RESUMEN
High-voltage-gated calcium channels have pivot role in the cellular and molecular mechanisms of various neurological disorders, including epilepsy. Similar to other calcium channels, P/Q-type calcium channels (Cav2.1) are also responsible for vesicle release at synaptic terminals. Up to date, there are very limited reports showing the mechanisms of Cav2.1 in epileptogenesis. In the present study, we investigated the anticonvulsive and neuroprotective effects of ω-agatoxin IVA, a specific Cav2.1 blocker, in a chemical kindling model of epileptogenesis. Righting reflex and inclined plane tests were used to assess motor coordination. Electroencephalography was recorded for electrophysiological monitoring of seizure activity in freely moving rats. Immunohistochemical analyses were performed for brain-derived neurotrophic factor (BDNF) and cleaved caspase-3 expressions in the prefrontal cortex, striatum, hippocampus, and thalamic nucleus. ω-Agatoxin IVA injected into the right lateral ventricle significantly prolonged the onset of seizures in a dose-dependent manner. In addition, repeated intraperitoneal administrations of ω-agatoxin IVA significantly suppressed the development of kindling and epileptic discharges without altering motor coordination. In addition, ω-agatoxin IVA significantly increased BDNF expressions, and decreased cleaved caspase-3 expressions in the brain when compared to PTZ + saline group. Our current study emphasizes the significance of the inhibition of P/Q type calcium channels by ω-agatoxin IVA, which suppresses the development of epileptogenesis and provides a new potential pathway for epilepsy treatment.
Asunto(s)
Bloqueadores de los Canales de Calcio , Epilepsia , Ratas , Animales , Bloqueadores de los Canales de Calcio/farmacología , omega-Agatoxina IVA , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Caspasa 3/metabolismo , omega-Conotoxina GVIA/metabolismo , omega-Conotoxina GVIA/farmacología , Canales de Calcio Tipo N/metabolismo , Encéfalo/metabolismo , Epilepsia/metabolismo , Convulsiones/metabolismo , Calcio/metabolismoRESUMEN
Depression is one of the most important and serious health problems in developing countries which affects millions of people. It is associated with the decrease of the quality of life as well as suicides and mortality. The disease may show recurrent episodes in some patients. Obviously, not all the patients with depression could be treated properly, because some individuals are drug-resistant and the options for the therapy are limited. Therefore, it is crucial to investigate new molecules and pathways that may have possible antidepressant activity. Sirtuin (SIRT), known as a class III histone deacetylase, which is regulated by nicotinamide adenine dinucleotide (NAD +), is one of these molecules. In the current study, we investigated the possible antidepressant-like effect of SIRT2 inhibitor AK-7. For this purpose, behavioral tests were performed in chronic AK-7-treated mice, and the expression levels of BDNF, NGF, NTF3, CREB, NTRK2, ERK1, ERK2, and GAP43 genes were evaluated by qRT-PCR analysis in brain tissues. Protein levels for BDNF, CREB1, and NTRK2 were determined by western blot. Our data showed that AK-7 significantly decreased immobility time and showed antidepressant-like effect. In addition, AK-7 treatment significantly increased mRNA levels of CREB and NTRK2 and protein levels of CREB1, BDNF, and NTRK2. Finally, our results suggest that SIRT2 and AK-7 may have a potential role in the cellular mechanisms of depression.
Asunto(s)
Sirtuina 2 , Suicidio , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Depresión/tratamiento farmacológico , Depresión/genética , Depresión/metabolismo , Humanos , Ratones , NAD/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Calidad de Vida , ARN Mensajero/metabolismo , Sirtuina 2/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
Parkinson's disease (PD) is the second most common neurodegenerative disorder, and the main cause of PD is still not known. Until now, no cure for Parkinson's disease is yet in sight. Caffeic acid phenethyl ester (CAPE) is a polyphenolic component of the propolis, which can be derived from honeybee hive propolis. We aimed to determine the effect of intrastriatal CAPE administration as a neuroprotective agent on 6-hydroxydopamine (6-OHDA)-induced PD model. Adult male Wistar rats weighing 280-320 g were used. The PD model was induced with unilateral intrastriatal 6-OHDA injection. Treatment groups received 20 µmol/5 µL/4 day and 80 µmol/5 µL/4 day CAPE 24 h after 6-OHDA injection. Eight days after 6-OHDA application, behavioral studies (adhesive tape removal test, open-field test, cylinder test, and apomorphine-induced asymmetric rotational behavior) were performed once more to compare the effects of CAPE on behavior tests. Striatal histological verifications, immunohistochemistry, and stereological quantitation were performed. Our results for the first time showed that, besides improving the motor performance, CAPE treatment also prevents 6-OHDA-induced loss of TH-positive neurons. From our results, CAPE may be a promising clinical agent in the treatment of PD.
RESUMEN
Parkinson's disease (PD) is one of the most common neurodegenerative disorders, which affects more than six million people in the world. While current available pharmacological therapies for PD in the early stages of the disease usually improve motor symptoms, they cause side effects, such as fluctuations and dyskinesias in the later stages. In this later stage, high frequency deep brain stimulation of the subthalamic nucleus (STN-DBS) is a treatment option which is most successful to treat drug resistant advanced PD. It has previously been demonstrated that activation of Rho/Rho-kinase pathway is involved in the dopaminergic cell degeneration which is one of the main characteristics of PD pathology. In addition, the involvement of this pathway has been suggested in diverse cellular events in the central nervous system; such as epilepsy, anxiety-related behaviors, regulation of dendritic and axonal morphology, antinociception, subarachnoid haemorrhage, spinal cord injury and amyotrophic lateral sclerosis. However, up to date, to our knowledge there are no previous reports showing the beneficial effects of the potent Rho-kinase inhibitor Y-27632 in the 6-hydroxydopamine (6-OHDA) rat model of PD. Therefore, in the present study, we investigated the behavioural effects of basal ganglia Y-27632 microinjections in this PD model. Our results indicated that basal ganglia Y-27632 microinjections significantly decreased the number of contralateral rotations-induced by apomorphine, significantly increased line crossings in the open-field test, contralateral forelimb use in the limb-use asymmetry test and contralateral tape playing time in the somatosensory asymmetry test, which may suggest that Y-27632 could be a potentially active antiparkinsonian agent.
Asunto(s)
Amidas/farmacología , Antiparkinsonianos/farmacología , Ganglios Basales/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Piridinas/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Amidas/uso terapéutico , Animales , Antiparkinsonianos/uso terapéutico , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/uso terapéutico , Masculino , Actividad Motora/efectos de los fármacos , Oxidopamina , Enfermedad de Parkinson Secundaria/metabolismo , Piridinas/uso terapéutico , RatasRESUMEN
BACKGROUND: G protein-coupled estrogen receptor 1 (GPER-1) has been demonstrated in several parts of the brain and may play an important role in estrogen downstream signaling pathway. However, the effects of this receptor on epileptic seizure are not clearly known. Therefore, the effects of GPER-1 agonist, G-1, GPER-1 antagonist, G-15 and the main estrogenic hormone, 17ß-estradiol were investigated on seizures and brain tissue oxidative damages induced by pentylenetetrazole (PTZ) in rats. METHODS: In this study, 30 adult male Wistar albino rats were used. Due to intraperitoneal (ip) injections of a subconvulsant dose of PTZ (35mg/kg) which was repeated 12 times every 48h, chemical kindling occurred and kindling seizure was recorded for 30min. The rats were injected with 17ß-estradiol (5µg/kg, ip) or G-1 (5µg/kg, ip), G-15 (5µg/kg, ip), Saline, Ethanol and Dimethyl sulfoxide (DMSO) 30min before each dose of PTZ. Observed seizures were classified between the phase 0-5. Thirty minutes later when the last 12. PTZ administration, all rats were sacrificed and the brain cortex, hippocampus sections were removed and the tissue superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) levels on these tissues were studied. RESULTS: GPER1 agonist, G-1 and estrogenic hormone, 17ß-estradiol significantly increased the development of PTZ kindling the seizures. However, GPER1 antagonist, G-15 did not change the development of PTZ kindling the seizures. In the cortex and hippocampus homogenates, the NO levels after G-1 administration had significantly increased (p<0.05) compared to the PTZ groups but SOD activities and MDA levels demonstrated no difference between the groups. CONCLUSIONS: This is the first study that explores that GPER-1 receptors have epileptogenic effect on PTZ-induced kindling rat. GPER1 may mediate the epileptogenic effect of estrogens by changing the oxidative or anti-oxidative parameters in the brain.
Asunto(s)
Epilepsia/inducido químicamente , Epilepsia/metabolismo , Excitación Neurológica/metabolismo , Pentilenotetrazol/toxicidad , Receptores de Estrógenos/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Ciclopentanos/farmacología , Ciclopentanos/toxicidad , Estradiol/farmacología , Estradiol/toxicidad , Excitación Neurológica/efectos de los fármacos , Masculino , Quinolinas/farmacología , Quinolinas/toxicidad , Ratas , Ratas WistarRESUMEN
Depression is one of the most common psychiatric disorders in the world; however, its mechanisms remain unclear. Recently, a new signal-transduction pathway, namely Rho/Rho-kinase signalling, has been suggested to be involved in diverse cellular events in the central nervous system; such as epilepsy, anxiety-related behaviors, regulation of dendritic and axonal morphology, antinociception, subarachnoid haemorrhage, spinal cord injury and amyotrophic lateral sclerosis. However there is no evidence showing the involvement of Rho-kinase pathway in depression. In addition, the infralimbic cortex, rodent equivalent to subgenual cingulate cortex has been shown to be responsible for emotional responses. Thus, in the present study, intracranial guide cannulae were stereotaxically implanted bilaterally into the infralimbic cortex, and the effects of repeated microinjections of a Rho-kinase (ROCK) inhibitor Y-27632 (10 nmol) were investigated in rats. Y-27632 significantly decreased immobility time and increased swimming and climbing behaviors when compared to fluoxetine (10 µg) and saline groups in the forced swim test. In addition, Y-27632 treatment did not affect spontaneous locomotor activity and forelimb use in the open-field and cylinder tests respectively; but it enhanced limb placing accuracy in the ladder rung walking test. Our results suggest that Y-27632 could be a potentially active antidepressant agent.
Asunto(s)
Amidas/farmacología , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Giro del Cíngulo/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Amidas/administración & dosificación , Animales , Giro del Cíngulo/enzimología , Masculino , Microinyecciones , Inhibidores de Proteínas Quinasas/administración & dosificación , Piridinas/administración & dosificación , RatasRESUMEN
Exposure to polychlorinated biphenyls impairs cognition and behavior in children. Two environmental PCBs 2,2',3,3',4,4',5-heptachlorobiphenyl (PCB170) and 2,2',3,5',6-pentachlorobiphenyl (PCB95) were examined in vitro for influences on synaptic transmission in rat hippocampal slices. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 region using a multi-electrode array. Perfusion with PCB170 (10 nM) had no effect on fEPSP slope relative to baseline period, whereas (100 nM) initially enhanced then depressed fEPSP slope. Perfusion of PCB95 (10 or 100 nM) persistently enhanced fEPSP slope >200%, an effect that could be inhibited by dantrolene, a drug that attenuates ryanodine receptor signaling. Perfusion with picrotoxin (PTX) to block GABA neurotransmission resulted in a modest increase in fEPSP slope, whereas PTX+PCB170 (1-100 nM) persistently enhanced fEPSP slope in a dose dependent manner. fEPSP slope reached >250% of baseline period in the presence of PTX+100 nM PCB170, conditions that evoked marked epileptiform after-potential discharges. PCB95 and PCB170 were found to differentially influence the Ca(2+)-dependence of [(3)H]ryanodine-binding to hippocampal ryanodine receptors. Non-coplanar PCB congeners can differentially alter neurotransmission in a manner suggesting they can elicit imbalances between inhibitory and excitatory circuits within the hippocampus. Differential sensitization of ryanodine receptors by Ca(2+) appears to mediate, at least in part, hippocampal excitotoxicity by non-coplanar PCBs.
Asunto(s)
Hipocampo/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Bifenilos Policlorados/toxicidad , Transmisión Sináptica/efectos de los fármacos , Animales , Dantroleno/toxicidad , Relación Dosis-Respuesta a Droga , Contaminantes Ambientales/toxicidad , Masculino , Estructura Molecular , Picrotoxina/toxicidad , Ratas , Ratas Sprague-Dawley , Canal Liberador de Calcio Receptor de Rianodina/metabolismoRESUMEN
BACKGROUND: Stress is a part of our daily life, inducing neurochemical and neurophysiological changes in the central nervous system. OBJECTIVE: The present study was designed to investigate the importance of sex differences in the interaction between dizocilpine (MK-801) pretreatment and acute cold-restraint stress (CRS) in pentylenetetrazole (PTZ)-induced seizures in Swiss albino mice. METHODS: A CRS protocol was applied to mice to investigate the interaction between MK-801 pretreatment (30 min before CRS) and stress (followed by PTZ injection) in epilepsy susceptibility. For this purpose, 6 groups were designated: (1) PTZ control group (received only PTZ); (2) stress group (received stress and PTZ); (3) saline group (received saline and PTZ); (4) MK-801 group (received MK-801 and PTZ); (5) saline + stress group (received saline, stress, and PTZ); and (6) MK-801 + stress group (received MK-801, stress, and PTZ). RESULTS: Pretreatment with MK-801 (0.125, 0.25, 0.50 mg/kg) significantly potentiated the protective effect of stress in PTZ-induced (65 mg/kg) seizures in both sexes by prolonging the onset of myoclonic jerks and clonic convulsions. Male mice had a significantly greater delay in the onset of myoclonic jerks (males, 66.7-295.5 sec; females, 54.0-247.5 sec; P < 0.05) and clonic convulsions (males, 123.5-789.8 sec; females, 94.5-757.2 sec; P < 0.05) compared with female mice in all groups (ie, PTZ control, stress, saline, MK-801, saline + stress, and MK-801 + stress groups). CONCLUSION: The findings of this study in mice suggest the involvement of sex hormones in the interaction between MK-801 pretreatment and acute CRS in PTZ-induced seizures.
Asunto(s)
Epilepsias Mioclónicas/fisiopatología , Convulsiones/fisiopatología , Estrés Psicológico/fisiopatología , Animales , Frío , Maleato de Dizocilpina/farmacología , Epilepsias Mioclónicas/inducido químicamente , Epilepsias Mioclónicas/tratamiento farmacológico , Femenino , Masculino , Ratones , Ratones Endogámicos , Modelos Animales , Fármacos Neuroprotectores/farmacología , Pentilenotetrazol , Restricción Física , Convulsiones/inducido químicamente , Convulsiones/complicaciones , Convulsiones/tratamiento farmacológico , Factores Sexuales , Estrés Psicológico/complicacionesRESUMEN
The aim of the present study was to determine whether tramadol, which has a potential antidepressant efficacy, evokes, when administered repeatedly, changes similar to the alterations induced by conventional antidepressant drugs. Repeated administration of tramadol (20 mg/kg i.p. for 21 days) enhanced the d-amphetamine-induced locomotor hyperactivity and increased the density of alpha(1)-adrenoceptors in the rat brain cortex, as measured by saturation analysis of [(3)H]prazosin binding. Autoradiographic analysis of [(3)H]7-OH-DPAT and [(3)H]raclopride binding revealed a significant up-regulation of dopamine D2 and D3 receptors in the rat nucleus accumbens upon repeated treatment with tramadol. All the above-mentioned effects induced by repeated administration of tramadol resemble the effects induced by conventional antidepressants. However, tramadol when administered repeatedly did not increase the levels of mRNA encoding for brain-derived neurotrophic factor (BDNF) and its receptor, TrkB. This is what differs tramadol from conventional antidepressants, since neurotrophic effects of these drugs have recently been postulated.
Asunto(s)
Antidepresivos/administración & dosificación , Encéfalo/efectos de los fármacos , Dopamina/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Tramadol/administración & dosificación , Animales , Antidepresivos/metabolismo , Encéfalo/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Ratas , Ratas Wistar , Tiempo , Tramadol/metabolismoRESUMEN
We analyzed the ability of the mu opioid peptide receptor ligands morphine and naloxone and several antidepressant drugs that are serotonin (fluoxetine), noradrenaline (reboxetine), mixed serotonin and noradrenaline (milnacipram and venlafaxine), dopamine (nomifensine) reuptake inhibitors, as well as roxindole (a nonselective drug) to substitute for, or alter, tramadol discrimination. Male Wistar rats were trained to discriminate tramadol (20 mg/kg) from saline in a two-choice water-reinforced paradigm. Out of the drugs studied, only morphine substituted for tramadol. In combination experiments, naloxone (0.1-1 mg/kg) attenuated the stimulus effects of tramadol (20 mg/kg) and the substitution evoked by morphine (2 mg/kg). Milnacipram (10 mg/kg) or reboxetine (10 mg/kg) enhanced the effects of tramadol (2.5-10 mg/kg); the other antidepressant drugs used failed to modulate tramadol discrimination. Our results indicate that tramadol can be used as a stimulus cue in rats, and that mu opioid peptide mechanisms are involved in its effects, while noradrenergic uptake inhibitors can enhance tramadol discrimination.
Asunto(s)
Monoaminas Biogénicas/metabolismo , Discriminación en Psicología/efectos de los fármacos , Receptores Opioides mu/metabolismo , Tramadol/farmacología , Inhibidores de Captación Adrenérgica/farmacología , Analgésicos Opioides/farmacología , Animales , Antidepresivos/farmacología , Monoaminas Biogénicas/antagonistas & inhibidores , Condicionamiento Operante , Ciclohexanoles/farmacología , Ciclopropanos/farmacología , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Fluoxetina/farmacología , Masculino , Milnaciprán , Morfina/farmacología , Morfolinas/farmacología , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Nomifensina/farmacología , Ratas , Ratas Wistar , Reboxetina , Receptores Opioides mu/antagonistas & inhibidores , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Cloruro de Sodio/farmacología , Clorhidrato de VenlafaxinaRESUMEN
In recent years, it has been postulated that tramadol, used mainly for the treatment of moderate to severe pain, might display a potential as an antidepressant drug. The present study investigated the effects of acute and repeated tramadol administration on the binding of [3H]RX 821002, a selective alpha2-adrenergic receptor ligand, in the rat brain. Male Wistar rats were used. Tramadol (20 mg/kg, i.p.) administered acutely (single dose), at 24 h after dosing, induced a significant decrease in the alpha2-adrenergic receptors in all brain regions studied. The most pronounced effects were observed in all subregions of the olfactory system, nucleus accumbens and septum, thalamus, hypothalamus, amygdala, and cerebral cortex. Repeated treatment with tramadol (20 mg/kg, i.p., once daily for 21 days) also induced statistically significant downregulation of [3H]RX 821002 binding sites in the rat brain. However, the effect--although statistically significant--was less pronounced than in the group treated acutely with the drug. Since drugs such as mianserin and mirtazapine are potent antagonists of central alpha2-adrenergic receptors and are effective antidepressants, it is tempting to suggest that, in addition to other alterations induced by tramadol, downregulation of these receptors may represent a potential antidepressant efficacy. On the other hand, one should be careful to avoid the treatment of chronic pain with tramadol in patients already receiving antidepressant drugs. Tramadol-induced downregulation of alpha2-adrenergic receptors--when combined with ongoing antidepressant therapy with drugs, which themselves inhibit serotonin reuptake or are antagonists of alpha2-adrenergic receptors--might cause threatening complications.
Asunto(s)
Encéfalo/efectos de los fármacos , Idazoxan/análogos & derivados , Narcóticos/farmacología , Receptores Adrenérgicos alfa 2/metabolismo , Tramadol/farmacología , Antagonistas Adrenérgicos alfa/farmacocinética , Análisis de Varianza , Animales , Autorradiografía/métodos , Encéfalo/anatomía & histología , Encéfalo/metabolismo , Esquema de Medicación , Idazoxan/farmacocinética , Masculino , Narcóticos/administración & dosificación , Unión Proteica/efectos de los fármacos , Ratas , Ratas Wistar , Tramadol/administración & dosificación , Tritio/farmacocinéticaRESUMEN
Recent findings have indicated that nitric oxide (NO) may change the duration of immobility biphasically in the forced swimming test, which is a useful experimental model for screening antidepressant-like activity in rodents. In the present study, we have investigated the role of serotonin and of potassium (K(+)) channels in the dual effects of NO in the mouse forced swimming test (MFST). For this purpose, we tested the effects of l-arginine, an NO precursor, the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME), and of K(+)-channel blockers tetraethylammonium (TEA) and 3,4-diaminopyridine (3,4-DAP). In addition, we used sertraline as a serotonin reuptake inhibitor and cyproheptadine as a serotonin antagonist. l-Arginine increased the duration of immobility in the MFST in low doses (25 mg/kg ip) but decreased it in higher doses (500 and 1000 mg/kg ip). Low doses of l-NAME (50 and 75 microg icv) decreased while higher dose of this drug (150 microg icv) increased the immobility time. TEA (5 microg icv) and 3,4-DAP (0.05 microg icv) significantly reduced the time, whereas K(+) channel opener pinacidil increased the duration of immobility. l-Arginine (100 mg/kg ip) significantly antagonised the effects of l-NAME (50 microg), 3,4-DAP and TEA. Higher dose of l-arginine (500 mg/kg ip) significantly potentiated the effects of 3,4-DAP and TEA, but reduced the effect of pinacidil. Low doses of l-arginine antagonized, but higher doses of l-arginine potentiated the antidepressant-like effect of sertraline. Sertraline potentiated the effects of 3,4-DAP and TEA, but reversed the effect of pinacidil. Cyproheptadine reduced the anti-immobility effect of l-arginine and 3,4-DAP. At the highest effective doses, drugs did not impair the motor functions. These data support the hypothesis that NO effects may involve the release of serotonin and/or modulation of K(+) channels.