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1.
Artigo em Inglês | MEDLINE | ID: mdl-31887407

RESUMO

In order to evaluate fatty acid (FA) sensing systems based on binding to FAT/CD36 in hypothalamus of Chinese perch (Siniperca chuatsi) and its sensitivity to FAs with the same chain length and different unsaturation levels. The effects of Stearate (SA; C18:0), oleate (OA; C18:1 n-9), linoleic acid (LA; C18:2 n-6), and α-linolenic acid (ALA; C18:3 n-3) on hypothalamic FA sensing were evaluated by intracerebroventricular (ICV) administration. Food intake was assessed after 2, 4, 6, 8 and 12 h. Gene expression associated with FA sensing mechanism such as cd36, pparα and srebp1c, and neuropeptides controlling appetite such as pomca, cart, agrp2 and npy were assessed after 6 h. The ICV treatment of OA, LA and ALA activated FAT/CD36 and PPARα, rather than SA, and modulated gene expression levels of hypothalamic neuropeptides associated with appetite. And then, OA, LA and ALA inhibited food intake, which was consistent with the activation of hypothalamus FA sensing. Our data indicated some mechanisms of the hypothalamic FA sensing systems also existed in Chinese perch. It's worth noting that polyunsaturated fatty acids (PUFA) could also activate hypothalamic FA sensing mechanisms in Chinese perch. The unsaturation of FA appears to be extremely important for FA sensing mechanisms, since no major influences in Chinese perch after SA treatment. Our findings will contribute to the study of long-chain FAs sensing mechanisms in fish hypothalamus and highlight the importance of PUFAs in fish species.


Assuntos
Antígenos CD36/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Ácidos Graxos Insaturados/administração & dosagem , Ácidos Graxos/administração & dosagem , Hipotálamo/efeitos dos fármacos , Neuropeptídeos/metabolismo , Percas/fisiologia , Animais , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Hipotálamo/metabolismo , Infusões Intraventriculares , PPAR alfa/metabolismo
2.
Life Sci ; 241: 117154, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31857087

RESUMO

AIM: Insulin resistance and neuroinflammation play roles in Alzheimer's (AD) etiology. Insulin receptors (IR) are developmentally expressed in neurons as well as astrocytes. Moreover, prolonged stress can induce brain insulin resistance and astrogliosis. Also, prenatal stress could advance AD-related abnormalities in a transgenic model of AD. Besides, postnatal maternal care (PMC) has antagonistic effects on prenatal stress (PS)-induced neuronal and immunological malfunctions. Using an icv-STZ subclinical model of sAD, we assessed PS and/or abnormal PMC impacts on advancing sAD-like pathology in adult male rats. We also sought astrocyte- and/or neuron-oriented change in central insulin programming. MAIN METHODS: Pregnant rats were exposed to PS. Thereafter, a group of pups was fostered onto unstressed mothers and the others remained intact. Real-time RT-PCR- for hippocampal IR, Tau, and ChAT transcripts- and immunohistochemistry analysis- for GFAP+ astrocytes- were performed at the first- and forth-postnatal-week, respectively. The other animals received icv-STZ0.5 mg/kg in adulthood and subjected to cognitive tests, molecular, and histological experiments at appropriate time-point post-injection. KEY FINDINGS: PS could advance sAD-related symptoms in icv-STZ-treated animals. PS changed expression levels of hippocampal IR in one-week-old and 5.5-month-old offspring. PS could worsen cognitive, molecular and histological impairments of icv-STZ. Adequate PMC prevented some destructive effects of PS. SIGNIFICANCE: PS can potentially change central insulin programming and induce long-lasting astrogliosis in rat hippocampus. PS-related cognitive and histological pathologies can rescue by PMC probably via IR-dependent pathways. Astrocyte involvement in AD-like neuropathology observed in stressed-animals needs more detailed investigations.


Assuntos
Doença de Alzheimer/patologia , Comportamento Animal , Modelos Animais de Doenças , Resistência à Insulina , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estreptozocina/toxicidade , Estresse Psicológico/complicações , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Animais , Animais Recém-Nascidos , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/toxicidade , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Infusões Intraventriculares , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Gravidez , Ratos , Ratos Wistar , Receptor de Insulina/metabolismo , Transdução de Sinais , Estreptozocina/administração & dosagem
3.
Zhongguo Fei Ai Za Zhi ; 22(8): 546-550, 2019 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-31451148

RESUMO

Leptomeningeal metastasis (LM) is one of the most severe complications of non-small-cell lung cancer (NSCLC), and its incidence is increasing gradually with the progress of targeted therapies. There are currently no standard guidelines for the therapy of LM. Intrathecal chemotherapy is the mainstay of treatment for NSCLC patients with LM, but the optimal drug, administration route and mode, and dosage remain unclear. We report a case of LM from NSCLC, who received the intrathecal chemotherapy with pemetrexed by Ommaya reservoir after prior targeted therapies. This local treatment improved the quality of life, and obtained the clearing of CSF cytology and stable lesions of LM without any notable side effects. After confirmation of LM, the patient has survived 17 months until now. Here we report the first case to demonstrate the potential effectiveness of intrathecal pemetrexed by Ommaya reservoir for the treatment of LM of NSCLC, summarize the safety and effectiveness of intrathecal chemotherapy in combination with related literatures, and provide a new strategy for local treatment of LM in clinical.
.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Neoplasias Meníngeas/tratamento farmacológico , Pemetrexede/administração & dosagem , Líquido Cefalorraquidiano/efeitos dos fármacos , Feminino , Humanos , Infusões Intraventriculares , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/secundário , Pessoa de Meia-Idade , Metástase Neoplásica
4.
Mol Biol Rep ; 46(5): 5257-5272, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31327120

RESUMO

We have chosen to test the safety of human intracerebroventricular (ICV) brain injections of autologous non-genetically-modified adipose-derived stromal vascular fraction (ADSVF). In this IRB-approved trial, 24 patients received ICV ADSVF via an implanted reservoir between 5/22/14 and 5/22/17. Seven others were injected via their ventriculo-peritoneal shunts. Ten patients had Alzheimer's disease (AD), 6 had amyotrophic lateral sclerosis (ALS), 6 had progressive multiple sclerosis (MS-P), 6 had Parkinson's "Plus" (PD+), 1 had spinal cord injury, 1 had traumatic brain injury, and 1 had stroke. Median age was 74 (range 41-83). Injections were planned every 2-3 months. Thirty-one patients had 113 injections. Patients received SVF injection volumes of 3.5-20 cc (median:4 cc) containing 4.05 × 105 to 6.2 × 107 cells/cc, which contained an average of 8% hematopoietic and 7.5% adipose stem cells. Follow-up ranged from 0 to 36 months (median: 9.2 months). MRIs post injection(s) were unchanged, except for one AD patient whose hippocampal volume increased from < 5th percentile to 48th percentile (NeuroQuant® volumetric MRI). Of the 10 AD patients, 8 were stable or improved in tests of cognition. Two showed improvement in P-tau and ß-amyloid levels. Of the 6 MS-P patients all are stable or improved. Four of 6 ALS patients died of disease progression. Twelve of 111 injections (11%) led to 1-4 days of transient meningismus, and mild temperature elevation, which resolved with acetaminophen and/or dexamethasone. Two (1.8% of injections) required hospitalization for these symptoms. One patient (0.9% of injections) had his reservoir removed and later replaced for presumed infection. In this Phase 1 safety trial, ADSVF was safely injected into the human brain ventricular system in patients with no other treatment options. Secondary endpoints of clinical improvement or stability were particularly promising in the AD and MS-P groups. These results will be submitted for a Phase 2 FDA-approved trial.


Assuntos
Tecido Adiposo/citologia , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Mesenquimais/métodos , Doenças Neurodegenerativas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/instrumentação , Células-Tronco Hematopoéticas , Humanos , Infusões Intraventriculares , Masculino , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Transplante de Células-Tronco Mesenquimais/instrumentação , Pessoa de Meia-Idade , Transplante Autólogo , Resultado do Tratamento , Derivação Ventriculoperitoneal
5.
Nat Commun ; 10(1): 2717, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31222048

RESUMO

Hepatic steatosis develops when lipid influx and production exceed the liver's ability to utilize/export triglycerides. Obesity promotes steatosis and is characterized by leptin resistance. A role of leptin in hepatic lipid handling is highlighted by the observation that recombinant leptin reverses steatosis of hypoleptinemic patients with lipodystrophy by an unknown mechanism. Since leptin mainly functions via CNS signaling, we here examine in rats whether leptin regulates hepatic lipid flux via the brain in a series of stereotaxic infusion experiments. We demonstrate that brain leptin protects from steatosis by promoting hepatic triglyceride export and decreasing de novo lipogenesis independently of caloric intake. Leptin's anti-steatotic effects are generated in the dorsal vagal complex, require hepatic vagal innervation, and are preserved in high-fat-diet-fed rats when the blood brain barrier is bypassed. Thus, CNS leptin protects from ectopic lipid accumulation via a brain-vagus-liver axis and may be a therapeutic strategy to ameliorate obesity-related steatosis.


Assuntos
Leptina/metabolismo , Fígado/metabolismo , Bulbo/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Humanos , Infusões Intraventriculares , Injeções Intraventriculares , Leptina/administração & dosagem , Lipogênese/fisiologia , Lipoproteínas VLDL , Fígado/inervação , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Polietilenoglicóis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Técnicas Estereotáxicas , Simpatectomia , Nervo Vago/fisiologia , Nervo Vago/cirurgia
6.
Horm Behav ; 114: 104545, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31228421

RESUMO

The memory-enhancing effects of 17ß-estradiol (E2) depend upon rapid activation of several cell-signaling cascades within the dorsal hippocampus (DH). Among the many cell-signaling pathways that mediate memory processes, Wnt/ß-catenin signaling has emerged as a potential key player because of its importance to hippocampal development and synaptic plasticity. However, whether E2 interacts with Wnt/ß-catenin signaling to promote memory consolidation is unknown. Therefore, the present study examined whether Wnt/ß-catenin signaling within the DH is necessary for E2-induced memory consolidation in ovariectomized mice tested in the object recognition and object placement tasks. Ovariectomized C57BL/6 mice received immediate post-training infusions of E2 or vehicle into the dorsal third ventricle plus the endogenous Wnt/ß-catenin antagonist Dickkopf-1 (Dkk-1) or vehicle into the DH to assess whether the memory-enhancing effects of E2 depend on activation of Wnt/ß-catenin signaling. Our results suggest that Dkk-1 blocks E2-induced memory enhancement as hypothesized, but may do so by only moderately blunting Wnt/ß-catenin signaling while concurrently activating Wnt/JNK signaling. The current study provides novel insights into the mechanisms through which E2 enhances memory consolidation in the DH, as well as critical information about the mechanistic actions of Dkk-1.


Assuntos
Estradiol/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Consolidação da Memória/efeitos dos fármacos , Animais , Feminino , Hipocampo/efeitos dos fármacos , Infusões Intraventriculares , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Ovariectomia , Transdução de Sinais/efeitos dos fármacos
7.
Appl Spectrosc ; 73(10): 1208-1217, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31219322

RESUMO

Brain ischemia represents a leading cause of death and disability in industrialized countries. To date, therapeutic intervention is largely unsatisfactory and novel strategies are required for getting better protection of neurons injured by cerebral blood flow restriction. Recent evidence suggests that brain insulin leads to protection of neuronal population undergoing apoptotic cell death via modulation of oxidative stress and mitochondrial cytochrome c (CytC), an effect to be better clarified. In this work, we investigate on the effect of insulin given intracerebroventricular (ICV) before inducing a transient global ischemia by bilateral occlusion of the common carotid arteries (BCCO) in Mongolian gerbils (MG). The transient (3 min) global ischemia in MG is observed to produce neurodegenerative effect mainly into CA3 hippocampal region, 72 h after cerebral blood restriction. Intracerebroventricular microinfusion of insulin significantly prevents the apoptosis of CA3 hippocampal neurons. Histological observation, after hematoxylin and eosin staining, puts in evidence the neuroprotective role of insulin, but Raman microimaging provides a clearer insight in the CytC mechanism underlying the apoptotic process. Above all, CytC has been revealed to be an outstanding, innate Raman marker for monitoring the cells status, thanks to its resonant scattering at 530 nm of incident wavelength and to its crucial role in the early stages of cells apoptosis. These data support the hypothesis of an insulin-dependent neuroprotection and antiapoptotic mechanism occurring in the brain of MG undergoing transient brain ischemia. The observed effects occurred without any peripheral change on serum glucose levels, suggesting an alternative mechanism of insulin-induced neuroprotection.


Assuntos
Apoptose , Isquemia Encefálica/tratamento farmacológico , Região CA3 Hipocampal/efeitos dos fármacos , Citocromos c/fisiologia , Insulina/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Gerbillinae , Infusões Intraventriculares , Insulina/administração & dosagem , Masculino , Mitocôndrias/efeitos dos fármacos , Neuroproteção , Fármacos Neuroprotetores/administração & dosagem , Análise Espectral Raman/métodos
8.
Nat Neurosci ; 22(7): 1089-1098, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31235908

RESUMO

Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here we generate an inducible pericyte-specific Cre line and cross pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor. After pericyte ablation with diphtheria toxin, mice showed acute blood-brain barrier breakdown, severe loss of blood flow, and a rapid neuron loss that was associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing of pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade that links pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings may have implications for the pathogenesis and treatment of neurological disorders that are associated with pericyte loss and/or neurovascular dysfunction.


Assuntos
Proteínas de Transporte/fisiologia , Citocinas/fisiologia , Degeneração Neural/fisiopatologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios/patologia , Pericitos/fisiologia , Choque/fisiopatologia , Animais , Isquemia Encefálica/fisiopatologia , Capilares/fisiopatologia , Proteínas de Transporte/uso terapêutico , Células Cultivadas , Circulação Cerebrovascular/fisiologia , Citocinas/deficiência , Citocinas/uso terapêutico , Células Endoteliais/citologia , Feminino , Genes Reporter , Infusões Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Degeneração Neural/tratamento farmacológico , Neuroglia/metabolismo , Neurônios/metabolismo , Neurotoxinas/toxicidade , Regiões Promotoras Genéticas , Proteínas Recombinantes de Fusão/metabolismo , Choque/metabolismo , Choque/patologia
9.
Respir Res ; 20(1): 110, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170972

RESUMO

BACKGROUND: Inhaled bradykinin (BK) has been reported to both sensitize and induce cough but whether BK can centrally sensitize the cough reflex is not fully established. In this study, using a conscious guinea-pig model of cough, we investigated the role of BK in the central sensitization of the cough reflex and in airway obstruction. METHODS: Drugs were administered, to guinea pigs, by the intracerebroventricular (i.c.v.) route. Aerosolized citric acid (0.2 M) was used to induce cough in a whole-body plethysmograph box, following i.c.v. infusion of drugs. An automated analyser recorded both cough and airway obstruction simultaneously. RESULTS: BK, administered by the i.c.v. route, dose-dependently enhanced the citric acid-induced cough and airway obstruction. This effect was inhibited following i.c.v. pretreatment with a B2 receptor antagonist, TRPV1 and TRPA1 channels antagonists and cyclooxygenase (COX) and 12-lipoxygenase (12-LOX) inhibitors. Furthermore, co-administration of submaximal doses of the TRPV1 and TRPA1 antagonists or the COX and 12-LOX inhibitors resulted in a greater inhibition of both cough reflex and airway obstruction. CONCLUSIONS: Our findings show that central BK administration sensitizes cough and enhances airway obstruction via a B2 receptor/TRPV1 and/or TRPA1 channels which are coupled via metabolites of COX and/or 12-LOX enzymes. In addition, combined blockade of TRPV1 and TRPA1 or COX and 12-LOX resulted in a greater inhibitory effect of both cough and airway obstruction. These results indicate that central B2 receptors, TRPV1/TRPA1 channels and COX/12-LOX enzymes may represent potential therapeutic targets for the treatment of cough hypersensitivity.


Assuntos
Araquidonato 12-Lipoxigenase/metabolismo , Bradicinina/administração & dosagem , Tosse/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Receptor B2 da Bradicinina/metabolismo , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Inibidores de Ciclo-Oxigenase/administração & dosagem , Feminino , Cobaias , Infusões Intraventriculares , Masculino , Receptor B2 da Bradicinina/agonistas , Canal de Cátion TRPA1/agonistas , Canais de Cátion TRPV/agonistas
10.
J Pharmacol Sci ; 140(2): 193-196, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31235271

RESUMO

We tested whether NNC 55-0396 (NNC), a T-type calcium channel (T-channel) blocker, reduces the brain injury caused by middle cerebral artery occlusion and reperfusion (MCAO/R) in mice. NNC, administered i.c.v. before the occlusion, greatly reduced the MCAO/R-induced brain infarct and neurological dysfunctions, although it, given toward the end of occlusion, was less effective. Systemic administration of NNC before the occlusion also attenuated the infarct and neurological dysfunctions. Our data imply that blood-brain-barrier-permeable T-channel blockers such as NNC are capable of reducing MCAO/R-induced brain damage, and that T-channels are involved in neuronal damage induced by ischemia rather than reperfusion.


Assuntos
Benzimidazóis/administração & dosagem , Lesões Encefálicas/etiologia , Lesões Encefálicas/prevenção & controle , Bloqueadores dos Canais de Cálcio/administração & dosagem , Ciclopropanos/administração & dosagem , Infarto da Artéria Cerebral Média/complicações , Naftalenos/administração & dosagem , Traumatismo por Reperfusão/complicações , Animais , Benzimidazóis/metabolismo , Barreira Hematoencefálica/metabolismo , Bloqueadores dos Canais de Cálcio/metabolismo , Canais de Cálcio Tipo T/fisiologia , Ciclopropanos/metabolismo , Infusões Intraventriculares , Infusões Parenterais , Masculino , Camundongos Endogâmicos , Naftalenos/metabolismo , Fatores de Tempo
11.
Fish Physiol Biochem ; 45(5): 1709-1716, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31140073

RESUMO

Agmatine, an endogenous biogenic amine, is considered to be a central neurotransmitter. And it plays an important role in mammal feeding behavior. However, there were few studies on the effect of agmatine on feeding behavior in fishes. Here, we investigated the impact of intracerebroventricular (ICV) injections of agmatine (1.25-20 nmol/fish) on food intake in mandarin fish (Siniperca chuatsi). At 1-h post-injection, food intake showed a significant decrease in agmatine-treated fishes compared with the saline treated. Furthermore, the food intake in agmatine treatment mostly did not differ from that in saline treatment at 4--24-h post-injection as well as the results of genes expression of neuropeptide Y (NPY), agouti-regulated peptide (AgRP), and anorexigenic melanocortin 4 receptor (MC4R). In accordance with the insulin level increasing in liver, the gene expression of insulin receptor substrate (IRS2) was significantly higher in agmatine treatment compared to saline treatment at 1-h post-injection. Thus, the anorexigenic effect of agmatine is likely to decrease NPY and AgRP expression levels and increase MC4R and IRS2 levels which was coupled with stimulation of insulin secretion. Although these initial findings are limited in dose, the data firstly provides evidence for the anorectic effects of agmatine in fish.


Assuntos
Agmatina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Peixes , Agmatina/administração & dosagem , Ração Animal/análise , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Infusões Intraventriculares , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
12.
Neuropharmacology ; 155: 142-149, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31145905

RESUMO

Here we investigate the involvement of the ventral pallidum (VP) in the anti-nausea effect of fatty acid amide hydrolase (FAAH) inhibition with PF-3845, and examine the pharmacological mechanism of such an effect. We explored the potential of intra-VP PF-3845 to reduce the establishment of lithium chloride (LiCl)-induced conditioned gaping (a model of acute nausea) in male Sprague-Dawley rats. As well, the role of the cannabinoid 1 (CB1) receptors and the peroxisome proliferator-activated receptors-α (PPARα) in the anti-nausea effect of PF-3845 was examined. Finally, the potential of intra-VP GW7647, a PPARα agonist, to reduce acute nausea was also evaluated. Intra-VP PF-3845 dose-dependently reduced acute nausea by a PPARα mechanism (and not a CB1 receptor mechanism). Intra-VP administration of GW7647, similarly attenuated acute nausea. These findings suggest that the anti-nausea action of FAAH inhibition may occur in the VP, and may involve activation of PPARα to suppress acute nausea.


Assuntos
Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Prosencéfalo Basal/efeitos dos fármacos , Prosencéfalo Basal/enzimologia , Náusea/tratamento farmacológico , Náusea/enzimologia , Animais , Butiratos/administração & dosagem , Infusões Intraventriculares , Cloreto de Lítio/toxicidade , Masculino , Náusea/induzido quimicamente , Compostos de Fenilureia/administração & dosagem , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Ratos , Ratos Sprague-Dawley
13.
Neurochem Res ; 44(7): 1690-1702, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31004260

RESUMO

Trigeminal neuralgia (TN) is a type of chronic neuropathic pain that is caused by peripheral nerve lesions that result from various conditions, including the compression of vessels, tumors and viral infections. MicroRNAs (miRs) are increasingly recognized as potential regulators of neuropathic pain. Previous evidence has demonstrated that miR-195 is involved in neuropathic pain, but the mechanism remains unclear. To investigate the pathophysiological role of miR-195 and Shh signaling in TN, persistent facial pain was induced by infraorbital nerve chronic constriction injury (CCI-IoN), and facial pain responses were evaluated by Von Frey hairs. qPCR and Western blotting were used to determine the relative expression of miR-195 and Patched1, the major receptor of the Sonic Hedgehog (Shh) signaling pathway, in the caudal brain stem at distinct time points after CCI-IoN. Here, we found that the expression of miR-195 was increased in a rat model of CCI-IoN. In contrast, the expression of Patched1 decreased significantly. Luciferase assays confirmed the binding of miR-195 to Patched1. In addition, the overexpression of miR-195 by an intracerebroventricular (i.c.v) administration of LV-miR-195 aggravated facial pain development, and this was reversed by upregulating the expression of Patched1. These results suggest that miR-195 is involved in the development of TN by targeting Patched1 in the Shh signaling pathway, thus regulating extracellular glutamate.


Assuntos
Proteínas Hedgehog/metabolismo , MicroRNAs/fisiologia , Receptor Patched-1/metabolismo , Transdução de Sinais/fisiologia , Neuralgia do Trigêmeo/fisiopatologia , Animais , Regulação para Baixo , Ácido Glutâmico/líquido cefalorraquidiano , Ácido Glutâmico/metabolismo , Infusões Intraventriculares , Lentivirus/genética , Masculino , MicroRNAs/administração & dosagem , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Receptor Patched-1/genética , Ratos Sprague-Dawley
14.
Medicine (Baltimore) ; 98(15): e15139, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30985683

RESUMO

RATIONALE: The treatment of intracranial Acinetobacter baumannii infections is made difficult by multidrug-resistance poor drug penetration through the blood-brain barrier (BBB). Although tigecycline appears to be effective against A baumannii, it is only administered intravenously because it does not readily cross the BBB. The addition of intraventricular (IVT) or intrathecal infusions of tigecycline could revolutionize clinical therapy for intracranial A baumannii infections. However, there are few reports on the successful use of such treatments. PATIENT CONCERNS: We report the case of a 17-year-old male who presented with high fever and neck rigidity after intracranial drainage. DIAGNOSIS: Intracranial infection with extensively drug-resistant A baumannii after intracranial drainage. INTERVENTIONS: On the advice of a clinical pharmacist, the patient was administered intrathecal infusions of tigecycline after treatment failure with IVT tigecycline. OUTCOMES: The patient's body temperature returned to normal. Thereafter, the patient was in good clinical condition without signs of cerebrospinal fluid infection and tuberculosis. LESSONS: However, when central nervous system infections fail IVT tigecycline, clinicians should consider changing to intrathecal tigecycline infusions rather than raising the dose of IVT tigecycline. In addition, the co-administration of tigecycline with other drugs that can penetrate the BBB should not be ruled out.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii , Antibacterianos/administração & dosagem , Encefalopatias/tratamento farmacológico , Infecções do Sistema Nervoso Central/tratamento farmacológico , Tigeciclina/administração & dosagem , Infecções por Acinetobacter/diagnóstico por imagem , Adolescente , Encefalopatias/diagnóstico por imagem , Infecções do Sistema Nervoso Central/diagnóstico por imagem , Farmacorresistência Bacteriana Múltipla , Humanos , Infusões Intraventriculares , Infusão Espinal , Masculino
15.
Mediators Inflamm ; 2019: 6197084, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881224

RESUMO

Sepsis remains one of the leading causes of mortality in intensive care units, but there is a shortage of effective treatments. A dysregulated host immune response and multiple organ injury are major factors for the pathogenesis and progression of sepsis, which require specific mechanism and treatment. In the present study, we performed an intracerebroventricular (ICV) injection of BoxA, a specific antagonist of high-mobility group box 1 protein (HMGB1), in septic rats that were produced by cecal ligation and puncture surgery; we further assessed the functional changes of multiple organs and splenic T lymphocytes. We found that the inhibition of cerebral HMGB1 significantly alleviated multiple organ damage under septic exposure, including damage to the heart, liver, lungs, and kidneys; reversed the immune dysfunction of T cells; and increased the survival of septic rats. These data suggest that central HMGB1 might be a potential therapeutic target for septic challenge and that inhibition of brain HMGB1 can protect against multiple organ dysfunction induced by sepsis.


Assuntos
Proteína HMGB1/metabolismo , Imunidade Celular/imunologia , Insuficiência de Múltiplos Órgãos/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Proteína HMGB1/antagonistas & inibidores , Infusões Intraventriculares , Masculino , Insuficiência de Múltiplos Órgãos/imunologia , Ratos , Ratos Sprague-Dawley , Sepse/imunologia , Sepse/metabolismo
16.
Neurotox Res ; 35(4): 823-837, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30848474

RESUMO

Propionic acid (PPA) is a dietary short chain fatty acid and an enteric bacterial metabolite. Intracerebroventricular (ICV) infusions of PPA in rodents have been shown to produce behavioral changes similar to those seen in autism spectrum disorders (ASD), including perseveration. The effects of ICV infusions of PPA on spatial cognition were examined by giving rats infusions of either PPA (0.26 M, pH 7.4, 4 µl/infusion) or phosphate-buffered saline (PBS, 0.1 M) twice a day for 7 days. The rats were then tested in the Morris water maze (MWM) for acquisition of spatial learning. After a recovery period of 1 week of no treatment, the rats were then tested for reversal of spatial learning in the MWM. PPA-treated rats showed impaired spatial learning in the maze, relative to controls, as demonstrated by increased search latencies, fewer direct and circle swims, and more time spent in the periphery of the maze than PBS controls. After a recovery period of 1 week of no treatment, these animals exhibited normal spatial reversal learning indicating that the behavioral cognitive deficits caused by PPA seem to be reversible.


Assuntos
Transtorno do Espectro Autista/psicologia , Modelos Animais de Doenças , Propionatos/administração & dosagem , Aprendizagem Espacial/efeitos dos fármacos , Animais , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/microbiologia , Comportamento Animal/efeitos dos fármacos , Microbioma Gastrointestinal , Infusões Intraventriculares , Masculino , Atividade Motora , Ratos Long-Evans
17.
Neurosci Lett ; 699: 140-144, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30716423

RESUMO

The participation of endocannabinoids in central and peripheral antinociception induced by several compounds has been shown by our group. In this study, we investigated the effect of endocannabinoids on the central antinociception induced by ketamine. The nociceptive threshold for thermal stimulation was measured using the tail-flick test in Swiss mice. The drugs were administered intracerebroventricularly. Probabilities less than 5% (p < 0.05) were considered to be statistically significant (Two-way ANOVA/Bonferroni's test). The CB1-selective cannabinoid receptor antagonist AM251 (2 and 4 µg) completely reversed the central antinociception induced by ketamine (4 µg) in a dose-dependent manner. In contrast, the CB2-selective cannabinoid receptor antagonist AM630 (2 and 4 µg) did not antagonize this effect. Additionally, the administration of the anandamide amidase inhibitor MAFP (0.2 µg) and anandamide uptake inhibitor VDM11 (4 µg) significantly enhanced the antinociception induced by a low dose of ketamine (2 µg). It was concluded that central antinociception induced by ketamine involves the activation of CB1 cannabinoid receptors. Mobilization of cannabinoids might be required for the activation of those receptors, since inhibitors of the endogenous cannabinoids potentiate the effect of Ketamine.


Assuntos
Analgésicos/farmacologia , Canabinoides/metabolismo , Ketamina/farmacologia , Receptor CB1 de Canabinoide/agonistas , Animais , Ácidos Araquidônicos/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Indóis/farmacologia , Infusões Intraventriculares , Ketamina/administração & dosagem , Ketamina/antagonistas & inibidores , Masculino , Camundongos , Organofosfonatos/farmacologia , Medição da Dor/efeitos dos fármacos , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores
18.
Artigo em Inglês | MEDLINE | ID: mdl-30776402

RESUMO

Individuals with fear-associated conditions such as panic disorder (PD) and posttraumatic stress disorder (PTSD) display increased emotional responses to interoceptive triggers, such as CO2 inhalation, that signal a threat to physiological homeostasis. Currently, effector systems and mechanisms underlying homeostatic modulation of fear memory are not well understood. In this regard, the renin angiotensin system (RAS), particularly the angiotensin receptor type 1 (AT1R), a primary homeostatic regulatory target, has gained attention. RAS polymorphisms have been reported in PD and PTSD, and recent studies report AT1R-mediated modulation of fear extinction. However, contribution of AT1Rs in fear evoked by the interoceptive threat of CO2 has not been investigated. Using pharmacological, behavioral, and AT1R/ACE gene transcription analyses, we assessed central AT1R recruitment in CO2-associated fear. CO2 inhalation led to significant AT1R and ACE mRNA upregulation in homeostatic regulatory regions, subfornical organ (SFO) and paraventricular nucleus (PVN), in a temporal manner. Intracerebroventricular infusion of selective AT1R antagonist, losartan, significantly attenuated freezing during CO2 inhalation, and during re-exposure to CO2 context, suggestive of AT1R modulation of contextual fear. Regional Fos mapping in losartan-treated mice post-behavior revealed significantly attenuated labeling in areas regulating defensive behavior, contextual fear, and threat responding; such as, the bed nucleus of stria terminalis, dorsal periaqueductal gray, hypothalamic nuclei, hippocampus, and prefrontal areas such as the prelimbic, infralimbic, and anterior cingulate cortices. Sub-regions of the amygdala did not show CO2-associated AT1R regulation or altered Fos labeling. Collectively, our data suggests central AT1R recruitment in modulation of fear behaviors associated with CO2 inhalation via engagement of neurocircuits regulating homeostasis and defensive behaviors. Our data provides mechanistic insights into the interoceptive regulation of fear, relevant to fear related disorders such as PD and PTSD.


Assuntos
Dióxido de Carbono/metabolismo , Medo/fisiologia , Vias Neurais/fisiologia , Receptor Tipo 1 de Angiotensina/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Encéfalo/fisiologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Homeostase/fisiologia , Infusões Intraventriculares , Losartan/farmacologia , Masculino , Camundongos , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Órgão Subfornical/metabolismo , Regulação para Cima
19.
Indian J Pediatr ; 86(4): 379-381, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30790188

RESUMO

Elizabethkingia meningoseptica, a gram negative bacillus ubiquitous in the hospital environment, is known to infrequently cause serious neonatal infections, particularly meningitis which is associated with high mortality and neuromorbidity in survivors. The authors describe a healthy term newborn with no apparent risk factors who developed Elizabethkingia meningoseptica sepsis and meningitis on day 6 of life. Diagnosis could be established only after a week of the illness by which time the baby developed refractory status epilepticus, ventriculitis and hydrocephalus. The isolate was susceptible to only ciprofloxacin, tigecycline and rifampicin and resistant to vancomycin. Apart from systemic combination therapy for 12 wk, intraventricular vancomycin was given through an external ventricular drain for 4 wk and later a ventriculo-peritoneal (VP) shunt was inserted. With this regime, authors demonstrated microbiologic and clinical cure. The baby is neurologically normal over a 6 mo follow-up.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Flavobacteriaceae/tratamento farmacológico , Flavobacteriaceae , Doenças do Recém-Nascido/microbiologia , Meningites Bacterianas/tratamento farmacológico , Vancomicina/uso terapêutico , Antibacterianos/administração & dosagem , Encéfalo/diagnóstico por imagem , Encéfalo/microbiologia , Flavobacteriaceae/efeitos dos fármacos , Infecções por Flavobacteriaceae/diagnóstico por imagem , Humanos , Recém-Nascido , Doenças do Recém-Nascido/tratamento farmacológico , Infusões Intravenosas , Infusões Intraventriculares , Imagem por Ressonância Magnética , Masculino , Meningites Bacterianas/diagnóstico por imagem , Neuroimagem , Vancomicina/administração & dosagem , Derivação Ventriculoperitoneal
20.
Artigo em Inglês | MEDLINE | ID: mdl-30763674

RESUMO

Clinical evidence indicates that major depression is a common comorbidity of chronic pain, including neuropathic pain. However, the cellular basis for chronic pain-mediated major depression remains unclear. High-mobility group box 1 protein (HMGB1) has a key role in innate immune responses and appears to be have a role in mediating diverse disorders, including neuropathic pain and depression. The current study aimed to characterize neuropathic pain-induced changes in affect over time and to determine whether HMGB1 has a role in neuropathic pain-induced changes in affect. Neuropathic pain was induced by partial sciatic nerve ligation (PSNL) in mice. Anxiodepressive-like behaviors in mice were evaluated over 10 weeks, in the social interaction, forced swim, and novelty suppressed feeding tests. Mice developed anxiodepressive-like behavior 6 to 8 weeks after induction of neuropathy. Accompanying anxiodepressive-like behavior, increased HMGB1 protein and microglia activation were observed in frontal cortex at 8 weeks after PSNL. Intracerebroventricular administration of rHMGB1 in naïve mice induced anxiodepressive-like behavior and microglia activation. Blockage of HMGB1 in PSNL mice with glycyrrhizic acid (GZA) or anti-HMGB1 antibody reduced microglia activation and anxiodepressive-like behavior. These results indicate that PSNL-induced anxiodepressive-like behavior is likely mediated by HMGB1. Furthermore, the data indicate that inhibition of HMGB1-dependent microglia activation could be a strategy for the treatment of depression associated with neuropathic pain.


Assuntos
Comportamento Animal/efeitos dos fármacos , Proteína HMGB1/metabolismo , Microglia/metabolismo , Neuralgia/complicações , Animais , Anticorpos/farmacologia , Depressão/induzido quimicamente , Depressão/complicações , Ácido Glicirrízico/farmacologia , Proteína HMGB1/administração & dosagem , Proteína HMGB1/antagonistas & inibidores , Proteína HMGB1/farmacologia , Infusões Intraventriculares , Ligadura , Masculino , Camundongos , Microglia/efeitos dos fármacos , Nervo Isquiático/lesões
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