal irreversible. El insulto epileptógenico presente al inicio de la enfermedad genera la muerte neuronal aguda y tardía, para dar lugar a la gliosis; pero también se desencadenan procesos compensatorios como la angiogénesis, la proliferación celular y una reorganización tanto de la matriz extracelular como de los receptores, canales y proteínas transportadoras de fármacos. En el caso de la neurogénesis y recrecimiento axonal, la edad de inicio es determinante para la formación de neuronas anormales y circuitos aberrantes como consecuencia de las convulsiones, dónde aproximadamente un 30 por ciento comienzan en el lóbulo temporal. Estas alteraciones se continúan en paralelo o de forma secuencia! durante la evolución de la epilepsia, lo que implica un gran desafío en la búsqueda de nuevos tratamientos...
Assuntos
Humanos , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/fisiopatologia , Degeneração Neural/etiologia , Degeneração Neural/fisiopatologia , Gliose , Inflamação , Neovascularização PatológicaRESUMO
The neuroactive metabolite at the kynunerine pathway, kynurenic acid (KYNA), is a well-known competitive antagonist at the co-agonist glycine site of the N-methyl-D-aspartate receptor (NMDAr), and also decreases the extracellular levels of glutamate by blocking α7-nicotinic acetylcholine receptor (α7-nAchr) located on glutamatergic terminals. KYNA has been often reported to be neuroprotective in different neurotoxic models. The systemic administration of L-kynurenine (L-KYN)--the precursor of KYNA--together with probenecid (PROB)--an inhibitor of organic acids transport--to rodents increases KYNA levels in the brain in a dose-dependent manner. The striatal infusion of the toxin 6-hydroxydopamine (6-OHDA) to rodents is one of the common models used to simulate Parkinson's disease (PD). Different studies have linked PD alterations with excessive glutamatergic transmission in the striatum since NMDAr antagonists exert beneficial effects in PD models. In this work we investigated the effect that a systemic administration of L-KYN+PROB exerted on the toxic model induced by 6-OHDA in rats. PROB (50 mg/kg, i.p.) + L-KYN (75 mg/kg, i.p.) were given to rats for seven consecutive days. On day two of treatment, the animals were infused with a single injection of 6-OHDA (20 µg/2 µl) into the right striatum. Fourteen days post-lesion, rotation behavior was assessed as a marker of motor impairment. The total levels of dopamine (DA) were also estimated in striatal tissue samples of 6-OHDA-treated animals as a neurochemical marker of damage. In addition, twenty eight days post-lesion, the striatal damage was assessed by hematoxylin/eosin staining and immunohistochemistry against glial fibrillary acidic protein (GFAP) in the same animals. Neurodegeneration was also assessed by Fluoro Jade staining. 6-OHDA infusion increased rotation behavior, striatal reactive gliosis and neurodegeneration, while DA levels were decreased. For all markers evaluated, we observed protective effects of L-KYN+PROB on the dopaminergic damage induced by 6-OHDA. Our results suggest that this strategy was useful to mitigate dopaminergic toxicity in the hemiparkinsonian model. The combined use of L-KYN and PROB is a valuable tool to modulate glutamatergic and cholinergic activities, presumably by means of increased levels of endogenous KYNA.
Assuntos
Corpo Estriado/efeitos dos fármacos , Ácido Cinurênico/metabolismo , Cinurenina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/prevenção & controle , Oxidopamina/toxicidade , Probenecid/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Cinurenina/administração & dosagem , Masculino , Fármacos Neuroprotetores/administração & dosagem , Síndromes Neurotóxicas/metabolismo , Probenecid/administração & dosagem , Ratos , Ratos WistarRESUMO
We studied the cellular damage in a patient with Dyke-Davidoff-Masson Syndrome and a history of chronic temporal lobe epilepsy resistant to treatment. The epileptogenic zone was localized to the right temporal lobe, and an extensive surgical removal of the temporal neocortex plus amygdala and hippocampus was performed. The specimens were immediately frozen in liquid nitrogen and stored at -75 degrees C for biochemical studies. Specimens were immersed and fixed in freshly prepared 4% paraformaldehyde for histopathological evaluation. Neurotransmitter levels were highest in the hippocampus compared to the temporal neocortex (T1, T2, and T3). In the amygdala, GABA was found whereas other amino acids were absent. We found marked dislamination in all areas of the cortex, neuronal loss, amylaceous bodies, and neuronal cytomegaly with cytoskeletal disorganization containing dense fibrillar cytoplasmic aggregates, nodular heterotopias, dysplastic and large neurons with high Nissl staining, intermixed with balloon cells with atypical nuclei, often with binucleation, and abundant glassy eosinophilic cytoplasm. Positive immunoreactive cells with nestin, vimentin, and enhanced expression of astrocytes were observed in all brain regions. This patient's syndrome should be considered as a postinfectious/post-stroke event that caused hemiparesis and later recurrent seizures. Higher expression of nestin and vimentin has been observed in proliferative neuronal cells, the expression in astrocytes may mainly reflect an early response of these cells to injury. Nestin may play a role in protecting the brain from injury. It has been proposed that re-expression of embryonic genes by mature cells is associated with morphological plasticity.
Assuntos
Encefalopatias/patologia , Encéfalo/patologia , Assimetria Facial/patologia , Lobo Temporal/patologia , Atrofia , Feminino , Humanos , Recém-Nascido , SíndromeRESUMO
We have recently demonstrated that S-allylcysteine (SAC) induces protection on neurochemical, biochemical and behavioral markers of striatal damage in different neurotoxic animal models - including a murine model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridinium (MPTP) injection to mice - indicating that pro-oxidant reactions underlie neurotoxicity in these models (García et al. 2008). In this work we investigated whether SAC can protect the striatum of mice from the morphological alterations in the MPTP toxic model, and if this response is correlated with a reduction in pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) expressions, and further reduction in astrocyte activation (glial fibrillary acidic protein (GFAP) expression). The striatal tissue from MPTP injected animals (30 mg/kg, i.p., ×5 days) showed a significant degree of cell damage and enhanced immunoreactivities to GFAP, TNF-α and iNOS, as well as an enhanced number of apoptotic nuclei. Treatment of mice with SAC (120 mg/kg, i.p., ×5 days) in parallel to MPTP significantly reduced or prevented all these markers. Our results suggest that MPTP-induced morphological alterations recruit a pro-inflammatory component triggered by cytokine TNF-α release and nitric oxide formation, which is sensitive to the antioxidant properties of SAC. This antioxidant is an effective experimental tool to reduce the brain lesions associated with oxidative damage and inflammatory responses.
Assuntos
Antioxidantes/uso terapêutico , Corpo Estriado/efeitos dos fármacos , Cisteína/análogos & derivados , Mediadores da Inflamação/metabolismo , Intoxicação por MPTP/prevenção & controle , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Cisteína/farmacologia , Cisteína/uso terapêutico , Modelos Animais de Doenças , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
There is no information concerning signal transduction mechanisms downstream of the opioid/nociceptin receptors in the human epileptic brain. The aim of this work was to evaluate the level of G-proteins activation mediated by DAMGO (a mu receptor selective peptide) and nociceptin, and the binding to mu and nociceptin (NOP) receptors and adenylyl cyclase (AC) in neocortex of patients with pharmacoresistant temporal lobe epilepsy. Patients with temporal lobe epilepsy associated with mesial sclerosis (MTLE) or secondary to tumor or vascular lesion showed enhanced [3H]DAMGO and [3H]forskolin binding, lower DAMGO-stimulated [35S]GTPgammaS binding and no significant changes in nociceptin-stimulated G-protein. [3H]Nociceptin binding was lower in patients with MTLE. Age of seizure onset correlated positively with [3H]DAMGO binding and DAMGO-stimulated [35S]GTPgammaS binding, whereas epilepsy duration correlated negatively with [3H]DAMGO and [3H]nociceptin binding, and positively with [3H]forskolin binding. In conclusion, our present data obtained from neocortex of epileptic patients provide strong evidence that a) temporal lobe epilepsy is associated with alterations in mu opioid and NOP receptor binding and signal transduction mechanisms downstream of these receptors, and b) clinical aspects may play an important role on these receptor changes.
Assuntos
Epilepsia do Lobo Temporal/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Neocórtex/metabolismo , Receptores Opioides mu/metabolismo , Receptores Opioides/metabolismo , Lobo Temporal/metabolismo , Adenilil Ciclases/metabolismo , Adulto , Fármacos do Sistema Nervoso Central/farmacologia , Colforsina/farmacologia , Ala(2)-MePhe(4)-Gly(5)-Encefalina/metabolismo , Feminino , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos Opioides/metabolismo , Radioisótopos de Enxofre , Trítio , Adulto Jovem , Receptor de Nociceptina , NociceptinaRESUMO
Excitotoxicity and disrupted energy metabolism are major events leading to nerve cell death in neurodegenerative disorders. These cooperative pathways share one common aspect: triggering of oxidative stress by free radical formation. In this work, we evaluated the effects of the antioxidant and energy precursor, levocarnitine (L-CAR), on the oxidative damage and the behavioral, morphological, and neurochemical alterations produced in nerve tissue by the excitotoxin and free radical precursor, quinolinic acid (2,3-pyrindin dicarboxylic acid; QUIN), and the mitochondrial toxin, 3-nitropropionic acid (3-NP). Oxidative damage was assessed by the estimation of reactive oxygen species formation, lipid peroxidation, and mitochondrial dysfunction in synaptosomal fractions. Behavioral, morphological, and neurochemical alterations were evaluated as markers of neurotoxicity in animals systemically administered with L-CAR, chronically injected with 3-NP and/or intrastriatally infused with QUIN. At micromolar concentrations, L-CAR reduced the three markers of oxidative stress stimulated by both toxins alone or in combination. L-CAR also prevented the rotation behavior evoked by QUIN and the hypokinetic pattern induced by 3-NP in rats. Morphological alterations produced by both toxins (increased striatal glial fibrillary acidic protein-immunoreactivity for QUIN and enhanced neuronal damage in different brain regions for 3-NP) were reduced by L-CAR. In addition, L-CAR prevented the synergistic action of 3-NP and QUIN to increase motor asymmetry and depleted striatal GABA levels. Our results suggest that the protective properties of L-CAR in the neurotoxic models tested are mostly mediated by its characteristics as an antioxidant agent.
Assuntos
Encéfalo/metabolismo , Carnitina/farmacologia , Metabolismo Energético/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Neurotoxinas/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Convulsivantes/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Metabolismo Energético/fisiologia , Radicais Livres/metabolismo , Gliose/tratamento farmacológico , Gliose/fisiopatologia , Gliose/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Transtornos dos Movimentos/tratamento farmacológico , Transtornos dos Movimentos/fisiopatologia , Transtornos dos Movimentos/prevenção & controle , Degeneração Neural/tratamento farmacológico , Degeneração Neural/fisiopatologia , Degeneração Neural/prevenção & controle , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/metabolismo , Nitrocompostos/toxicidade , Estresse Oxidativo/fisiologia , Propionatos/toxicidade , Ácido Quinolínico/metabolismo , Ácido Quinolínico/toxicidade , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Resultado do TratamentoRESUMO
Reactive oxygen and nitrogen species formation leads to DNA damage in animals treated with quinolinic acid. Poly(ADP-ribose) polymerase-1 (PARP-1) is a protein involved in the DNA base excision repair system. Its overactivation promotes cellular energy deficit and necrosis. Here, we evaluated the effect of PJ-34, a potent inhibitor of PARP-1, on the neuronal damage induced by quinolinic acid. Animals were administered with PJ-34 (10 mg/kg, i.p.), 1 h before and 1 h after a striatal infusion of 1 microl of quinolinic acid (240 nmol). PJ-34 clearly attenuated the circling behavior produced by quinolinic acid and completely prevented the histological damage induced by the toxin. The protective effect of PJ-34 suggests that PARP-1 activation is playing an active role in the neuronal death induced by quinolinic acid.
Assuntos
Neurônios/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Ácido Quinolínico/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/citologia , Morte Celular/efeitos dos fármacos , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Masculino , Fenantrenos/farmacologia , Ratos , Ratos Wistar , Comportamento Estereotipado/efeitos dos fármacosRESUMO
The main goal of the present study was to evaluate binding to serotonin in the neocortex surrounding the epileptic focus of patients with mesial temporal lobe epilepsy (MTLE). Binding to 5-HT, 5-HT(1A), 5-HT(4), 5-HT(7) receptors and serotonin transporter (5-HTT) in T1-T2 gyri of 15 patients with MTLE and their correlations with clinical data, neuronal count and volume were determined. Autopsy material acquired from subjects without epilepsy (n=6) was used as control. The neocortex from MTLE patients demonstrated decreased cell count in layers III-IV (21%). No significant changes were detected on the neuronal volume. Autoradiography experiments showed the following results: reduced 5-HT and 5-HT(1A) binding in layers I-II (24% and 92%, respectively); enhanced 5-HT(4) binding in layers V-VI (32%); no significant changes in 5-HT(7) binding; reduced 5-HTT binding in all layers (I-II, 90.3%; III-IV, 90.3%, V-VI, 86.9%). Significant correlations were found between binding to 5-HT(4) and 5-HT(7) receptors and age of seizure onset, duration of epilepsy and duration of antiepileptic treatment. The present results support an impaired serotoninergic transmission in the neocortex surrounding the epileptic focus of patients with MTLE, a situation that could be involved in the initiation and propagation of seizure activity.
Assuntos
Autorradiografia , Epilepsia do Lobo Temporal/patologia , Neocórtex/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Adulto , Idade de Início , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neocórtex/efeitos dos fármacos , Neocórtex/patologia , Neurônios/metabolismo , Neurônios/patologia , Mudanças Depois da Morte , Serotoninérgicos/farmacocinética , Distribuição TecidualRESUMO
Excitotoxicity elicited by overactivation of N-methyl-D-aspartate receptors is a well-known characteristic of quinolinic acid-induced neurotoxicity. However, since many experimental evidences suggest that the actions of quinolinic acid also involve reactive oxygen species formation and oxidative stress as major features of its pattern of toxicity, the use of antioxidants as experimental tools against the deleterious effects evoked by this neurotoxin becomes more relevant. In this work, we investigated the effect of a garlic-derived compound and well-characterized free radical scavenger, S-allylcysteine, on quinolinic acid-induced striatal neurotoxicity and oxidative damage. For this purpose, rats were administered S-allylcysteine (150, 300 or 450 mg/kg, i.p.) 30 min before a single striatal infusion of 1 microl of quinolinic acid (240 nmol). The lower dose (150 mg/kg) of S-allylcysteine resulted effective to prevent only the quinolinate-induced lipid peroxidation (P < 0.05), whereas the systemic administration of 300 mg/kg of this compound to rats decreased effectively the quinolinic acid-induced oxidative injury measured as striatal reactive oxygen species formation (P < 0.01) and lipid peroxidation (P < 0.05). S-Allylcysteine (300 mg/kg) also prevented the striatal decrease of copper/zinc-superoxide dismutase activity (P < 0.05) produced by quinolinate. In addition, S-allylcysteine, at the same dose tested, was able to reduce the quinolinic acid-induced neurotoxicity evaluated as circling behavior (P < 0.01) and striatal morphologic alterations. In summary, S-allylcysteine ameliorates the in vivo quinolinate striatal toxicity by a mechanism related to its ability to: (a) scavenge free radicals; (b) decrease oxidative stress; and (c) preserve the striatal activity of Cu,Zn-superoxide dismutase (Cu,Zn-SOD). This antioxidant effect seems to be responsible for the preservation of the morphological and functional integrity of the striatum.
Assuntos
Antioxidantes/farmacologia , Cisteína/análogos & derivados , Cisteína/farmacologia , Alho/química , Síndromes Neurotóxicas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Ácido Quinolínico/antagonistas & inibidores , Ácido Quinolínico/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Western Blotting , Peso Corporal , Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Neostriado/efeitos dos fármacos , Neostriado/enzimologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superóxido Dismutase/metabolismoRESUMO
Cadmium (Cd) is neurotoxic metal which induces histopathological damage and oxidative stress through free radicals over production. Metallothionein (MT) is a protein able to scavenge free radicals and to chelate metals. In this study we describe the lipid peroxidation (LPO) and MT content in the brain of developing rats exposed at Cd 1 mg/kg/day intra peritoneally (i.p.) and dexamethasone (Dx) 2 mg/kg/day (i.p.) alone and combined during 5 days. At those doses, cadmium significantly increases the levels of LPO in parietal cortex, striatum and cerebellum as compared to a control group while, in the hippocampus no modifications in the LPO levels were observed. In the group treated with Cd+Dx, Dx significantly diminished the levels of LPO in parietal cortex, striatum and cerebellum. On the other hand, the MT levels showed a significant increase in all regions of the groups treated with Dx and Cd+Dx as compared with the control group. These results show that Dx treatment prevented the increase in LPO levels associated to Cd exposure, probably through the increase in MT content.
Assuntos
Anti-Inflamatórios/farmacologia , Química Encefálica/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Cádmio/antagonistas & inibidores , Cádmio/toxicidade , Dexametasona/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Metalotioneína/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Feminino , Corantes Fluorescentes , Indicadores e Reagentes , Masculino , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/prevenção & controle , Ratos , Ratos WistarRESUMO
Quinolinic acid (QUIN), a well known excitotoxin that produces a pharmacological model of Huntington's disease in rats and primates, has been shown to evoke degenerative events in nerve tissue via NMDA receptor (NMDAr) overactivation and oxidative stress. In this study, the antioxidant selenium (as sodium selenite) was tested against different markers of QUIN-induced neurotoxicity under both in vitro and in vivo conditions. In the in vitro experiments, a concentration-dependent effect of selenium was evaluated on the regional peroxidative action of QUIN as an index of oxidative toxicity in rat brain synaptosomes. In the in vivo experiments, selenium (0.625 mg per kg per day, i.p.) was administered to rats for 5 days, and 2 h later animals received a single unilateral striatal injection of QUIN (240 nmol/ micro L). Rats were killed 2 h after the induction of lesions with QUIN to measure lipid peroxidation and glutathione peroxidase (GPx) activity in striatal tissue. In other groups, the rotation behavior, GABA content, morphologic alterations, and the corresponding ratio of neuronal damage were all evaluated as additional markers of QUIN-induced striatal toxicity 7 days after the intrastriatal injection of QUIN. Selenium decreased the peroxidative action of QUIN in synaptosomes both from whole rat brain and from the striatum and hippocampus, but not in the cortex. A protective concentration-dependent effect of selenium was observed in QUIN-exposed synaptosomes from whole brain and hippocampus. Selenium pre-treatment decreased the in vivo lipid peroxidation and increased the GPx activity in QUIN-treated rats. Selenium also significantly attenuated the QUIN-induced circling behavior, the striatal GABA depletion, the ratio of neuronal damage, and partially prevented the morphologic alterations in rats. These data suggest that major features of QUIN-induced neurotoxicity are partially mediated by free radical formation and oxidative stress, and that selenium partially protects against QUIN toxicity.
Assuntos
Antioxidantes/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Ácido Quinolínico , Selênio/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Química Encefálica , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Selenito de Sódio/uso terapêutico , Sinaptossomos/química , Sinaptossomos/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismoRESUMO
Cocaine is a common drug of abuse, and its use has emerged as a major public health problem with neurological complications. In this work, the authors studied microscopic lesions produced in brain by chronic cocaine administration to rats. Twenty-five Wistar rats were exposed to 30 mg/kg/day ip of cocaine and sacrificed at 15, 30, 45, 60, and 90 days after treatment and compared to 25 control rats injected daily with saline. The parietal cortex (Cx), hippocampus (Hp), substantia nigra (SN), and cerebellum (Ce) were morphologically analyzed. The authors found progressive light microscopic lesions in all regions studied, including nuclear pyknosis and atrophy, interstitial edema, broken fibers, and necrosis. Results show that chronic treatment with cocaine in rats leads to selective severe lesions in different brain regions.
Assuntos
Encéfalo/patologia , Transtornos Relacionados ao Uso de Cocaína/patologia , Cocaína/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Neurônios/efeitos dos fármacos , Neurônios/patologia , Especificidade de Órgãos , Ratos , Ratos Wistar , Comportamento Estereotipado/efeitos dos fármacosRESUMO
Los solventes industriales constituyen una mezcla denominada thinner. Se usa en industrias de pintura, pieles, hule, pegamento, barnices, etc., y tienen importante acción neurotóxica. Por inhalación laboral o espontánea pasan al sistema nervioso y desencadenan cambios de conducta, euforia, alucionaciones auditivas, visuales y ataxia. La inhalación crónica produce demencia esquizofrénica-paranóica debido a la destrucción neuronal y fibras nerviosas encefálicas y periféricas, acompañada de ceguera y parálisis. Otra droga neurotóxica es la cocaína. Produce euforia, hipertensión arterial y acción estimulante. Por adicción crónica compulsiva desencadena demencia paranoide al destruir neuronas y fibras nerviosas encefálicas y periféricas. Frecuentemente hay suicidio terminal