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1.
Life Sci ; 273: 119310, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33667517

RESUMO

AIMS: Alzheimer's disease (AD) is a leading health problem in which increased amyloid ß (Aß) accumulation may occur due to abnormal Aß precursor protein processing by ß-secretase 1 (BACE1) enzyme. Lately, neuro-inflammation was recognized as a significant contributor to its pathogenesis. Although the causes of AD are not yet well understood, much evidence has suggested that dyslipidemia has harmful effects on cognitive function and is inextricably involved in AD pathogenesis. Cholesterol is a vital molecule involved in neuronal development. Alteration in neuronal cholesterol levels affects Aß metabolism and results in neurodegeneration. Proprotein-convertase-subtilisin/kexin type-9 (PCSK9) was found to decrease neuronal cholesterol uptake by degradation of LDL-receptor related protein 1 (LRP-1) responsible for neuronal cholesterol uptake. Accordingly, this study was designed to evaluate the effect of PCSK9-inhibition by alirocumab (Aliro) in high-fat-cholesterol-diet (HFCD)-induced-AD-like condition. MAIN METHODS: Wistar Rats were divided into six groups; control; HFCD; HFCD and Memantine; HFCD and Aliro (4, 8 and 16 mg/kg/week) to test for ability of Aliro to modulate cognitive impairment, amyloidosis, brain cholesterol homeostasis and neuro-inflammation in HFCD-induced-AD-like condition. KEY FINDINGS: Our results demonstrated an association between PCSK9 inhibition by Aliro and amelioration of cognitive deficit, cholesterol hemostasis and reduction of neuro-inflammation. Aliro was able to alleviate hippocampal LRP-1expression levels and reduce brain cholesterol, hippocampal BACE1, Aß42, high-mobility-group-box-1 protein, receptor for advanced-glycation-end-products and toll like receptor-4 with subsequent decrease of different inflammatory mediators as nuclear-factor-kappa-B (NF-κB), tumor-necrosis-factor-alpha (TNF-α), interleukin-1beta (IL-1ß) and IL-6. SIGNIFICANCE: PCSK9-inhibition may represent a new therapeutic target in AD especially for HFCD-induced-AD-like condition.


Assuntos
Amiloidose/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Colesterol/toxicidade , Disfunção Cognitiva/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Memantina/farmacologia , Pró-Proteína Convertase 9/antagonistas & inibidores , Amiloidose/etiologia , Amiloidose/metabolismo , Amiloidose/patologia , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Ratos , Ratos Wistar , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
2.
Life Sci ; 270: 119012, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33422543

RESUMO

AIMS: Memantine is a non-competitive antagonist of glutamatergic NMDA receptor that is mainly used in the treatment of Alzheimer's disease. The excitatory toxicity mediated by glutamate via glutamatergic receptor signals is considered to be one of the mechanisms mediating neuronal injury and cognitive impairment after exposure to a hypoxic environment at a high altitude. Therefore, in this study, we hypothesized that inhibiting glutamate signaling using memantine could alleviate neuronal injury and cognitive impairment in rats exposed to chronic hypoxia. MAIN METHODS: we made animal models in the natural environment of the Qinghai-Tibet Plateau at an altitude of 4300 m, and used animal behavior, morphology, molecular biology and other methods to evaluate the impact of chronic hypoxia exposure on cognitive function and the neuroprotective effect of Memantine. KEY FINDINGS: Our results showed that the expression of NMDA receptors increased, while the expression of AMPA receptors decreased, after 4 weeks of chronic hypoxia exposure. Concomitantly, apoptotic neuronal cell death in the hippocampus and frontal cortex was significantly increased, along with levels of oxidative stress, whereas innate ability to inhibit free radicals decreased. Moreover, after 8 weeks of hypoxia exposure, learning, memory, and space exploration abilities were significantly decreased. Notably, after treatment with memantine, apoptotic neuronal cell death, oxidative stress, and free radical levels decreased, and the cognitive function of the animals improved. SIGNIFICANCE: Present study shows that chronic hypoxia can produce the excitatory toxicity leading to neural injury and cognitive impairment that can be suppressed with memantine treatment by inhibiting excitatory toxicity.


Assuntos
Doença da Altitude/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Memantina/farmacologia , Altitude , Doença da Altitude/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Animais , Morte Celular/efeitos dos fármacos , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Hipóxia/metabolismo , Masculino , Memantina/metabolismo , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo
3.
Int J Mol Sci ; 21(24)2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33348808

RESUMO

Both α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) have been reported as targets for treatment of epilepsy. To investigate the roles and interactions of AMPAR and NMDAR in ictogenesis of epileptic hippocampus, we analyzed AMPAR antagonists (perampanel and GYKI 52466)-mediated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulation and glutamate ionotropic receptor NMDA type subunit 2B (GluN2B) tyrosine (Y) 1472 phosphorylation in epilepsy rats. Both perampanel and GYKI 52466 increased PTEN expression and its activity (reduced phosphorylation), concomitant with decreased activities (phosphorylations) of Src family-casein kinase 2 (CK2) signaling pathway. Compatible with these, they also restored the upregulated GluN2B Y1472 and Ca2+/cAMP response element-binding protein (CREB) serine (S) 133 phosphorylations and surface expression of glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) to basal level in the epileptic hippocampus. These effects of perampanel and GYKI 52466 are observed in responders (whose seizure activities are responsive to AMPAR antagonists), but not non-responders (whose seizure activities were uncontrolled by AMPAR antagonists). Therefore, our findings suggest that Src/CK2/PTEN-mediated GluN2B Y1472 and CREB S133 regulations may be one of the responsible signaling pathways for the generation of refractory seizures in non-responders to AMPAR antagonists.


Assuntos
Benzodiazepinas/farmacologia , Epilepsia/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores de AMPA/antagonistas & inibidores , Animais , Caseína Quinase II/genética , Caseína Quinase II/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Epilepsia/patologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais , Quinases da Família src/genética , Quinases da Família src/metabolismo
4.
J Headache Pain ; 21(1): 83, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32615921

RESUMO

BACKGROUND: Purine receptors play roles in peripheral and central sensitization and are associated with migraine headache. We investigated the possibility that ATP plays a permissive role in the activation of AMPA receptors thus inducing Glu release from nerve terminals isolated from the rat trigeminal caudal nucleus (TCN). METHODS: Nerve endings isolated from the rat TCN were loaded with [3H]D-aspartic acid ([3H]D-ASP), layered into thermostated superfusion chambers, and perfused continuously with physiological medium, alone or with various test drugs. Radioactivity was measured to assess [3H]D-ASP release under different experimental conditions. RESULTS: Synaptosomal [3H]D-ASP spontaneous release was stimulated by ATP and to an even greater extent by the ATP analogue benzoylbenzoylATP (BzATP). The stimulation of [3H]D-ASP basal release by the purinergic agonists was prevented by the selective P2X7 receptor antagonist A438079. AMPA had no effect on basal [3H]D-ASP release, but the release observed when synaptosomes were exposed to AMPA plus a purinoceptor agonist exceeded that observed with ATP or BzATP alone. The selective AMPA receptor antagonist NBQX blocked this "excess" release. Co-exposure to AMPA and BzATP, each at a concentration with no release-stimulating effects, evoked a significant increase in [3H]D-ASP basal release, which was prevented by exposure to a selective AMPA antagonist. CONCLUSIONS: P2X7 receptors expressed on glutamatergic nerve terminals in the rat TCN can mediate Glu release directly and indirectly by facilitating the activation of presynaptic AMPA receptors. The high level of glial ATP that occurs during chronic pain states can promote widespread release of Glu as well as can increase the function of AMPA receptors. In this manner, ATP contributes to the AMPA receptor activation involved in the onset and maintenance of the central sensitization associated with chronic pain.


Assuntos
Terminações Nervosas/efeitos dos fármacos , Terminações Nervosas/metabolismo , Receptores de AMPA/metabolismo , Receptores Pré-Sinápticos/metabolismo , Receptores Purinérgicos P2X7/fisiologia , Núcleo Inferior Caudal do Nervo Trigêmeo/metabolismo , Animais , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Agonistas do Receptor Purinérgico P2X , Antagonistas do Receptor Purinérgico P2X/farmacologia , Ratos , Transmissão Sináptica , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo
5.
Neuron ; 106(5): 715-726, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32497508

RESUMO

Ketamine exerts rapid antidepressant action in depressed and treatment-resistant depressed patients within hours. At the same time, ketamine elicits a unique form of functional synaptic plasticity that shares several attributes and molecular mechanisms with well-characterized forms of homeostatic synaptic scaling. Lithium is a widely used mood stabilizer also proposed to act via synaptic scaling for its antimanic effects. Several studies to date have identified specific forms of homeostatic synaptic plasticity that are elicited by these drugs used to treat neuropsychiatric disorders. In the last two decades, extensive work on homeostatic synaptic plasticity mechanisms have shown that they diverge from classical synaptic plasticity mechanisms that process and store information and thus present a novel avenue for synaptic regulation with limited direct interference with cognitive processes. In this review, we discuss the intersection of the findings from neuropsychiatric treatments and homeostatic plasticity studies to highlight a potentially wider paradigm for treatment advance.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Homeostase/efeitos dos fármacos , Ketamina/farmacologia , Compostos de Lítio/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Animais , Antimaníacos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Ketamina/uso terapêutico , Compostos de Lítio/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Sinapses/efeitos dos fármacos
6.
Psychopharmacology (Berl) ; 237(8): 2469-2483, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32445054

RESUMO

RATIONALE: MK801, like other NMDA receptor open-channel blockers (e.g., ketamine and phencyclidine), increases the locomotor activity of rats and mice. Whether this behavioral effect ultimately relies on monoamine neurotransmission is of dispute. OBJECTIVE: The purpose of this study was to determine whether these psychopharmacological effects and underlying neural mechanisms vary according to sex and age. METHODS: Across four experiments, male and female preweanling and adolescent rats were pretreated with vehicle, the monoamine-depleting agent reserpine (1 or 5 mg/kg), the dopamine (DA) synthesis inhibitor ∝-methyl-DL-p-tyrosine (AMPT), the serotonin (5-HT) synthesis inhibitor 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), or both AMPT and PCPA. The locomotor activity of preweanling and adolescent rats was then measured after saline or MK801 (0.3 mg/kg) treatment. RESULTS: As expected, MK801 increased the locomotor activity of all age groups and both sexes, but the stimulatory effects were significantly less pronounced in male adolescent rats. Preweanling rats and adolescent female rats were more sensitive to the effects of DA and 5-HT synthesis inhibitors, as AMPT and PCPA caused only small reductions in the MK801-induced locomotor activity of male adolescent rats. Co-administration of AMPT+PCPA or high-dose reserpine (5 mg/kg) treatment substantially reduced MK801-induced locomotor activity in both age groups and across both sexes. CONCLUSIONS: These results, when combined with other recent studies, show that NMDA receptor open-channel blockers cause pronounced age-dependent behavioral effects that can vary according to sex. The neural changes underlying these sex and age differences appear to involve monoamine neurotransmission.


Assuntos
Maleato de Dizocilpina/farmacologia , Dopamina/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Locomoção/fisiologia , Serotonina/fisiologia , Maturidade Sexual/fisiologia , Inibidores da Captação Adrenérgica/farmacologia , Fatores Etários , Animais , Animais Recém-Nascidos , Antagonistas de Dopamina/farmacologia , Feminino , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Antagonistas da Serotonina/farmacologia , Fatores Sexuais , Maturidade Sexual/efeitos dos fármacos
7.
J Neurosci ; 40(25): 4881-4887, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32430298

RESUMO

Understanding how disruption of prefrontal cortex (PFC) maturation during adolescence is crucial to reveal which neural processes could contribute to the onset of psychiatric disorders that display frontal cortical deficits. Of particular interest is the gain of GABAergic function in the PFC during adolescence and its susceptibility to the impact of transient blockade of NMDA receptor function. Here we assessed whether exposure to MK-801 during adolescence in male rats triggers a state of excitatory-inhibitory imbalance in the PFC that limits its functional capacity to regulate behavior in adulthood. Recordings from PFC brain slices revealed that MK-801 exposure during adolescence preferentially reduces the presynaptic functionality of GABAergic activity over that of excitatory synapses. As a result, an imbalance of excitatory-inhibitory synaptic activity emerges in the PFC that correlates linearly with the GABAergic deficit. Notably, the data also suggest that the diminished prefrontal GABAergic function could arise from a deficit in the recruitment of fast-spiking interneurons by excitatory inputs during adolescence. At the behavioral level, MK-801 exposure during adolescence did not disrupt the acquisition of trace fear conditioning, but markedly increased the level of freezing response during extinction testing. Infusion of the GABAA receptor-positive allosteric modulator Indiplon into the PFC before extinction testing reduced the level of freezing response in MK-801-treated rats to control levels. Collectively, the results indicate NMDA receptor signaling during adolescence enables the gain of prefrontal GABAergic function, which is required for maintaining proper excitatory-inhibitory balance in the PFC and its control of behavioral responses.SIGNIFICANCE STATEMENT A developmental disruption of prefrontal cortex maturation has been implicated in the pathophysiology of cognitive deficits in psychiatric disorders. Of particular interest is the susceptibility of the local GABAergic circuit to the impact of transient disruption of NMDA receptors. Here we found that NMDA receptor signaling is critical to enable the gain of prefrontal GABAergic transmission during adolescence for maintaining proper levels of excitatory-inhibitory balance in the PFC and its control of behavior.


Assuntos
Medo/fisiologia , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/fisiologia , Animais , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos
8.
J Neurosci ; 40(18): 3631-3645, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32245827

RESUMO

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that play critical roles in neuronal development and nervous system function. Here, we developed a model to study NMDARs in early development in zebrafish, by generating CRISPR-mediated lesions in the NMDAR genes, grin1a and grin1b, which encode the obligatory GluN1 subunits. While receptors containing grin1a or grin1b show high Ca2+ permeability, like their mammalian counterpart, grin1a is expressed earlier and more broadly in development than grin1b Both grin1a -/- and grin1b -/- zebrafish are viable. Unlike in rodents, where the grin1 knockout is embryonic lethal, grin1 double-mutant fish (grin1a -/- ; grin1b -/-), which lack all NMDAR-mediated synaptic transmission, survive until ∼10 d dpf (days post fertilization), providing a unique opportunity to explore NMDAR function during development and in generating behaviors. Many behavioral defects in the grin1 double-mutant larvae, including abnormal evoked responses to light and acoustic stimuli, prey-capture deficits, and a failure to habituate to acoustic stimuli, are replicated by short-term treatment with the NMDAR antagonist MK-801, suggesting that they arise from acute effects of compromised NMDAR-mediated transmission. Other defects, however, such as periods of hyperactivity and alterations in place preference, are not phenocopied by MK-801, suggesting a developmental origin. Together, we have developed a unique model to study NMDARs in the developing vertebrate nervous system.SIGNIFICANCE STATEMENT Rapid communication between cells in the nervous system depends on ion channels that are directly activated by chemical neurotransmitters. One such ligand-gated ion channel, the NMDAR, impacts nearly all forms of nervous system function. It has been challenging, however, to study the prolonged absence of NMDARs in vertebrates, and hence their role in nervous system development, due to experimental limitations. Here, we demonstrate that zebrafish lacking all NMDAR transmission are viable through early development and are capable of a wide range of stereotypic behaviors. As such, this zebrafish model provides a unique opportunity to study the role of NMDAR in the development of the early vertebrate nervous system.


Assuntos
Sistema Nervoso/embriologia , Sistema Nervoso/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Estimulação Acústica/métodos , Animais , Animais Geneticamente Modificados , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Células HEK293 , Humanos , Masculino , Sistema Nervoso/efeitos dos fármacos , Estimulação Luminosa/métodos , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Peixe-Zebra , Proteínas de Peixe-Zebra/antagonistas & inibidores
9.
World Neurosurg ; 139: e455-e462, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32311563

RESUMO

OBJECTIVE: A large body of evidence has suggested that the disruptions of neural plasticity in the brain play a pivotal role in major depressive disorder (MDD). Electroacupuncture (EA) therapy has been shown to be an effective treatment modality for MDD. However, the mechanism underling the antidepressive effect of EA treatment has not been clearly elucidated. This study aimed to investigate the antidepressant-like effects of EA associated with its protection effect of synaptic structural plasticity. METHODS: An MDD model was induced by exposing Sprague Dawley rats to chronic unpredictable mild stress (CUMS). EA stimulation (Hegu and Taichong) and AMPA receptor (AMPAR) antagonist NBQX intrahippocampal injection were used to treat the depressed rats. RESULTS: We found EA improved behavioral performance, enhanced synaptic structural plasticity, and upregulated gene and protein levels of GluR1, GluR2, Stargazin, Pick1, SYP, PSD-95, and GAP-43. AMPAR antagonist NBQX had the opposite effect on behavioral performance, synaptic plasticity, and the aforementioned genes and proteins. CONCLUSIONS: These results suggest that EA has a potent antidepressant effect, likely through upregulated expression of the AMPAR and protected neural plasticity in CUMS-treated rats.


Assuntos
Depressão/terapia , Eletroacupuntura/métodos , Hipocampo , Receptores de AMPA , Estresse Psicológico/complicações , Sinapses/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Doença Crônica , Depressão/etiologia , Depressão/psicologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Plasticidade Neuronal , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/antagonistas & inibidores , Estresse Psicológico/psicologia
10.
Psychopharmacology (Berl) ; 237(5): 1421-1433, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32130432

RESUMO

RATIONALE: The rapid-onset and long-lasting antidepressant properties of ketamine have prompted investigations into a variety of agents that target N-methyl-D-aspartate receptors (NMDARs) for the treatment of major depressive disorder (MDD). According to the literature, ifenprodil (a GluN2B-containing NMDAR antagonist) can potentiate the antidepressant-like effects of certain antidepressant drugs in mice. Here, we report that a single injection of ifenprodil (3 mg/kg, intraperitoneally (i.p.)) was sufficient to provoke rapid antidepressant-like effects in chronic unpredictable mild stress (CUMS) rats. Moreover, ifenprodil activated mTOR signaling and reversed the CUMS-induced elevation of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the hippocampus after acute administration. Unfortunately, in our study, ifenprodil had no influence on corticosterone levels in the plasma. Our data indicate that ifenprodil per se might exert antidepressant-like effects by modulating neuroplasticity and inflammatory processes rather than the typical hormonal factors affected by stressors. OBJECTIVES: To explore the potential rapid antidepressant-like effects and mechanisms of ifenprodil, a GluN2B subunit-selective NMDAR antagonist. METHODS: Male Sprague-Dawley rats were used in 3 separate experiments. In experiment 1, we used the forced swim test (FST) and sucrose preference test (SPT) to identify the rapid antidepressant-like effects of ifenprodil in chronic unpredictable mild stress (CUMS) rats after acute administration. In experiment 2, we assessed neurochemical changes involved in synaptic plasticity within the hippocampus of CUMS rats. In experiment 3, we assessed the levels of corticosterone in the plasma and proinflammatory cytokines in the hippocampus in CUMS rats after ifenprodil treatment. RESULTS: Ifenprodil rapidly ameliorated depressive-like behaviors in the FST and SPT, activated mTOR signaling, dephosphorylated eukaryotic elongation factor 2, enhanced BDNF expression, and promoted the synthesis of the synaptic protein GluA1 synthesis after acute administration. Moreover, ifenprodil reversed the CUMS-induced elevation of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the hippocampus after acute administration. Unfortunately, ifenprodil had no influence on corticosterone levels in the plasma in our study. CONCLUSIONS: Our data indicate that ifenprodil per se might exert antidepressant-like effects through its effects on neuroplasticity and inflammatory processes rather than the typical hormonal factors affected by stressors.


Assuntos
Citocinas/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Hipocampo/metabolismo , Piperidinas/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Citocinas/antagonistas & inibidores , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Hipocampo/efeitos dos fármacos , Masculino , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
11.
Int J Mol Sci ; 21(5)2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32151061

RESUMO

BACKGROUND: Glaucoma is an optic neuropathy and involves the progressive degeneration of retinal ganglion cells (RGCs), which leads to blindness in patients. We investigated the role of the neuroprotective kynurenic acid (KYNA) in RGC death against retinal ischemia/reperfusion (I/R) injury. METHODS: We injected KYNA intravenously or intravitreally to mice. We generated a knockout mouse strain of kynurenine 3-monooxygenase (KMO), an enzyme in the kynurenine pathway that produces neurotoxic 3-hydroxykynurenine. To test the effect of mild hyperglycemia on RGC protection, we used streptozotocin (STZ) induced diabetic mice. Retinal I/R injury was induced by increasing intraocular pressure for 60 min followed by reperfusion and RGC numbers were counted in the retinal flat mounts. RESULTS: Intravenous or intravitreal administration of KYNA protected RGCs against I/R injury. The I/R injury caused a greater loss of RGCs in wild type than in KMO knockout mice. KMO knockout mice had mildly higher levels of fasting blood glucose than wild type mice. Diabetic mice showed significantly lower loss of RGCs when compared with non-diabetic mice subjected to I/R injury. CONCLUSION: Together, our study suggests that the absence of KMO protects RGCs against I/R injury, through mechanisms that likely involve higher levels of KYNA and glucose.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Modelos Animais de Doenças , Glaucoma/prevenção & controle , Ácido Cinurênico/farmacologia , Quinurenina 3-Mono-Oxigenase/fisiologia , Traumatismo por Reperfusão/complicações , Células Ganglionares da Retina/efeitos dos fármacos , Animais , Antagonistas de Aminoácidos Excitatórios/farmacologia , Glaucoma/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia
12.
J Neurosci ; 40(17): 3348-3359, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32169968

RESUMO

Nitric oxide (NO) is an important signaling molecule that fulfills diverse functional roles as a neurotransmitter or diffusible second messenger in the developing and adult CNS. Although the impact of NO on different behaviors such as movement, sleep, learning, and memory has been well documented, the identity of its molecular and cellular targets is still an area of ongoing investigation. Here, we identify a novel role for NO in strengthening inhibitory GABAA receptor-mediated transmission in molecular layer interneurons of the mouse cerebellum. NO levels are elevated by the activity of neuronal NO synthase (nNOS) following Ca2+ entry through extrasynaptic NMDA-type ionotropic glutamate receptors (NMDARs). NO activates protein kinase G with the subsequent production of cGMP, which prompts the stimulation of NADPH oxidase and protein kinase C (PKC). The activation of PKC promotes the selective strengthening of α3-containing GABAARs synapses through a GΑΒΑ receptor-associated protein-dependent mechanism. Given the widespread but cell type-specific expression of the NMDAR/nNOS complex in the mammalian brain, our data suggest that NMDARs may uniquely strengthen inhibitory GABAergic transmission in these cells through a novel NO-mediated pathway.SIGNIFICANCE STATEMENT Long-term changes in the efficacy of GABAergic transmission is mediated by multiple presynaptic and postsynaptic mechanisms. A prominent pathway involves crosstalk between excitatory and inhibitory synapses whereby Ca2+-entering through postsynaptic NMDARs promotes the recruitment and strengthening of GABAA receptor synapses via Ca2+/calmodulin-dependent protein kinase II. Although Ca2+ transport by NMDARs is also tightly coupled to nNOS activity and NO production, it has yet to be determined whether this pathway affects inhibitory synapses. Here, we show that activation of NMDARs trigger a NO-dependent pathway that strengthens inhibitory GABAergic synapses of cerebellar molecular layer interneurons. Given the widespread expression of NMDARs and nNOS in the mammalian brain, we speculate that NO control of GABAergic synapse efficacy may be more widespread than has been appreciated.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Cerebelo/metabolismo , Interneurônios/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais/fisiologia , Animais , Cerebelo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Interneurônios/efeitos dos fármacos , Masculino , Camundongos , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Técnicas de Patch-Clamp , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
13.
J Neurosci ; 40(13): 2737-2752, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32075899

RESUMO

Microinjections of a glutamate AMPA antagonist (DNQX) in medial shell of nucleus accumbens (NAc) can cause either intense appetitive motivation (i.e., 'desire') or intense defensive motivation (i.e., 'dread'), depending on site along a flexible rostrocaudal gradient and on environmental ambience. DNQX, by blocking excitatory AMPA glutamate inputs, is hypothesized to produce relative inhibitions of NAc neurons. However, given potential alternative explanations, it is not known whether neuronal inhibition is in fact necessary for NAc DNQX microinjections to generate motivations. Here we provide a direct test of whether local neuronal inhibition in NAc is necessary for DNQX microinjections to produce either desire or dread. We used optogenetic channelrhodopsin (ChR2) excitations at the same local sites in NAc as DNQX microinjections to oppose relative neuronal inhibitions induced by DNQX in female and male rats. We found that same-site ChR2 excitation effectively reversed the ability of NAc DNQX microinjections to generate appetitive motivation, and similarly reversed ability of DNQX microinjections to generate defensive motivation. Same-site NAc optogenetic excitations also attenuated recruitment of Fos expression in other limbic structures throughout the brain, which was otherwise elevated by NAc DNQX microinjections that generated motivation. However, to successfully reverse motivation generation, an optic fiber tip for ChR2 illumination needed to be located within <1 mm of the corresponding DNQX microinjector tip; that is, both truly at the same NAc site. Thus, we confirm that localized NAc neuronal inhibition is required for AMPA-blocking microinjections in medial shell to induce either positively-valenced 'desire' or negatively-valenced 'dread'.SIGNIFICANCE STATEMENT A major hypothesis posits neuronal inhibitions in nucleus accumbens generate intense motivation. Microinjections in nucleus accumbens of glutamate antagonist, DNQX, which might suppress local neuronal firing, generate either appetitive or defensive motivation, depending on site and environmental factors. Is neuronal inhibition in nucleus accumbens required for such pharmacologically-induced motivations? Here we demonstrate that neuronal inhibition is necessary to generate appetitive or defensive motivations, using local optogenetic excitations to oppose putative DNQX-induced inhibitions. We show that excitation at the same site prevents DNQX microinjections from recruiting downstream limbic structures into neurobiological activation, and simultaneously prevents generation of either appetitive or defensive motivated behaviors. These results may be relevant to roles of nucleus accumbens mechanisms in pathological motivations, including addiction and paranoia.


Assuntos
Inibição Psicológica , Motivação/fisiologia , Núcleo Accumbens/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Masculino , Microinjeções , Motivação/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Optogenética , Quinoxalinas/farmacologia , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley
14.
Neurourol Urodyn ; 39(3): 935-944, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32068300

RESUMO

AIMS: The aim of this study is to investigate whether ketamine could relieve the social stress (SS)-related bladder dysfunction in mice. MATERIALS AND METHODS: The FVB mice were randomly assigned to either undergo SS exposure for 60 minutes per day on seven consecutive days for 4 weeks (SS1) or control without SS (SS0). The SS0 were then allocated to single or no injection of ketamine (SS0K1 and SS0K0). In the group of SS1, the SS1 mice were allocated to receive single injection of saline (SS1K0), single dose (SS1K1) or five daily dose of (SS1K5) ketamine injection (25 mg/kg/day/ip) since day 22. In vivo cystometry and tissue bath wire myography were performed on day 29. Serum and urine level of brain-derived neurotrophic factor (BDNF) were measured with enzyme-linked immunosorbent assay. RESULTS: In mice without social stress exposure, ketamine administration did not significantly affect voiding frequency (P > .05). SS1 K0 , SS1 K1, and SS1 K5 had significantly lower voiding frequency than that of control (SS1 K0 ) (each n = 15, P < .05). Ketamine administration reversed the trend of decreased voiding frequency in SS1 mice. Stressed mice had significant higher serum level of BDNF that reduced by short-term ketamine. Stressed mice had detrusor overactivity and impaired detrusor contractility which were not reversed by short-term ketamine. CONCLUSIONS: Social stress leads to elevated serum BDNF, infrequent voiding, detrusor overactivity, and impaired contractility. Short-term administration of ketamine may improve SS-related infrequent voiding and elevated serum BDNF level. However, ketamine did not improve SS-related bladder dysfunction on urodynamic and myography studies.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Contração Muscular/efeitos dos fármacos , Estresse Psicológico/fisiopatologia , Bexiga Urinária/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/sangue , Masculino , Camundongos , Contração Muscular/fisiologia , Comportamento Social , Estresse Psicológico/sangue , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/fisiopatologia , Urodinâmica
15.
J Neurosci ; 40(12): 2458-2470, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32051326

RESUMO

Many tasks demand that information is kept online for a few seconds before it is used to guide behavior. The information is kept in working memory as the persistent firing of neurons encoding the memorized information. The neural mechanisms responsible for persistent activity are not yet well understood. Theories attribute an important role to ionotropic glutamate receptors, and it has been suggested that NMDARs are particularly important for persistent firing because they exhibit long time constants. Ionotropic AMPARs have shorter time constants and have been suggested to play a smaller role in working memory. Here we compared the contribution of AMPARs and NMDARs to persistent firing in the dlPFC of male macaque monkeys performing a delayed saccade to a memorized spatial location. We used iontophoresis to eject small amounts of glutamate receptor antagonists, aiming to perturb, but not abolish, neuronal activity. We found that both AMPARs and NMDARs contributed to persistent activity. Blockers of the NMDARs decreased persistent firing associated with the memory of the neuron's preferred spatial location but had comparatively little effect on the representation of the antipreferred location. They therefore decreased the information conveyed by persistent firing about the memorized location. In contrast, AMPAR blockers decreased activity elicited by the memory of both the preferred and antipreferred location, with a smaller effect on the information conveyed by persistent activity. Our results provide new insights into the contribution of AMPARs and NMDARs to persistent activity during working memory tasks.SIGNIFICANCE STATEMENT Working memory enables us to hold on to information that is no longer available to the senses. It relies on the persistent activity of neurons that code for the memorized information, but the detailed mechanisms are not yet well understood. Here we investigated the role of NMDARs and AMPARs in working memory using iontophoresis of antagonists in the PFC of monkeys remembering the location of a visual stimulus for an eye movement response. AMPARs and NMDARs both contributed to persistent activity. NMDAR blockers mostly decreased persistent firing associated with the memory of the neuron's preferred spatial location, whereas AMPAR blockers caused a more general suppression. These results provide new insight into the contribution of AMPARs and NMDARs to working memory.


Assuntos
Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/fisiologia , Receptores de AMPA/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Fenômenos Eletrofisiológicos/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Iontoforese , Macaca mulatta , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Neurônios/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Receptores de AMPA/antagonistas & inibidores , Receptores Ionotrópicos de Glutamato/efeitos dos fármacos , Receptores Ionotrópicos de Glutamato/fisiologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Movimentos Sacádicos/efeitos dos fármacos , Movimentos Sacádicos/fisiologia , Percepção Espacial/efeitos dos fármacos , Percepção Espacial/fisiologia
16.
Pharmacol Rep ; 72(2): 472-480, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32048268

RESUMO

BACKGROUND: N-methyl-D-aspartate (NMDA) receptor is a tetrameric protein complex composed of glycine-linked NR1 subunits and glutamate-linked NR2 subunits. There are four NR2 subunits (A-D) that differ in development, anatomy, and function profiles. They play various roles in normal and neuropathologic conditions. Specific agonists, antagonists, and modulators of subunits for selective NMDA receptors may be precious mediational tools and potent agents for treating diseases. The objective of this study was to determine the effect of poricoic acid A on NMDA receptor known to mediate excitatory synaptic transmission factors and cause changes in synaptic strength. Inhibitory effect of poricoic acid A on NR1a combined with NR2A, NR2B, NR2C, or NR2D receptor was evaluated. METHODS: Glutamate-mediated currents for each NR1a and NR2 subunits were investigated using two-electrode voltage-clamp techniques. Molecular modeling and molecular dynamics simulation studies were carried out with Autodock Tools. Poricoic acid A and NMDA receptor protein complex were examined with Ligplot and Pymol docking program. Ligplot shows binding activity at the protein and the ligand. RESULTS: The inhibitory effect of poricoic acid A on glutamate-induced inward current in a concentration-dependent manner that was reversible. Half inhibitory concentrations of glutamate on NR1a/NR2A, NR1a/NR2B, NR1a/NR2C, and NR1a/NR2D receptors were 9.6 ± 1.2, 5.7 ± 0.4, 46.1 ± 21.5, and 21.5 ± 8.2 µM, respectively. This corresponded to the order of inhibitory effect of oocyte expressing NR1a and NR2s subunit of NR1a/NR2B > NR1a/NR2A > NR1a/NR2C > NR1a/NR2D. CONCLUSIONS: Taken together, these results indicate that poricoic acid A can modulate the expression of NMDA receptor. In addition, the regulation of excitatory ligand-gating ion channel by poricoic acid A may have pharmaceutical functions on excitatory synaptic transmission of neuronal system.


Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Triterpenos/farmacologia , Animais , Sítios de Ligação , Ácido Glutâmico/farmacologia , Simulação de Dinâmica Molecular , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Ligação Proteica , Subunidades Proteicas , Receptores de N-Metil-D-Aspartato/genética , Xenopus
17.
Exp Neurol ; 327: 113222, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32027929

RESUMO

Traumatic brain injury (TBI) is a major cause of death and physical as well as cognitive disability for which an effective treatment option remains to be identified. Evidence in preclinical models has indicated that antagonists of the α-amino-3-hydroxy-5-methyl-4-isozazole propionate (AMPA) receptor exert neuroprotective effects after mechanical injury in vitro and in vivo. In particular, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate (perampanel), a selective AMPA receptor antagonist with good bioavailability, was recently shown to therapeutically protect against the sequelae of TBI in the rodent controlled cortical impact model. However, this model induces a largely focal injury and is less representative of diffuse injury components that occur in TBI resulting from acceleration/deceleration forces. Here, we investigated the neuroprotective effects of perampanel in the rodent lateral fluid percussion injury model (LFPI), which produces both focal and diffuse injury. Pre- or post-injury administration of perampanel in male adult rats attenuated the injury-induced increase in the pro-apoptotic bax/bcl-xL ratio in the hippocampus; reduced impairments in learning and memory, assessed by the Morris water maze test; and reduced impairments in reward-seeking behavior, assessed by a female encounter test. Although additional studies are needed to determine the sex-related differences in the neuroprotective effects, these results provide support for the therapeutic potential of perampanel in TBI.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Piridonas/uso terapêutico , Receptores de AMPA/antagonistas & inibidores , Animais , Lesões Encefálicas Traumáticas/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Piridonas/farmacologia , Ratos , Ratos Sprague-Dawley , Memória Espacial/efeitos dos fármacos , Resultado do Tratamento , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismo
18.
J Neurochem ; 153(6): 693-709, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32031240

RESUMO

Autoimmune optic neuritis (AON), a model of multiple sclerosis-associated optic neuritis, is accompanied by degeneration of retinal ganglion cells (RGCs) and optic nerve demyelination and axonal loss. In order to investigate the role of N-methyl-d-aspartate (NMDA) receptors in mediating RGC degeneration, upstream changes in the optic nerve actin cytoskeleton and associated deterioration in visual function, we induced AON in Brown Norway rats by immunization with myelin oligodendrocyte glycoprotein. Subsequently, visual acuity was assessed by recording visual evoked potentials and electroretinograms prior to extraction of optic nerves for western blot analysis and retinas for quantification of RGCs. As previously reported, in Brown Norway rats RGC degeneration is observed prior to onset of immune cell infiltration and demyelination of the optic nerves. However, within the optic nerve, destabilization of the actin cytoskeleton could be seen as indicated by an increase in the globular to filamentous actin ratio. Interestingly, these changes could be mimicked by intravitreal injection of glutamate, and similarly blocked by application of the NMDA receptor blocker MK-801, leading us to propose that prior to optic nerve lesion formation, NMDA receptor activation within the retina leads to retinal calcium accumulation, actin destabilization within the optic nerve as well as a deterioration of visual acuity during AON.


Assuntos
Neurite Óptica/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Retina/metabolismo , Animais , Maleato de Dizocilpina/farmacologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Potenciais Evocados Visuais/efeitos dos fármacos , Potenciais Evocados Visuais/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Glicoproteína Mielina-Oligodendrócito/toxicidade , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/imunologia , Nervo Óptico/metabolismo , Neurite Óptica/induzido quimicamente , Neurite Óptica/imunologia , Ratos , Ratos Endogâmicos BN , Receptores de N-Metil-D-Aspartato/imunologia , Retina/efeitos dos fármacos , Retina/imunologia
19.
Cell ; 180(4): 666-676.e13, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32084339

RESUMO

The mystery of general anesthesia is that it specifically suppresses consciousness by disrupting feedback signaling in the brain, even when feedforward signaling and basic neuronal function are left relatively unchanged. The mechanism for such selectiveness is unknown. Here we show that three different anesthetics have the same disruptive influence on signaling along apical dendrites in cortical layer 5 pyramidal neurons in mice. We found that optogenetic depolarization of the distal apical dendrites caused robust spiking at the cell body under awake conditions that was blocked by anesthesia. Moreover, we found that blocking metabotropic glutamate and cholinergic receptors had the same effect on apical dendrite decoupling as anesthesia or inactivation of the higher-order thalamus. If feedback signaling occurs predominantly through apical dendrites, the cellular mechanism we found would explain not only how anesthesia selectively blocks this signaling but also why conscious perception depends on both cortico-cortical and thalamo-cortical connectivity.


Assuntos
Anestésicos Gerais/farmacologia , Córtex Cerebral/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Animais , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Antagonistas Colinérgicos/farmacologia , Estado de Consciência , Dendritos/efeitos dos fármacos , Dendritos/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Retroalimentação Fisiológica , Feminino , Masculino , Camundongos , Células Piramidais/fisiologia , Transmissão Sináptica , Tálamo/citologia , Tálamo/efeitos dos fármacos , Tálamo/fisiologia
20.
Sci Rep ; 10(1): 969, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969611

RESUMO

Rotenone, a mitochondrial complex I inhibitor, causes retinal degeneration via unknown mechanisms. To elucidate the molecular mechanisms of its action, we further characterized a rat model of rotenone-induced retinal degeneration. Intravitreal injection of rotenone (2 nmol/eye) damaged mainly the inner retinal layers, including cell loss in the ganglion cell and inner nuclear layers, which were very similar to those induced by 10 nmol/eye N-methyl-D-aspartate (NMDA). These morphological changes were accompanied by the reduced b-wave amplitude of electroretinogram, and increased immunostaining of 2,4-dinitrophenyl, an oxidative stress marker. Rotenone also downregulated expression of neurofilament light-chain gene (Nfl) as a retinal ganglion cell (RGC) marker. This effect was prevented by simultaneous injection of rotenone with antioxidants or NMDA receptor antagonists. More importantly, voltage-dependent sodium and L-type calcium channel blockers and intracellular calcium signaling modulators remarkably suppressed rotenone-induced Nfl downregulation, whereas none of these agents modified NMDA-induced Nfl downregulation. These results suggest that rotenone-induced inner retinal degeneration stems from indirect postsynaptic NMDA stimulation that is triggered by oxidative stress-mediated presynaptic intracellular calcium signaling via activation of voltage-dependent sodium and L-type calcium channels.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Degeneração Retiniana/induzido quimicamente , Rotenona/efeitos adversos , Desacopladores/efeitos adversos , Canais de Sódio Disparados por Voltagem/metabolismo , Animais , Antioxidantes/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Eletrorretinografia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Retina/efeitos dos fármacos , Retina/metabolismo , Degeneração Retiniana/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo
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