RESUMEN
This review focuses on the possible roles of phytocannabinoids, synthetic cannabinoids, endocannabinoids, and "transient receptor potential cation channel, subfamily V, member 1" (TRPV1) channel blockers in epilepsy treatment. The phytocannabinoids are compounds produced by the herb Cannabis sativa, from which Δ9-tetrahydrocannabinol (Δ9-THC) is the main active compound. The therapeutic applications of Δ9-THC are limited, whereas cannabidiol (CBD), another phytocannabinoid, induces antiepileptic effects in experimental animals and in patients with refractory epilepsies. Synthetic CB1 agonists induce mixed effects, which hamper their therapeutic applications. A more promising strategy focuses on compounds that increase the brain levels of anandamide, an endocannabinoid produced on-demand to counteract hyperexcitability. Thus, anandamide hydrolysis inhibitors might represent a future class of antiepileptic drugs. Finally, compounds that block the TRPV1 ("vanilloid") channel, a possible anandamide target in the brain, have also been investigated. In conclusion, the therapeutic use of phytocannabinoids (CBD) is already in practice, although its mechanisms of action remain unclear. Endocannabinoid and TRPV1 mechanisms warrant further basic studies to support their potential clinical applications. This article is part of the Special Issue "NEWroscience 2018".
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Cannabidiol , Cannabinoides , Cannabis , Epilepsia , Animales , Cannabidiol/uso terapéutico , Cannabinoides/uso terapéutico , Dronabinol , Epilepsia/tratamiento farmacológico , HumanosRESUMEN
Background: Clinical and experimental evidence indicates that olfactory stimulation modulates limbic seizures, either blocking or inducing ictal activity. Objective: We aim to evaluate the behavioral and electroencephalographic (EEGraphic) effects of dihydro-2,4,5-trimethylthiazoline (TMT) olfactory exposure on limbic seizures induced by amygdala rapid kindling (ARK). Materials and Methods: Wistar male rats (280-300 g) underwent stereotaxic surgery for electrode implantation in piriform cortex (PC), hippocampal formation (HIP), and amygdaloid complex (AMYG). Part of the animals was exposed to a saturated chamber with water or TMT, while others had ARK and olfactory exposure prior to the 21st stimulus. Behavioral responses were measured by traditional seizure severity scales (Racine and Pinel and Rovner) and/or by sequential analysis/neuroethology. The electrographic activity of epileptogenic limbic networks was quantified by the occurrence of the first and second EEG afterdischarges, comparing the 1st and 21st stimulus. The spectral analysis [Fast Fourier Transform (FFT)] of the first afterdischarge was performed at the 21st stimulus. Results: TMT olfactory exposure reduced the seizure severity in kindled rats, altering the displayed behavioral sequence. Moreover, TMT decreased the occurrence of first and second afterdischarges, at the 21st stimulus, and altered the spectral features. Conclusions: Both behavioral and EEGraphic evaluations indicated that TMT, a potent molecule with strong biological relevance, in fact, "predator odor," suppressed the epileptiform activity in limbic networks.
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Although loneliness is a human experience, it can be estimated in laboratory animals deprived from physical contact with conspecifics. Rodents under social isolation (SI) tend to develop emotional distress and cognitive impairment. However, it is still to be determined whether those conditions present a common neural mechanism. Here, we conducted a series of behavioral, morphological, and neurochemical analyses in adult mice that underwent to 1 week of SI. We observed that SI mice display a depressive-like state that can be prevented by enriched environment, and the antidepressants fluoxetine (FLX) and desipramine (DES). Interestingly, chronic administration of FLX, but not DES, was able to counteract the deleterious effect of SI on social memory. We also analyzed cell proliferation, neurogenesis, and astrogenesis after the treatment with antidepressants. Our results showed that the olfactory bulb (OB) was the neurogenic niche with the highest increase in neurogenesis after the treatment with FLX. Considering that after FLX treatment social memory was rescued and depressive-like behavior decreased, we propose neurogenesis in the OB as a possible mechanism to unify the FLX ability to counteract the deleterious effect of SI.
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Fluoxetina , Bulbo Olfatorio , Animales , Antidepresivos/farmacología , Fluoxetina/farmacología , Memoria , Ratones , NeurogénesisRESUMEN
BACKGROUND: Zika virus (ZIKV) infection during pregnancy may cause major congenital defects, including microcephaly, ocular, articular and muscle abnormalities, which are collectively defined as Congenital Zika Syndrome. Here, we performed an in-depth characterization of the effects of congenital ZIKV infection (CZI) in immunocompetent mice. METHODS: Pregnant dams were inoculated with ZIKV on embryonic day 5.5 in the presence or absence of a sub-neutralizing dose of a pan-flavivirus monoclonal antibody (4G2) to evaluate the potential role of antibody-dependent enhancement phenomenon (ADE) during short and long outcomes of CZI. FINDINGS: ZIKV infection induced maternal immune activation (MIA), which was associated with occurrence of foetal abnormalities and death. Therapeutic administration of AH-D antiviral peptide during the early stages of pregnancy prevented ZIKV replication and death of offspring. In the post-natal period, CZI was associated with a decrease in whole brain volume, ophthalmologic abnormalities, changes in testicular morphology, and disruption in bone microarchitecture. Some alterations were enhanced in the presence of 4G2 antibody. INTERPRETATION: Our results reveal that early maternal ZIKV infection causes several birth defects in immunocompetent mice, which can be potentiated by ADE phenomenon and are associated with MIA. Additionally, antiviral treatment with AH-D peptide may be beneficial during early maternal ZIKV infection. FUND: This work was supported by the Brazilian National Science Council (CNPq, Brazil), Minas Gerais Foundation for Science (FAPEMIG), Funding Authority for Studies and Projects (FINEP), Coordination of Superior Level Staff Improvement (CAPES), National Research Foundation of Singapore and Centre for Precision Biology at Nanyang Technological University.
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Acrecentamiento Dependiente de Anticuerpo/inmunología , Interacciones Huésped-Patógeno/inmunología , Complicaciones Infecciosas del Embarazo , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/virología , Virus Zika/fisiología , Animales , Anticuerpos Antivirales/inmunología , Antivirales/farmacología , Huesos/diagnóstico por imagen , Huesos/patología , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/patología , Encéfalo/virología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Péptidos/farmacología , Embarazo , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/patología , Bazo/virología , Síndrome , Resultado del Tratamiento , Carga Viral , Infección por el Virus Zika/diagnóstico , Infección por el Virus Zika/tratamiento farmacológicoRESUMEN
The absence of companion may jeopardize mental health in social animals. Here, we tested the hypothesis that social isolation impairs social recognition memory by altering the excitability and the dialog between the olfactory bulb (OB) and the dorsal hippocampus (dHIP). Adult male Swiss mice were kept grouped (GH) or isolated (SI) for 7 days. Social memory (LTM) was evaluated using social recognition test. SI increased glutamate release in the OB, while decreased in the dHIP. Blocking AMPA and NMDA receptors into the OB or activating AMPA into the dHIP rescued LTM in SI mice, suggesting a cause-effect relationship between glutamate levels and LTM impairment. Additionally, during memory retrieval, phase-amplitude coupling between OB and dHIP decreased in SI mice. Our results indicate that SI impaired the glutamatergic signaling and the normal communication between OB and HIP, compromising the persistence of social memory.
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Ácido Glutámico/metabolismo , Hipocampo/fisiología , Memoria , Bulbo Olfatorio/fisiología , Reconocimiento en Psicología , Aislamiento Social , Animales , Fenómenos Electrofisiológicos , Masculino , Ratones , Modelos AnimalesRESUMEN
Although the functional role for newborn neurons in neural circuits is still matter of investigation, there is no doubt that neurogenesis modulates learning and memory in rodents. In general, boosting neurogenesis before learning, using genetic-target tools or drugs, improves hippocampus-dependent memories. However, inhibiting neurogenesis may yield contradictory results depending on the type of memory evaluated. Here we tested the hypothesis that inhibiting constitutive neurogenesis would compromise social recognition memory (SRM). Male Swiss mice were submitted to three distinct procedures to inhibit neurogenesis: (1) intra-cerebral infusion of Cystosine-ß-D-Arabinofuranoside (AraC); (2) intra-peritoneal injection of temozolomide (TMZ) and (3) cranial gamma irradiation. All three methods decreased cell proliferation and neurogenesis in the dentate gyrus of the dorsal (dDG) and ventral hippocampus (vDG), and the olfactory bulb (OB). However, the percentage inhibition diverged between methods and brain regions. Ara-C, TMZ and gamma irradiation impaired SRM, though only gamma irradiation did not cause side effects on weight gain, locomotor activity and anxiety. Finally, we examined the contribution of cell proliferation in vDG, dDG and OB to SRM. The percent of inhibition in the dDG correlates with SRM, independently of the method utilized. This correlation was observed for granular cell layer of OB and vDG, only when the inhibition was induced by gamma irradiation. Animal's performance was restrained by the inhibition of dDG cell proliferation, suggesting that cell proliferation in the dDG has a greater contribution to SRM. Altogether, our results demonstrate that SRM, similarly to other hippocampus-dependent memories, has its formation impaired by reducing constitutive neurogenesis.
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Proliferación Celular/fisiología , Hipocampo/fisiología , Memoria a Largo Plazo/fisiología , Neurogénesis/fisiología , Bulbo Olfatorio/fisiología , Reconocimiento en Psicología/fisiología , Percepción Social , Animales , Antineoplásicos Alquilantes/farmacología , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Conducta Animal/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Glicósido Hidrolasas/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/efectos de la radiación , Masculino , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Largo Plazo/efectos de la radiación , Ratones , Neurogénesis/efectos de los fármacos , Neurogénesis/efectos de la radiación , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/efectos de la radiación , Traumatismos Experimentales por Radiación , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/efectos de la radiación , Temozolomida/farmacologíaRESUMEN
Cerebral malaria (CM) is a life-threatening complication of Plasmodium falciparum infection, which can result in long-term cognitive and behavioral deficits despite successful anti-malarial therapy. Due to the substantial social and economic burden of CM, the development of adjuvant therapies is a scientific goal of highest priority. Apart from vascular and immune responses, changes in glutamate system have been reported in CM pathogenesis suggesting a potential therapeutic target. Based on that, we hypothesized that interventions in the glutamatergic system induced by blockage of N-methyl-D-aspartate (NMDA) receptors could attenuate experimental CM long-term cognitive and behavioral outcomes. Before the development of evident CM signs, susceptible mice infected with Plasmodium berghei ANKA (PbA) strain were initiated on treatment with dizocilpine maleate (MK801, 0.5 mg/kg), a noncompetitive NMDA receptor antagonist. On day 5 post-infection, mice were treated orally with a 10-day course chloroquine (CQ, 30 mg/kg). Control mice also received saline, CQ or MK801 + CQ therapy. After 10 days of cessation of CQ treatment, magnetic resonance images (MRI), behavioral and immunological assays were performed. Indeed, MK801 combined with CQ prevented long-term memory impairment and depressive-like behavior following successful PbA infection resolution. In addition, MK801 also modulated the immune system by promoting a balance of TH1/TH2 response and upregulating neurotrophic factors levels in the frontal cortex and hippocampus. Moreover, hippocampus abnormalities observed by MRI were partially prevented by MK801 treatment. Our results indicate that NMDA receptor antagonists can be neuroprotective in CM and could be a valuable adjuvant strategy for the management of the long-term impairment observed in CM.
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Conducta Animal , Cognición , Maleato de Dizocilpina/uso terapéutico , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Malaria Cerebral/tratamiento farmacológico , Malaria Cerebral/fisiopatología , Fármacos Neuroprotectores/uso terapéutico , Receptores de Glutamato/metabolismo , Animales , Ansiedad/complicaciones , Ansiedad/tratamiento farmacológico , Ansiedad/fisiopatología , Conducta Animal/efectos de los fármacos , Cognición/efectos de los fármacos , Citocinas/sangre , Citocinas/metabolismo , Depresión/complicaciones , Depresión/tratamiento farmacológico , Depresión/fisiopatología , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Ácido Glutámico/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Leucocitos/metabolismo , Imagen por Resonancia Magnética , Malaria Cerebral/complicaciones , Malaria Cerebral/patología , Memoria a Corto Plazo/efectos de los fármacos , Ratones Endogámicos C57BL , Factores de Crecimiento Nervioso/metabolismo , Fármacos Neuroprotectores/farmacología , Tamaño de los Órganos , Parasitemia/sangre , Parasitemia/complicaciones , Parasitemia/patología , Fenotipo , Plasmodium berghei/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Análisis de Supervivencia , Regulación hacia ArribaRESUMEN
Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB1 receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB1 receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity.
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Cocaína/toxicidad , Endocannabinoides/metabolismo , Receptor Cannabinoide CB1/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Benzamidas/farmacología , Carbamatos/farmacología , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Endocannabinoides/agonistas , Hipocampo/efectos de los fármacos , Hipocampo/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/farmacología , Receptor Cannabinoide CB1/agonistas , Transducción de Señal/fisiologíaRESUMEN
It is well known that estradiol (E2) replacement therapy is effective on restoring memory deficits and mood disorders that may occur during natural menopause or after surgical ovarian removal (ovariectomy, OVX). However, it is still unknown the effectiveness of acute and localized E2 administration on the effects of chronic OVX. Here we tested the hypothesis that the intra-hippocampal E2 infusion, as well as specific agonists of estrogen receptors (ERs) alpha (ERα) and beta (ERß), are able to mend novel object recognition (NOR) memory deficit and depressive-like behavior caused by 12 weeks of OVX. We found that both ERα and ERß activation, at earlier stages of consolidation, recovered the NOR memory deficit caused by 12 w of OVX. Conversely, only the ERß activation was effective in decreasing the depressive-like behavior caused by 12 w of OVX. Furthermore, we investigated the effect of OVX on hippocampal volume and ERs expression. The structural MRI showed no alteration in the hippocampus volume of 12 w OVX animals. Interestingly, ERα expression in the hippocampus decreased after one week of OVX, but increased in 12 w OVX animals. Overall, we may conclude that the chronic estrogen deprivation, induced by 12 weeks of OVX, modulates the hippocampal ERα expression and induces NOR memory deficit and depressive-like behaviors. Nonetheless, it is noteworthy that the acute effects of E2 on NOR memory and depressive-like behavior are still apparent even after 12 weeks of OVX.
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Depresión/etiología , Estradiol/farmacología , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Hipocampo/metabolismo , Trastornos de la Memoria/etiología , Ovariectomía/efectos adversos , Animales , Depresión/tratamiento farmacológico , Depresión/metabolismo , Femenino , Hipocampo/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos AnimalesRESUMEN
Many studies have shown that minocycline, an antibacterial tetracycline, suppresses experimental pain. While minocycline's positive effects on pain resolution suggest that clinical use of such drugs may prove beneficial, minocycline's antibiotic actions and divalent cation (Ca(2+); Mg(2+)) chelating effects detract from its potential utility. Thus, we tested the antiallodynic effect induced by a non-antibacterial, non-chelating minocycline derivative in a model of neuropathic pain and performed an initial investigation of its anti-inflammatory effects in vitro. Intraperitoneal minocycline (100mg/kg) and 12S-hydroxy-1,12-pyrazolinominocycline (PMIN; 23.75 mg/kg, 47.50mg/kg or 95.00 mg/kg) reduce the mechanical allodynia induced by chronic constriction injury of mouse sciatic nerve. PMIN reduces the LPS-induced production of PGE2 by primary microglial cell cultures. Human embryonic kidney cells were transfected to express human toll-like receptors 2 and 4, and the signaling via both receptors stimulated with PAM3CSK4 or LPS (respectively) was affected either by minocycline or PMIN. Importantly, these treatments did not affect the cell viability, as assessed by MTT test. Altogether, these results reinforce the evidence that the anti-inflammatory and experimental pain suppressive effects induced by tetracyclines are neither necessarily linked to antibacterial nor to Ca(2+) chelating activities. This study supports the evaluation of the potential usefulness of PMIN in the management of neuropathic pain, as its lack of antibacterial and Ca(2+) chelating activities might confer greater safety over conventional tetracyclines.
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Antiinflamatorios no Esteroideos/farmacología , Dinoprostona/biosíntesis , Hiperalgesia/tratamiento farmacológico , Lipopolisacáridos/farmacología , Microglía/efectos de los fármacos , Minociclina/farmacología , Nervio Ciático/lesiones , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Células Cultivadas , Femenino , Humanos , Hiperalgesia/fisiopatología , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Minociclina/uso terapéutico , Neuralgia/tratamiento farmacológico , Neuralgia/fisiopatología , Estimulación Física , Ratas , Ratas Wistar , Nervio Ciático/fisiopatología , Transducción de Señal , TactoRESUMEN
Cannabinoids and drugs that increase endocannabinoid levels inhibit neuronal excitability and restrain epileptic seizures through CB1 receptor activation. Nevertheless, the results have not been entirely consistent, since pro-convulsant effects have also been reported. The present study aimed to further investigate the effects of cannabinoid-related compounds on seizures induced by pentylenetetrazole (PTZ) in rats. Video-EEG recordings were used to determine both electrographic and behavioral thresholds to ictal activity. The animals received injections of WIN-55,212-2 (0.3-3 mg/kg, non-selective) or ACEA (1-4 mg/kg, CB1-selective), two synthetic cannabinoids, or URB-597 (0.3-3 mg/kg), an anandamide-hydrolysis inhibitor (FAAH enzyme inhibitor), followed by PTZ. Both WIN-55,212-2 (1 mg/kg) and ACEA (1-4 mg/kg) reduced the threshold for myoclonic seizures and enhanced epileptiform EEG activity, typical pro-convulsive effects. On the contrary, URB-597 (1 mg/kg) had an anti-convulsive effect, as it increased the threshold for the occurrence of minimal seizures and reduced EEG epileptiform activity. None of the drugs tested altered the tonic-clonic maximal seizure threshold. These data suggest that the effects of CB1 signaling upon seizure activity may depend on how this receptor is activated. Contrary to direct agonists, drugs that increase anandamide levels seem to promote an optimal tonus and represent a promising strategy for treating myoclonic seizures.
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Benzamidas/uso terapéutico , Cannabinoides/uso terapéutico , Carbamatos/uso terapéutico , Endocannabinoides/uso terapéutico , Convulsiones/tratamiento farmacológico , Animales , Benzoxazinas/uso terapéutico , Convulsivantes/antagonistas & inhibidores , Modelos Animales de Enfermedad , Electroencefalografía/métodos , Hidrólisis , Masculino , Morfolinas/uso terapéutico , Naftalenos/uso terapéutico , Pentilenotetrazol , Ratas , Ratas Wistar , Convulsiones/inducido químicamente , Convulsiones/fisiopatologíaRESUMEN
The critical window hypothesis predicts that estrogen replacement therapy (ERT) must be administered early on the menopause or ovariectomy (OVX) to positively affect cognition. However, the neural substrates, underling the time dependent efficacy of ERT, are still not completely known. In order to address this issue, we submitted female mice to 12 weeks of OVX followed by 5 weeks of chronic ERT (OVX(E2)). Within the first 12 weeks, the OVX animals showed a progressive compromised performance in the object recognition memory (ORM) task. After ERT, OVXE2 mice, but not the control group (OVXoil), were able to recognize the new object in the test session. Further, we evaluated the c-Fos expression in hippocampus, perirhinal cortex (PC) and central amygdala (CeA) of OVXoil and OVX(E2) mice, after context exposure (CTX) or object exploration (OBJ). We observed that ERT increased c-Fos expression unspecifically for CTX and OBJ. In addition, only the OVX(E2) group showed significantly higher c-Fos expression in the PC and CeA after object exploration. Thus, our results showed that delayed chronic ERT improves ORM (compromised by OVX) and increases constitutive c-Fos expression in temporal lobe regions. Furthermore, we showed for the first time that PC and CeA, but not the hippocampus, present a distinct pattern of activation in response to object exploration in ovariectomized females that underwent delayed-ERT.
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Encéfalo/efectos de los fármacos , Estradiol/farmacología , Terapia de Reemplazo de Estrógeno/métodos , Estrógenos/farmacología , Menopausia/fisiología , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Encéfalo/metabolismo , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Menopausia/efectos de los fármacos , Menopausia/metabolismo , Ratones , Ratones Endogámicos C57BL , Ovariectomía , Proteínas Proto-Oncogénicas c-fos/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Lóbulo Temporal/efectos de los fármacos , Lóbulo Temporal/metabolismo , Factores de TiempoRESUMEN
Although it is well known that regular exercise may promote neuroprotection, the mechanisms underlying this effect are still not fully understood. We investigated if swim training promotes neuroprotection by potentiating antioxidant pathways, thereby decreasing the effects of oxidative stress on glutamate and nitric oxide release. Male Wistar rats (n=36) were evenly randomized into a trained group (TRA) (5 days/week, 8 weeks, 30 min) and a sedentary group (SED). Forty-eight hours after the last session of exercise, animals were killed and brain was collected for in vitro ischemia. Cortical slices were divided into two groups: a group in which oxidative stress was induced by oxygen and glucose deprivation (OGD), and a group of non-deprived controls (nOGD). Interestingly, exercise by itself increased superoxide dismutase activity (nOGD, SED vs. TRA animals) with no effect on pro-oxidative markers. In fact, TRA-OGD slices showed lowered levels of lactate dehydrogenase when compared with SED-OGD controls, reinforcing the idea that exercise affords a neuroprotective effect. We also demonstrated that exercise decreased glutamate and nitrite release as well as lipid membrane damage in the OGD cortical slices. Our data suggest that under conditions of metabolic stress, swim training prevents oxidative damage caused by glutamate and nitric oxide release.
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Corteza Cerebral/metabolismo , Glucosa/metabolismo , Estrés Oxidativo/fisiología , Oxígeno/metabolismo , Condicionamiento Físico Animal/fisiología , Natación/fisiología , Animales , Hipoxia de la Célula/fisiología , Corteza Cerebral/patología , Glucosa/deficiencia , Masculino , Técnicas de Cultivo de Órganos , Condicionamiento Físico Animal/métodos , Ratas , Ratas WistarRESUMEN
Although neuroimmune interactions associated with the development of pain sensitization in models of neuropathic pain have been widely studied, there are some aspects that require further investigation. Thus, we aimed to evaluate whether the local intraneural or perineural injections of dexamethasone, an efficacious anti-inflammatory and immunosuppressant drug, delays the development of both thermal hyperalgesia and mechanical allodynia in an experimental model of neuropathic pain in rats. Hargreaves and electronic von Frey tests were applied. The chronic constriction injury (CCI) of right sciatic nerve was performed. Single intraneural dexamethasone administration at the moment of constriction delayed the development of sensitization for thermal hyperalgesia and mechanical allodynia. However, perineural administration of dexamethasone, at the highest dose, did not delay experimental pain development. These results show that inflammation/immune response at the site of nerve lesion is an essential trigger for the pathological changes that lead to both hyperalgesia and allodynia. In conclusion, this approach opens new opportunities to study cellular and molecular neuroimmune interactions associated with the development of pain derived from peripheral neuropathies.
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Dexametasona/administración & dosificación , Dexametasona/farmacología , Hiperalgesia/prevención & control , Neuralgia/prevención & control , Nervio Ciático/efectos de los fármacos , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Péptido Relacionado con Gen de Calcitonina/biosíntesis , Hiperalgesia/complicaciones , Hiperalgesia/inmunología , Hiperalgesia/patología , Inflamación/complicaciones , Inflamación/inmunología , Inflamación/patología , Inflamación/prevención & control , Masculino , Neuralgia/complicaciones , Neuralgia/inmunología , Neuralgia/patología , Ratas , Ratas Wistar , Nervio Ciático/lesionesRESUMEN
Prolonged permanence of animals under social isolation (SI) arouses a variety of psychological symptoms like aggression, stress, anxiety and depression. However, short-term SI is commonly used to evaluate social memory. Interestingly, the social memory cannot be accessed with delays higher than 30min in SI mice. Our hypothesis is that SI with intermediate duration, like one week (1w), impairs the long-term storage of new social information (S-LTM), without affecting anxiety or other types of memories, because the SI compromises the olfactory function of the animal. Our results demonstrated that SI impaired S-LTM, without affecting other kinds of memory or anxiety. In addition, the SI increased the latency in the buried-food finding task, but did not affect the habituation or the discrimination of odors. Next, we postulated that if continuous input to the olfactory system is fundamental for the maintenance of the olfactory function and social memory persistence, isolated mice under odor-enriched environment (OEE) should behave like group-housed (GH) animals. In fact, the OEE prevented the S-LTM deficit imposed by the SI. However, OEE did not restore the SI mice olfaction to the GH mice level. Our results suggest that SI modulates olfaction and social memory persistence, probably, by independent mechanisms. We also showed for the first time that OEE rescued S-LTM in SI mice through a mechanism not necessarily involved with olfaction.
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Ambiente , Memoria a Largo Plazo/fisiología , Odorantes , Olfato/fisiología , Aislamiento Social/psicología , Análisis de Varianza , Animales , Animales Recién Nacidos , Reacción de Prevención , Discriminación en Psicología , Conducta Exploratoria , Habituación Psicofisiológica , Inhibición Psicológica , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Reconocimiento en Psicología , Conducta SocialRESUMEN
Tetracyclines are natural or semi-synthetic bacteriostatic agents which have been used since late 1940s against a wide range of gram-positive and gram-negative bacteria and atypical organisms such as chlamydia, mycoplasmas, rickettsia, and protozoan parasites. After the discovery of the first tetracyclines, a second generation of compounds was sought in order to improve water solubility for parenteral administration or to enhance bioavailability after oral administration. This approach resulted in the development of doxycycline and minocycline in the 1970s. Doxycycline was included in the World Health Organization Model List of Essential Medicines either as antibacterial or to prevent malaria or to treat patients with this disease. Additional development led to the third generation of tetracyclines, being tigecycline the only medicine of this class to date. Besides antibacterial activities, the anti-inflammatory, antihypernociceptive and neuroprotective activities of tetracyclines began to be widely studied in the late 1990s. Indeed, there has been an increasing interest in investigating the effects induced by minocycline as this liposoluble derivative is known to cross the blood-brain barrier to the greatest extent. Minocycline induces antihypernociceptive effects in a wide range of animal models of nociceptive, inflammatory and neuropathic pain. In this study, we discuss the antihypernociceptive activity of tetracyclines and summarise its underlying cellular and molecular mechanisms.
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Analgésicos/uso terapéutico , Dolor/tratamiento farmacológico , Tetraciclinas/uso terapéutico , Animales , Humanos , Dolor/metabolismo , Dolor/fisiopatologíaRESUMEN
It has been shown that the brain has its own intrinsic renin-angiotensin system (RAS) and angiotensin-(1-7) (Ang-(1-7)) is particularly interesting, because it appears to counterbalance most of the Ang II effects. Ang-(1-7) exerts its biological function through activation of the G-protein-coupled receptor Mas. Interestingly, hippocampus is one of the regions with higher expression of Mas. However, the role of Ang-(1-7)/Mas axis in hippocampus-dependent memories is still poorly understood. Here we demonstrated that Mas ablation, as well as the blockade of Mas in the CA1-hippocampus, impaired object recognition memory (ORM). We also demonstrated that the blockade of Ang II receptors AT1, but not AT2, recovers ORM impairment of Mas-deficient mice. Considering that high concentrations of Ang-(1-7) may activate AT1 receptors, nonspecifically, we evaluate the levels of Ang-(1-7) and its main precursors Ang I and Ang II in the hippocampus of Mas-deficient mice. The Ang I and Ang II levels are unaltered in the whole hipocampus of MasKo. However, Ang-(1-7) concentration is increased in the whole hippocampus of MasKo mice, as well as in the CA1 area. Taken together, our findings suggest that the functionality of the Ang-(1-7)/Mas axis is essential for normal ORM processing.
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Angiotensina I/metabolismo , Hipocampo/metabolismo , Fragmentos de Péptidos/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Reconocimiento en Psicología/fisiología , Angiotensina I/genética , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 2 de Angiotensina II/farmacología , Animales , Hipocampo/efectos de los fármacos , Imidazoles/farmacología , Losartán/farmacología , Ratones , Ratones Noqueados , Fragmentos de Péptidos/genética , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/genética , Piridinas/farmacología , Receptores de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/genética , Reconocimiento en Psicología/efectos de los fármacosRESUMEN
The key neural substrates involved in memory and cognitive tasks have been reported to receive important modulation from ovarian hormones. In fact, neurochemical systems associated with cognitive functions, such as the cholinergic system, are, at least in part, under modulation of estrogens. Here we show that vesicular acetylcholine transporter (VAChT) mutant mice, which express lower levels of the VAChT (VAChT KD) and reduced acetylcholine release, present sexual dimorphism on memory. We evaluate short- and long-term object recognition memories (STM and LTM) in both sexes. We have showed previously, and confirm here, that VAChT KDHET male mice present deficits in both STM and LTM object recognition memories in comparison with WT. In contrast, VAChT KDHET female mice present deficit in LTM, but not in STM. To test if the female hormones levels could be a determinant factor on sexual dimorphism observed, we submitted female mice to ovariectomy (OVX) or sham-surgery. After 1 week (1 w), we evaluate STM. Female hormone deprivation promotes STM impairment in VAChT KDHET, but not in WT female mice. Our results strongly suggest that the sexual dimorphism observed in VAChT KDHET mice on STM is due to modulation of cholinergic system by ovarian hormones.
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Memoria/fisiología , Caracteres Sexuales , Proteínas de Transporte Vesicular de Acetilcolina/genética , Acetilcolina/metabolismo , Animales , Femenino , Hormonas Esteroides Gonadales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , OvariectomíaRESUMEN
The pilocarpine (PILO) animal model of Temporal Lobe Epilepsy (TLE) portrays the most common changes in hippocampal circuitry found in human TLE. The acute cholinergic insult induces status epilepticus (SE), which triggers an overwhelming set of plastic events that result on late spontaneous recurrent limbic seizures. It has been suggested that the cholinergic system plays an important role in the synchronization required for ictogenesis. We took advantage of a knock-down animal model for the vesicular acetylcholine transporter (VAChT KD) to investigate seizure genesis in a model of cholinergic dysfunction. We induced SE in VAChT KD and wild-type (WT) mice by a single intraperitoneal injection of PILO in order to evaluate susceptibility to seizures. Video-EEG recordings evaluated epileptiform activity and ictal behavior onset. The hypothesis tested is that innate cholinergic hypofunction could result in increased susceptibility to PILO. VAChT KD(HOM) mice showed shorter latency for the first epileptiform discharge and for the first seizure episode, when compared to other groups. The duration of these seizure episodes, however, were not statistically different among experimental groups. On the other hand, VAChT KD(HOM) had the shortest latency to isoelectric EEG, when compared to WT and KD(HET). Our results indicate that a reduction of brain VAChT protein to the levels found in VAChT KD(HOM) mice alters the epileptic response to PILO. Thus, fine-tuning modulation of cholinergic tone can affect the susceptibility of epileptic responses to pilocarpine.
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Susceptibilidad a Enfermedades , Pilocarpina , Estado Epiléptico/inducido químicamente , Proteínas de Transporte Vesicular de Acetilcolina/deficiencia , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Noqueados , Estado Epiléptico/genéticaRESUMEN
Earlier studies from the authors' laboratory showed that malnourishment induces alterations in the cardiovascular homeostasis increasing the basal mean arterial pressure and heart rate. In this study, the authors evaluated whether the sympathetic and parasympathetic efferent activities contribute to changes in the cardiovascular homeostasis through altered modulation of the arterial baroreflex of malnourished rats. After weaning, male Fischer rats were given 15% (Normal Protein--NP) or 6% (Low Protein--LP) protein diet for 35 d. The baroreflex gain and latency were evaluated before and after selective autonomic blockades in control and malnourished rats. It was observed that malnourishment affected the baroreflex gain in response to activation and deactivation of the arterial baroreflex. Moreover, malnourished rats showed increased baroreflex latency as compared to that of control rats. Regarding the autonomic efferent activity directed to the heart, the data showed increased sympathetic and decreased parasympathetic efferent activities in malnourished rats, and such alterations could be related to the observed changes in the arterial baroreflex gain as well as in the basal mean arterial pressure and heart rate.