RESUMO
This study investigated the respiratory activity in adult Wistar rats across different behavioral seizure severity induced by pentylenetetrazole (PTZ). Animals underwent surgery for electrodes implantation, allowing simultaneous EEG and diaphragm EMG (DIAEMG) recordings and the respiratory frequency and DIAEMG amplitude were measured. Seizures were acutely induced through PTZ injection and classified based on a pre-established score, with absence-like seizures (spike wave discharge (SWD) events on EEG) representing the lowest score. The respiratory activity was grouped into the different seizure severities. During absence-like and myoclonic jerk seizures, the breathing frequency decreased significantly (â¼50% decrease) compared to pre- and post-ictal periods. Pronounced changes occurred with more severe seizures (clonic and tonic) with periods of apnea, especially during tonic seizures. Apnea duration was significantly higher in tonic compared to clonic seizures. Notably, during PTZ-induced tonic seizures the apnea events were marked by tonic DIAEMG contraction (tonic-phase apnea). In the majority of animals (5 out of 7) this was a fatal event in which the seizure-induced respiratory arrest preceded the asystole. In conclusion, we provide an assessment of the respiratory activity in the PTZ-induced acute seizures and showed that breathing dysfunction is more pronounced in seizures with higher severity.
Assuntos
Apneia , Pentilenotetrazol , Ratos , Animais , Pentilenotetrazol/toxicidade , Ratos Wistar , Convulsões/induzido quimicamente , Taxa RespiratóriaRESUMO
Epilepsy is a chronic condition characterized by recurrent spontaneous seizures. The interaction between astrocytes and neurons has been suggested to play a role in the abnormal neuronal activity observed in epilepsy. However, the exact way astrocytes influence neuronal activity in the epileptogenic brain remains unclear. Here, using the PTZ-induced kindling mouse model, we evaluated the interaction between astrocyte and synaptic function by measuring astrocytic Ca2+ activity, neuronal excitability, and the excitatory/inhibitory balance in the hippocampus. Compared to control mice, hippocampal slices from PTZ-kindled mice displayed an increase in glial fibrillary acidic protein (GFAP) levels and an abnormal pattern of intracellular Ca2+-oscillations, characterized by an increased frequency of prolonged spontaneous transients. PTZ-kindled hippocampal slices also showed an increase in the E/I ratio towards excitation, likely resulting from an augmented release probability of excitatory inputs without affecting inhibitory synapses. Notably, the alterations in the release probability seen in PTZ-kindled slices can be recovered by reducing astrocyte hyperactivity with the reversible toxin fluorocitrate. This suggests that astroglial hyper-reactivity enhances excitatory synaptic transmission, thereby impacting the E/I balance in the hippocampus. Altogether, our findings support the notion that abnormal astrocyte-neuron interactions are pivotal mechanisms in epileptogenesis.
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Epilepsia , Excitação Neurológica , Camundongos , Animais , Pentilenotetrazol/efeitos adversos , Astrócitos/metabolismo , Epilepsia/metabolismo , Excitação Neurológica/metabolismo , Convulsões/metabolismo , Hipocampo/metabolismoRESUMO
Pentylenetetrazol (PTZ) blocks the inhibitory action of GABA, triggering a Glu-mediated hyperexcitation of the dendritic spines in hippocampal CA1 pyramidal neurons that leads to the generation of epileptiform seizures. The aim of this work was to determine the effect of PTZ on the electrical activity of the hippocampal pyramidal neurons in male rats. Bipolar electrodes were implanted stereotaxically in the right and left hippocampal CA1 fields of adults, and PTZ (65 mg/kg) was administered i.p. Simultaneous recordings of the field activity and the firing rate (multiunitary activity, MUA) were analyzed at 10, 20, and 30 min post-administration of PTZ. Only rats that presented tonic-clonic seizures during the first 1-5 min after PTZ treatment were included in the study. The recordings of the field activity were analyzed in 4 frequency bands. In both the right and left hippocampal CA1 fields, the relative power corresponding to the slow waves (4-7 Hz) increased, while in the bands 13-30 Hz and 31-50 Hz, it decreased at 10, 20, and 30 min post-PTZ. MUA recordings were analyzed at four levels. The highest levels corresponded to larger amplitudes of the action potentials in the pyramidal neurons. The firing rates of the PTZ-treated rats did not differ from baseline but presented a significant decrement at 10, 20, and 30 min post-PTZ. The decreased firing rate of the hippocampal CA1 pyramidal neurons after PTZ treatment could be associated with plastic changes of dendritic spines along with some microenvironmental adaptations at synaptic level, after neuronal PTZ-mediated hyperexcitation.
Assuntos
Pentilenotetrazol , Células Piramidais , Ratos , Masculino , Animais , Pentilenotetrazol/farmacologia , Convulsões/induzido quimicamente , Hipocampo , Potenciais de AçãoRESUMO
BACKGROUND: The phytocannabinoid cannabidiol (CBD) has previously shown to have anticonvulsant effects in preclinical and clinical studies. Recently, CBD has been approved to treat certain types of drug-resistant epileptic syndromes. However, the underlying mechanism of action remains unclear. The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been proposed to modulate seizures and might be recruited by CBD. Thus, we tested the hypothesis that the anticonvulsant effect of CBD involves PI3K in a seizure model induced by pentylenetetrazole (PTZ). METHODS: We employed pharmacological and genetic approaches to inhibit PI3K and quantified its effects on seizure duration, latency, and number. RESULTS: PI3K genetic ablation increased the duration and number of seizures. CBD inhibited PTZ-induced seizures in mice. Genetic deletion of PI3K or pretreatment with the selective inhibitor LY294002 prevented CBD effects. CONCLUSION: Our data strengthen the hypothesis that the CBD anticonvulsant effect requires the PI3K signaling pathway.
Assuntos
Canabidiol , Pentilenotetrazol , Animais , Camundongos , Pentilenotetrazol/toxicidade , Canabidiol/farmacologia , Anticonvulsivantes/uso terapêutico , Fosfatidilinositol 3-Quinases , Fosfatidilinositol 3-Quinase , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/metabolismoRESUMO
Pharmacological treatments of central nervous system diseases are always challenging due to the restrictions imposed by the blood-brain barrier: while some drugs can effectively cross it, many others, some antiepileptic drugs among them, display permeability issues to reach the site of action and exert their pharmacological effects. The development of last-generation therapeutic nanosystems capable of enhancing drug biodistribution has gained ground in the past few years. Lipid-based nanoparticles are promising systems aimed to improve or facilitate the passage of drugs through biological barriers, which have demonstrated their effectiveness in various therapeutic fields, without signs of associated toxicity. In the present work, nanostructured lipid carriers (NLCs) containing the antiepileptic drug phenobarbital were designed and optimized by a quality by design approach (QbD). The optimized formulation was characterized by its entrapment efficiency, particle size, polydispersity index, and Z potential. Thermal properties were analyzed by DSC and TGA, and morphology and crystal properties were analyzed by AFM, TEM, and XRD. Drug localization and possible interactions between the drug and the formulation components were evaluated using FTIR. In vitro release kinetic, cytotoxicity on non-tumoral mouse fibroblasts L929, and in vivo anticonvulsant activity in an animal model of acute seizures were studied as well. The optimized formulation resulted in spherical particles with a mean size of ca. 178 nm and 98.2% of entrapment efficiency, physically stable for more than a month. Results obtained from the physicochemical and in vitro release characterization suggested that the drug was incorporated into the lipid matrix losing its crystalline structure after the synthesis process and was then released following a slower kinetic in comparison with the conventional immediate-release formulation. The NLC was non-toxic against the selected cell line and capable of delivering the drug to the site of action in an adequate amount and time for therapeutic effects, with no appreciable neurotoxicity. Therefore, the developed system represents a promising alternative for the treatment of one of the most prevalent neurological diseases, epilepsy.
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Epilepsy is the most common neurological condition worldwide and is largely associated with memory impairment, both in human as well as animal models. Furthermore, differences in seizure onset and severity have already been observed between the sexes. The induction of epilepsy through multiple systemic injections of pentylenetetrazole (PTZ), a protocol known as chemical kindling, is a well-established tool for studies regarding epileptogenesis, as well as the efficacy of antiseizure medication. The aim of this study was to compare possible sex-related differences in seizure severity, memory, neuronal damage as well as the effects of the estrous cycle on seizure severity. Male (nâ¯=â¯10) and Female (nâ¯=â¯11) animals received 30â¯mg/kg i.p. injections three days a week for 6â¯weeks and, after the last application, were tested for short and long-term memory. Control, Male (nâ¯=â¯8) and Female (nâ¯=â¯5) groups did not receive PTZ injections. Although PTZ did not promote important changes into the estrous cycle phases throughout the entire experiment, female animals presented lower seizure scores but had both short and long-term memory impairments associated with cell loss in the hippocampus and anterior cingulate area. Male rats presented higher seizure scores associated with pronounced cell loss, but only long-term memory deficits. Our results demonstrate that the PTZ kindling protocol results in higher seizure scores with increased vulnerability in male rats, but female rats displayed more intense memory deficits.
Assuntos
Excitação Neurológica , Pentilenotetrazol , Animais , Feminino , Humanos , Masculino , Transtornos da Memória/induzido quimicamente , Pentilenotetrazol/toxicidade , Ratos , Ratos Wistar , Memória EspacialRESUMO
The GABAergic and glutamatergic neurotransmission systems are involved in seizures and other disorders of the central nervous system (CNS). Benzofuran derivatives often serve as the core in drugs used to treat such neurological disorders. The aim of this study was to synthesize new γ-amino acids structurally related to GABA and derived from 2,3-disubstituted benzofurans, analyze in silico their potential toxicity, ADME properties, and affinity for the GluN1-GluN2A NMDA receptor, and evaluate their potential activity and neuronal mechanisms in a murine model of pentylenetetrazol (PTZ)- and 4-aminopyridine (4-AP)-induced seizures. The in silico analysis evidenced a low risk of toxicity for the test compounds as well as the probability that they can cross the blood-brain barrier (BBB) to reach their targets in the CNS. According to docking simulations, these compounds bind at the active site of the NMDA glutamate receptor with high affinity. The in vivo assays demonstrated that 4 protects against 4-AP-induced seizure episodes, suggesting negative allosteric modulation (NAMs) at the glutamatergic NMDA receptor. Contrarily, 3 (the regioisomer of 4) and its racemic derivatives (cis-2,3-dihydrobenzofurans) were previously described to exacerbate such episodes, pointing to their positive allosteric modulation (PAMs) of the same receptor.
Assuntos
Benzofuranos , Receptores de N-Metil-D-Aspartato , Aminoácidos , Animais , Benzofuranos/farmacologia , Ligantes , Camundongos , Pentilenotetrazol , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Epilepsy accounts for one of the most serious neurological disorders, and its treatment remains a challenge, due to high cost and harmful side effects. Bioactive molecules extracted from arthropod venoms are considered a promising therapy since these compounds are known for their highly selective and potent profiles. The purpose of this study was to identify and characterize the potential antiseizure effect of the peptide Ppnp7, extracted from the venom of the social wasp Polybia paulista, and also the effect of the bioinspired peptide, named Neuropolybin, in the same parameters. Additionally, we also evaluated the electroencephalographic (EEG) profile in the PTZ-induced acute seizures in animals treated with Neuropolybin, and potential adverse effects of both peptides in general spontaneous activity (Open Field analysis). Interestingly, Ppnp7 and Neuropolybin showed a noteworthy antiseizure effect in rats and mice, respectively. Curves of protection against the maximum seizure were obtained for both peptides, and EEG records demonstrated that Neuropolybin protected 80% of animals from tonic-clonic seizures when applied with a dose of 3 nmol (an approximate Ppnp7 ED50 found in rats). Neuropolybin and Ppnp7 did not cause changes in the general spontaneous activity of the animals in any of the doses evaluated. Therefore, this study demonstrated how compounds isolated from wasps' venom may be essential resources in the search for new drugs, and can also be considered valuable therapeutic and biotechnological tools for the study and future treatment of epileptic disorders.
Assuntos
Anticonvulsivantes/farmacologia , Epilepsia/prevenção & controle , Peptídeos/farmacologia , Convulsões/prevenção & controle , Animais , Anticonvulsivantes/química , Anticonvulsivantes/uso terapêutico , Eletroencefalografia , Epilepsia/induzido quimicamente , Epilepsia/fisiopatologia , Feminino , Masculino , Camundongos , Pentilenotetrazol , Peptídeos/química , Peptídeos/uso terapêutico , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Venenos de Vespas/química , Venenos de Vespas/metabolismoRESUMO
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are the predominant mediators of glutamate-induced excitatory neurotransmission. It is widely accepted that AMPA receptors are critical for the generation and spread of epileptic seizure activity. Dysfunction of AMPA receptors as a causal factor in patients with intractable epilepsy results in neurotransmission failure. Brain-specific serine/threonine-protein kinase 1 (SAD-B), a serine-threonine kinase specifically expressed in the brain, has been shown to regulate AMPA receptor-mediated neurotransmission through a presynaptic mechanism. In cultured rat hippocampal neurons, the overexpression of SAD-B significantly increases the frequency of miniature excitatory postsynaptic currents (mEPSCs). Here, we showed that SAD-B downregulation exerted antiepileptic activity by regulating AMPA receptors in patients with temporal lobe epilepsy (TLE) and in the pentylenetetrazol (PTZ)-induced epileptic model. We first used immunoblotting and immunohistochemistry analysis to demonstrate that SAD-B expression was increased in the epileptic rat brain. Subsequently, to explore the function of SAD-B in epilepsy, we used siRNA to knock down SAD-B protein and observed behavior after PTZ-induced seizures. We found that SAD-B downregulation attenuated seizure severity and susceptibility in the PTZ-induced epileptic model. Furthermore, we showed that the antiepileptic effect of SAD-B downregulation on PTZ-induced seizure was abolished by CNQX (an AMPA receptor inhibitor), suggesting that SAD-B modulated epileptic seizure by regulating AMPA receptors in the brain. Taken together, these findings suggest that SAD-B may be a potential and novel therapeutic target to limit epileptic seizures.
Assuntos
Humanos , Animais , Masculino , Feminino , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Medicamentos de Ervas Chinesas/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de AMPA/metabolismo , Agonistas de Aminoácidos Excitatórios/metabolismo , Epilepsia do Lobo Temporal/tratamento farmacológico , Pentilenotetrazol , Ratos Sprague-Dawley , Epilepsia do Lobo Temporal/induzido quimicamenteRESUMO
Background and Objectives: The cannabinoid receptor 2 (CB2) was previously implicated in brain functions, including complex behaviors. Here, we assessed the role of CB2 in selected swimming behaviors in zebrafish larvae and developed an in vivo upscalable whole-organism approach for CB2 ligand screening. Experimental Approach: Using CRISPR-Cas9 technology, we generated a novel null allele (cnr2upr1 ) and a stable homozygote-viable loss-of-function (CB2-KO) line. We measured in untreated wild-type and cnr2upr1/upr1 larvae, photo-dependent (swimming) responses (PDR) and center occupancy (CO) to establish quantifiable anxiety-like parameters. Next, we measured PDR alteration and CO variation while exposing wild-type and mutant animals to an anxiolytic drug (valproic acid [VPA]) or to an anxiogenic drug (pentylenetetrazol [PTZ]). Finally, we treated wild-type and mutant larvae with two CB2-specific agonists (JWH-133 and HU-308) and two CB2-specific antagonists, inverse agonists (AM-630 and SR-144528). Results: Untreated CB2-KO showed a different PDR than wild-type larvae as well as a decreased CO. VPA treatments diminished swimming activity in all animals but to a lesser extend in mutants. CO was strongly diminished and even more in mutants. PTZ-induced inverted PDR was significantly stronger in light and weaker in dark periods and the CO lower in PTZ-treated mutants. Finally, two of four tested CB2 ligands had a detectable activity in the assay. Conclusions: We showed that larvae lacking CB2 behave differently in complex behaviors that can be assimilated to anxiety-like behaviors. Mutant larvae responded differently to VPA and PTZ treatments, providing in vivo evidence of CB2 modulating complex behaviors. We also established an upscalable combined genetic/behavioral approach in a whole organism that could be further developed for high-throughput drug discovery platforms.
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BACKGROUND: Benzofurans are heterocyclic compounds with neurotropic activity. Some have been developed for the treatment of acute and degenerative neuronal injuries. OBJECTIVE: The study aimed to evaluate the in silico binding of some promising benzofurans on the GABA receptors, and the in vivo neurotropic activity of benzofuran analogues (BZF 6-10) of gamma-aminobutyric acid (GABA) on a seizure model. METHODS: The ligands with the best physicochemical attributes were docked on two GABA receptors (the alpha-1 subunit of GABAA-R and GBR1 subunit of GABAB-R). Selected benzofuran derivatives were synthesized by a multistep procedure and characterized. To examine the neurotropic effects, mice were pretreated with different concentrations of the compounds prior to PTZ- or 4- AP-induced seizures. We assessed acute toxicity, motor behavior, and the effects on seizures. RESULTS: The tested ligands that complied with Lipinski's rule of five were tested in silico with GABAA-R (ΔG = -5.51 to -5.84 kcal/mol) at the allosteric site for benzodiazepines. They bound to a similar cluster of residues as the reference compound (gaboxadol, ΔG = -5.51 kcal/mol). Synthesis was achieved with good overall yields (42-9.7%). Two compounds were selected for biological tests (BZF-7 and rac-BZF-10) on a mouse model of seizures, induced by pentylenetetrazol (PTZ) or 4-aminopyridine (4-AP). PTZ-induced seizures are associated with GABA receptors, and those 4-AP-induced with the blockage of the delayed rectifier-type potassium channel, which promotes the release of the NMDA-sensitive glutamatergic ionotropic receptor and other neurotransmitters. The biological assays demonstrated that BZF-7 and rac-BZF-10 do not protect against seizures. Indeed, BZF-7 increased the number of PTZ-induced seizures and decreased latency time. The 4-AP model apparently showed a potentiation of seizure effects after administration of the BZF-analogues, evidenced by the incidence and severity of the seizures and reduced latency time. CONCLUSION: The results suggest that the test compounds are GABAergic antagonists with stimulatory activity on the CNS.
Assuntos
Benzofuranos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-B/farmacologia , Animais , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/toxicidade , Estimulantes do Sistema Nervoso Central/síntese química , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/toxicidade , Antagonistas de Receptores de GABA-A/síntese química , Antagonistas de Receptores de GABA-A/química , Antagonistas de Receptores de GABA-A/toxicidade , Antagonistas de Receptores de GABA-B/síntese química , Antagonistas de Receptores de GABA-B/química , Antagonistas de Receptores de GABA-B/toxicidade , Humanos , Ligantes , Masculino , Camundongos , Simulação de Acoplamento Molecular , Receptores de GABA-A/química , Receptores de GABA-B/químicaRESUMO
Astrocytes are the major glial cells in brain tissue and are involved, among many functions, ionic and metabolic homeostasis maintenance of synapses. These cells express receptors and transporters for neurotransmitters, including GABA. GABA signaling is reportedly able to affect astroglial response to injury, as evaluated by specific astrocyte markers such as glial fibrillary acid protein and the calcium-binding protein, S100B. Herein, we investigated the modulatory effects of the GABAA receptor on astrocyte S100B secretion in acute hippocampal slices and astrocyte cultures, using the agonist, muscimol, and the antagonists pentylenetetrazol (PTZ) and bicuculline. These effects were analyzed in the presence of tetrodotoxin (TTX), fluorocitrate (FLC), cobalt and barium. PTZ positively modify S100B secretion in hippocampal slices and astrocyte cultures; in contrast, bicuculline inhibited S100B secretion only in hippocampal slices. Muscimol, per se, did not change S100B secretion, but prevented the effects of PTZ and bicuculline. Moreover, PTZ-induced S100B secretion was prevented by TTX, FLC, cobalt and barium indicating a complex GABAA communication between astrocytes and neurons. The effects of two putative agonists of GABAA, ß-hydroxybutyrate and methylglyoxal, on S100B secretion were also evaluated. In view of the neurotrophic role of extracellular S100B under conditions of injury, our data reinforce the idea that GABAA receptors act directly on astrocytes, and indirectly on neurons, to modulate astroglial response.
Assuntos
Astrócitos/metabolismo , Hipocampo/efeitos dos fármacos , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Bicuculina/farmacologia , Células Cultivadas , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Masculino , Muscimol/farmacologia , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos Wistar , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismoRESUMO
Thalidomide was originally developed to treat primary neurological and psychiatric diseases. There are reports of anticonvulsant effects of thalidomide in rats and antiepileptic effects in patients. Hence, thalidomide (100, 200 and 400 mg/kg) was herein administered to mice to evaluate possible protection against seizures induced by the systemic administration of neurotoxins: 10 mg/kg of 4-aminopyridine (4-AP), 90 mg/kg of pentylenetetrazol (PTZ), or 380 mg/kg of pilocarpine. The effect of an NO and COX inhibitor (7-NI and ibuprofen, respectively) was also examined. The results show that thalidomide (1) induces the typical sedative effects, (2) has no anticonvulsant effect in mice treated with 4-AP, and (3) has anticonvulsant effect (400 mg/kg) in mice treated with PTZ and pilocarpine. It was found that 7-NI has an anticonvulsant effect in the pilocarpine model and that thalidomide's effect is not enhanced by its presence. However, thalidomide (200 mg/kg) plus 7-NI or ibuprofen tend to have a toxic effect in PTZ model. On the other hand, the combination of thalidomide and 7-NI or ibuprofen protects against pilocarpine-induced seizures. In conclusion, thalidomide did not exert an anticonvulsant effect for clonic-tonic type convulsions (4-AP), but it did so for seizures induced by PTZ and pilocarpine (representing absence seizures and status epilepticus, respectively). NO and prostaglandins were involved in the convulsive process elicited by pilocarpine.
Assuntos
Anticonvulsivantes , Neurotoxinas/efeitos adversos , Pentilenotetrazol/efeitos adversos , Pilocarpina/efeitos adversos , Convulsões/prevenção & controle , Talidomida/administração & dosagem , Talidomida/farmacologia , 4-Aminopiridina/efeitos adversos , Doença Aguda , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Ibuprofeno/administração & dosagem , Indazóis/administração & dosagem , Masculino , Camundongos Endogâmicos , Óxido Nítrico , Convulsões/induzido quimicamenteRESUMO
OBJECTIVES: Epilepsy is a common brain disease and a major worldwide public health problem. The seizures in a significant number of patients suffering from epilepsy remain inadequately controlled by currently available pharmacological treatments. Accordingly, there is a need for the discovery of new anticonvulsant approaches with improved efficacy and a better safety profile. In this context, natural products can be a valuable source of substances with potential anticonvulsant activity. In the present study, we tested the anticonvulsant potential of Caryocar coriaceum Wittm., a plant native from the Brazilian Cerrado biome (tropical savanna ecoregion). METHODS: Adult male C57BL/6 mice were treated with increasing doses of the fixed oil obtained from the pulp of Caryocar coriaceum Wittm. Seizure activity was induced by PTZ (60 mg/kg, i.p.), and evaluated by behavioral and electrographic methods. Potential adverse effects were investigated in the open-field, rotarod, forced swim, or object recognition tests. The antioxidant potential of the oil was evaluated by the DPPH scavenging assay. RESULTS: Administration of the oil at the dose of 100 mg/kg increased the latency for the first myoclonic jerk and the first generalized tonic-clonic seizures. The duration of generalized convulsions induced by PTZ was not altered. No significant behavioral adverse effects were detected in the open-field, rotarod, forced swim, or object recognition tests. Interestingly, a significant antioxidant activity of Caryocar coriaceum Wittm. fixed pulp oil was detected in the DPPH scavenging assay. DISCUSSION: Natural products can be a valuable source of substances with potential anticonvulsant activity and improved safety profile. Further studies are needed to evaluate the mechanisms underlying the anticonvulsant effects of Caryocar coriaceum Wittm. fixed pulp oil as well as the potential of the oil as a source of new anticonvulsant compounds.
Assuntos
Anticonvulsivantes/farmacologia , Ericales , Óleos de Plantas/farmacologia , Convulsões , Animais , Convulsivantes/toxicidade , Eletroencefalografia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pentilenotetrazol/toxicidade , Convulsões/induzido quimicamenteRESUMO
Increasing evidence suggests that plant-derived extracts and their isolated components are useful for treatment of seizures and, hence, constitute a valuable source of new antiepileptic drugs with improved efficacy and better adverse effect profile. ß-Caryophyllene is a natural bicyclic sesquiterpene that occurs in a wide range of plant species and displays a number of biological actions, including neuroprotective activity. In the present study, we tested the hypothesis that ß-caryophyllene displays anticonvulsant effects. In addition, we investigated the effect of ß-caryophyllene on behavioral parameters and on seizure-induced oxidative stress. Adult C57BL/6 mice received increasing doses of ß-caryophyllene (0, 10, 30, or 100mg/kg). After 60 min, we measured the latencies to myoclonic and generalized seizures induced by pentylenetetrazole (PTZ, 60 mg/kg). We found that ß-caryophyllene increased the latency to myoclonic jerks induced by PTZ. This result was confirmed by electroencephalographic analysis. In a separate set of experiments, we found that mice treated with an anticonvulsant dose of ß-caryophyllene (100mg/kg) displayed an improved recognition index in the object recognition test. This effect was not accompanied by behavioral changes in the open-field, rotarod, or forced swim tests. Administration of an anticonvulsant dose of ß-caryophyllene (100mg/kg) did not prevent PTZ-induced oxidative stress (i.e., increase in the levels of thiobarbituric acid-reactive substances or the decrease in nonprotein thiols content). Altogether, the present data suggest that ß-caryophyllene displays anticonvulsant activity against seizures induced by PTZ in mice. Since no adverse effects were observed in the same dose range of the anticonvulsant effect, ß-caryophyllene should be further evaluated in future development of new anticonvulsant drugs.
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Anticonvulsivantes/uso terapêutico , Convulsivantes , Pentilenotetrazol , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Epilepsias Mioclônicas/induzido quimicamente , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sesquiterpenos Policíclicos , Equilíbrio Postural/efeitos dos fármacos , Reconhecimento Psicológico , Convulsões/psicologia , Natação/psicologiaRESUMO
Cysteinyl leukotrienes (CysLTs) have been implicated in seizures and kindling; however, the effect of CysLT receptor antagonists on seizure frequency in kindled animals and changes in CysLT receptor expression after pentylenetetrazol (PTZ)-induced kindling have not been investigated. In this study, we evaluated whether the CysLT1 inverse agonist montelukast, and a classical anticonvulsant, phenobarbital, were able to reduce seizures in PTZ-kindled mice and alter CysLT receptor expression. Montelukast (10 mg/kg, sc) and phenobarbital (20 mg/kg, sc) increased the latency to generalized seizures in kindled mice. Montelukast increased CysLT1 immunoreactivity only in non-kindled, PTZ-challenged mice. Interestingly, PTZ challenge decreased CysLT2 immunoreactivity only in kindled mice. CysLT1 antagonists appear to emerge as a promising adjunctive treatment for refractory seizures. Nevertheless, additional studies are necessary to evaluate the clinical implications of this research.
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Animais , Masculino , Camundongos , Acetatos/farmacologia , Anticonvulsivantes/farmacologia , Antagonistas de Leucotrienos/farmacologia , Quinolinas/farmacologia , Convulsões/tratamento farmacológico , Acetatos/uso terapêutico , Anticonvulsivantes/uso terapêutico , Western Blotting , Convulsivantes , Excitação Neurológica/efeitos dos fármacos , Antagonistas de Leucotrienos/uso terapêutico , Pentilenotetrazol , Fenobarbital/farmacologia , Fenobarbital/uso terapêutico , Quinolinas/uso terapêutico , Receptores de Leucotrienos/efeitos dos fármacos , Convulsões/induzido quimicamente , Fatores de Tempo , Resultado do TratamentoRESUMO
The brain has a central role in the regulation of energy stability of the organism. It is the organ with the highest energetic demands, the most susceptible to energy deficits, and is responsible for coordinating behavioral and physiological responses related to food foraging and intake. Dietary interventions have been shown to be a very effective means to extend lifespan and delay the appearance of age-related pathological conditions, notably those associated with brain functional decline. The present review focuses on the effects of these interventions on brain metabolism and cerebral redox state, and summarizes the current literature dealing with dietary interventions on brain pathology.
Assuntos
Encéfalo/metabolismo , Restrição Calórica , Metabolismo Energético , Envelhecimento , Doença de Alzheimer/dietoterapia , Esclerose Lateral Amiotrófica/dietoterapia , Animais , Núcleo Arqueado do Hipotálamo/fisiologia , Autofagia , Suplementos Nutricionais , Epilepsia/dietoterapia , Ácidos Graxos/metabolismo , Comportamento Alimentar/fisiologia , Humanos , Resistência à Insulina , Longevidade , Mitocôndrias/metabolismo , Modelos Biológicos , Núcleo Accumbens/fisiologia , Oxirredução , Núcleo Hipotalâmico Paraventricular/fisiologia , Doença de Parkinson/dietoterapia , Transdução de Sinais , Sirtuína 1/fisiologia , Acidente Vascular Cerebral/dietoterapiaRESUMO
The cholinergic system is implicated in emotional regulation. The injection of non-convulsant doses of the muscarinic receptor agonist pilocarpine (PILO) induces long-lasting anxiogenic responses in rats evaluated at different time-points (24h to 3 months). To investigate the underlying mechanisms, rats treated with PILO (150mg/kg) were injected 24h or 1 month later with an anxiolytic (diazepam, 1mg/kg, DZP) or anxiogenic (pentylenetetrazole, 15mg/kg, PTZ) drug and evaluated in the elevated plus-maze (EPM). Prefrontal cortex (PFC) and hippocampal (HIP) electroencephalographic recordings and acetylcolinesterase (AChE) activity were also analyzed after PILO treatment. Anxiogenic responses observed in the EPM 24h or 1 month after PILO treatment (e.g., decreased time spent and number of entries into the open arms of the maze) were blocked by DZP but not affected by PTZ. No epileptiform events were registered in the HIP or PFC at 24h or 1 month after PILO injection, but enhanced theta activity was observed in the HIP. DZP decreased hippocampal theta of PILO-treated rats in contrast with PTZ, which increased this parameter in saline- and PILO-treated rats. The HIP and PFC AChE activity did not change after PILO treatment. Our findings demonstrate that the long-term effects on the emotionality of rats induced by PILO are associated with electrophysiological changes in the HIP and sensitive to pharmacological manipulation of the GABAergic system. The present work may support this new research model of long-lasting anxiety, while also highlighting the muscarinic system as a potential target involved in anxiety disorders.
Assuntos
Ansiedade/fisiopatologia , Moduladores GABAérgicos/farmacologia , Hipocampo/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Receptores de GABA-A/efeitos dos fármacos , Ritmo Teta/efeitos dos fármacos , Animais , Ansiedade/tratamento farmacológico , Diazepam/farmacologia , Modelos Animais de Doenças , Eletroencefalografia , Emoções/fisiologia , Antagonistas GABAérgicos/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Pentilenotetrazol/farmacologia , Pilocarpina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
El uso de plantas para el tratamiento de las convulsiones es amplia en diversas culturas, pero en muchos casos no se cuenta con un respaldo científico, es el propósito de la presente investigación realizar el análisis frtoquímico cualitativo, la evaluación de la actividad anticonvulsivante y toxicidad aguda del extracto acuoso de las partes aéreas de Berberís boliviana L. "Ch'eqche" en animales de experimentación. Para evaluar la actividad anticonvulsivante se empleó el modelo de convulsión química inducida por pentilentetrazol (PTZ 85 mglkg v.i.p.), usando como metodología un cuasiexperimental. Se utilizó 5 grupos de 6 ratones Bald/c/CNPB; grupo 1 (control), grupo 2 (diazepam 1mglkg) y grupo 3, 4, 5 (400, 800 y 1200 mg/kg de extracto acuoso). El tratamiento fue por v.i.p 30 minutos antes de la inducción de las convulsiones. Se midió el período de latencia para la primera convulsión clónica, la duración de las convulsiones, número de convulsiones que duran por lo menos 3 segundos y la protección frente a la mortalidad. Para la prueba de toxicidad aguda por v.o se utilizaron 12 ratones albinos, para la primera fase a dosis de (10, 100 y 1000 mglkg de extracto acuoso) y 3 ratones por grupo, para la segunda fase a dosis de (1600, 2900 y 5000 mglkg de extracto acuoso) y un ratón por grupo. Resultados: Se evidenció la presencia de compuestos fenólicos, alcaloides, taninos, cumarinas, quinonas, lactonas, glicósidos, aminoácidos, saponinas, flavonoides y resinas. Se observó que los extracto acuoso de las partes aéreas de Berberís boliviana L.(Ch'eqche) a las dosis de 400, 800 y 1200 mg/kg incrementaron el período de latencia en 60,67%, 73,13% y 88,70%, disminuyeron la duración de las convulsiones en 21,85%, 45,23% y 52,22%, disminuyeron el número de convulsiones que duran por lo menos 3 segundos en 36,11%, 66,67% y 80,56%; con respecto al grupo control y la protección frente a la mortalidad fue de 33,3%, 50,0% y 100,0% (ANOVA p<0,05). El valor de la DL50 del extracto acuoso por el método de Lorke es mayor a 5000 mg/kg. Conclusiones: Se caracterizaron los metabolitos secundarios de la especie Berberís boliviana L. (Ch'eqche), se demostró la actividad anticonvulsivante a la dosis de 1200 mg/kg del extracto frente a convulsiones clónicas, presentando valores próximos al del diazepam y un 100% de protección frente a los efectos letales del agente convulsivante PTZ. La DL50 del extracto acuoso por vía oral es mayor a 5000 mg/kg.
Assuntos
Animais , Camundongos , Berberis , Compostos Fitoquímicos , Anticonvulsivantes , Modelos AnimaisRESUMO
Magnesium sulfate (MgSO4) has been used to prevent seizures in eclampsia. This study examined the central effects of MgSO4 on different types of pentylenetetrazole (PTZ)-induced seizures. Male Wistar rats were submitted to intracerebroventricular (ICV) administration of MgSO4 at different doses followed by intraperitoneal administration of PTZ. The latency to the onset of the first seizure induced by PTZ was significantly increased by ICV administration of MgSO4 at a dose of 100 µg compared to the control treatment. In addition, the total period during which animals presented with seizures was significantly reduced at this dose of MgSO4. Furthermore, the latency to the onset of the first partial complex seizure was significantly increased by the lowest dose of MgSO4. However, a high dose of MgSO4 had no effect or even potentiated the effect of PTZ. These results suggest that, depending on the dose, MgSO4 may be important in prevention of epileptic seizures.
Sulfato de magnésio (MgSO4) é utilizado para prevenir crises epilépticas na eclampsia. Este estudo examina os efeitos do MgSO4 em diferentes tipos de crise induzidas por pentilenotetrazol (PTZ). Ratos Wistar foram submetidos à administração intracerebroventricular (ICV) de diferentes doses de MgSO4 seguida de administração intraperitoneal de PTZ. A latência para o início da primeira crise induzida por PTZ foi aumentada pela administração ICV de MgSO4 na dose de 100 µg quando comparada ao tratamento controle. Além disso, o período durante o qual os animais apresentaram crises foi reduzido com a mesma dose de MgSO4. A latência para o início da primeira crise parcial complexa também foi aumentada com a dose menor de MgSO4 (32 µg). No entanto, a maior dose (320 µg) de MgSO4 não foi efetiva ou até potencializou os efeitos do PTZ. Esses resultados sugerem que, dependendo da dose, o MgSO4 pode ser útil na prevenção de crises epilépticas.