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1.
J BUON ; 24(5): 2168-2172, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31786891

RESUMO

PURPOSE: Farnesol has been shown to exhibit important anticancer potential. However, its antiproliferative effects have not been examined against the optic nerve sheath meningioma cells. In this study the potential of Farnesol in the treatment of optic nerve meningioma was evaluated by examining its antiproliferative effects against the HBL-52 cells. METHODS: The MTT assay was used to determine cell viability of HBL-52 cells. Autophagy was detected by transfection assay. The cell migration and invasion of HBL-52 cells was determined by transwell assay. Protein expression was checked by western blot assay. RESULTS: The results showed that Farnesol decreased significantly the viability of HBL-52 cells and showed an IC50 of 25 µM. The antiproliferative effects were due to the activation of the autophagy in the HBL-52 cells. The autophagy was also accompanied by upsurge of LC3 II and Beclin 1 expression. Farnesol also triggered the cell cycle arrest of the HBL-52 at the G2/M phase of the cell cycle which was accompanied by suppression of cyclin B1. The cell migration and invasion of the HBL-52 cells was also suppressed by Farnesol via inhibition of MMP-2 and 9 expressions. CONCLUSIONS: To sum up, Farnesol may prove beneficial in the treatment of optic nerve sheath meningioma as it has shown significant antiproliferative effects against this rare form of tumor.


Assuntos
Proliferação de Células/efeitos dos fármacos , Farneseno Álcool/farmacologia , Meningioma/tratamento farmacológico , Neoplasias do Nervo Óptico/tratamento farmacológico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Meningioma/genética , Meningioma/patologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/patologia , Neoplasias do Nervo Óptico/genética , Neoplasias do Nervo Óptico/patologia , Transdução de Sinais/efeitos dos fármacos
2.
Int J Mol Sci ; 20(21)2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31652855

RESUMO

The aim of this study was to evaluate the pharmacological efficacy of persimmon leaves in two glaucoma models, microbeads-induced ocular hypertension (OHT) and DBA/2 mouse. Thus, we demonstrated that Ethanol Extract of Diospyros kaki (EEDK) reduced elevated intraocular pressure (IOP) in both mouse models of glaucoma by measurements with a tonometer. In particular, we revealed that retinal ganglion cell loss and optic nerve damage caused by IOP elevation were markedly diminished as assessed by TUNEL assay, H&E staining, and fluorescent staining, while the expression of soluble guanylate cyclase (sGCα-1) increased, when EEDK was administered, as revealed by western blot. Moreover, the b-wave magnitude indicating functional scotopic vision was significantly improved in EEDK-administered DBA/2 mice during the 10-week follow-up study, as observed with electroretinography. Collectively, our results suggested that EEDK could be an effective therapeutic and IOP-lowering agent for preventing and treating retinal degenerative diseases such as glaucoma.


Assuntos
Diospyros/química , Glaucoma/tratamento farmacológico , Pressão Intraocular , Extratos Vegetais/uso terapêutico , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nervo Óptico/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Guanilil Ciclase Solúvel/metabolismo
3.
Exp Neurol ; 322: 113063, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31518568

RESUMO

Visual deficits after traumatic brain injury (TBI) are common, but interventions that limit the post-trauma impairments have not been identified. We have found that treatment with the cannabinoid type-2 receptor (CB2) inverse agonist SMM-189 for 2 weeks after closed-head blast TBI greatly attenuates the visual deficits and retinal pathology this otherwise produces in mice, by modulating the deleterious role of microglia in the injury process after trauma. SMM-189, however, has not yet been approved for human use. Raloxifene is an FDA-approved estrogen receptor drug that is used to treat osteoporosis, but it was recently found to also show noteworthy CB2 inverse agonism. In the current studies, we found that a high pressure air blast in the absence of raloxifene treatment yields deficits in visual acuity and contrast sensitivity, reductions in the A-wave and B-wave of the scotopic electroretinogram (ERG), light aversion, and increased pupil constriction to light. Raloxifene delivered daily for two weeks after blast at 5-10 mg/kg mitigates or eliminates these abnormalities (with the higher dose generally more effective). This functional rescue with raloxifene is accompanied by a biasing of microglia from the harmful M1 to the helpful M2 state, and reductions in retinal, optic nerve, and oculomotor nucleus pathology. We also found that raloxifene treatment is still effective even when delayed until 48 h after TBI, and that raloxifene benefit appears attributable to its CB2 inverse agonism rather than its estrogenic actions. Our studies show raloxifene is effective in treating visual injury after brain and/or eye trauma, and they provide basis for phase-2 efficacy testing in human clinical trials.


Assuntos
Concussão Encefálica/complicações , Fármacos Neuroprotetores/farmacologia , Cloridrato de Raloxifeno/farmacologia , Receptor CB2 de Canabinoide/efeitos dos fármacos , Transtornos da Visão/etiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/patologia , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/patologia , Receptor CB2 de Canabinoide/agonistas , Retina/patologia , Transtornos da Visão/patologia
4.
Transl Psychiatry ; 9(1): 211, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477687

RESUMO

Astrocytes are multifunctional glial cells that play essential roles in supporting synaptic signalling and white matter-associated connectivity. There is increasing evidence that astrocyte dysfunction is involved in several brain disorders, including bipolar disorder (BD), depression and schizophrenia. The mood stabiliser lithium is a frontline treatment for BD, but the mechanisms of action remain unclear. Here, we demonstrate that astrocytes are direct targets of lithium and identify unique astroglial transcriptional networks that regulate specific molecular changes in astrocytes associated with BD and schizophrenia, together with Alzheimer's disease (AD). Using pharmacogenomic analyses, we identified novel roles for the extracellular matrix (ECM) regulatory enzyme lysyl oxidase (LOX) and peroxisome proliferator-activated receptor gamma (PPAR-γ) as profound regulators of astrocyte morphogenesis. This study unravels new pathophysiological mechanisms in astrocytes that have potential as novel biomarkers and potential therapeutic targets for regulating astroglial responses in diverse neurological disorders.


Assuntos
Astrócitos/efeitos dos fármacos , Lítio/farmacologia , PPAR gama/metabolismo , Proteína-Lisina 6-Oxidase/metabolismo , Animais , Astrócitos/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Camundongos , Camundongos Transgênicos , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/metabolismo
5.
Medicine (Baltimore) ; 98(33): e16772, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415378

RESUMO

BACKGROUND: Pneumoperitoneum and steep Trendelenburg position during robot-assisted laparoscopic prostatectomy (RALP) can increase intracranial pressure (ICP). Dexmedetomidine, a highly selective alpha-2 adrenergic receptor agonist, can cause cerebral vasoconstriction and decrease cerebral blood flow by stimulating the postsynaptic alpha-2 adrenergic receptors on cerebral blood vessels. However, the effects of dexmedetomidine on ICP are controversial and have not been evaluated during RALP under the establishment of pneumoperitoneum in the steep Trendelenburg position. Therefore, we evaluated the effect of dexmedetomidine on optic nerve sheath diameter (ONSD) as a surrogate for assessing ICP during RALP. METHODS: Patients were randomly allocated to receive dexmedetomidine (n = 63) (loading dose, 1 µg/kg for 10 minutes and continuous infusion, 0.4 µg/kg/hr) or normal saline (n = 63). The ONSD was measured at 10 minutes after induction of anesthesia in the supine position (T1), 30 minutes (T2) and 60 minutes (T3) after establishment of pneumoperitoneum in the steep Trendelenburg position, and at closing the skin in the supine position (T4). Hemodynamic and respiratory variables were measured at every time point. RESULTS: ONSDs at T2, T3, and T4 were significantly smaller in the dexmedetomidine group than in the control group (5.26 ±â€Š0.25 mm vs 5.71 ±â€Š0.26 mm, 5.29 ±â€Š0.24 mm vs 5.81 ±â€Š0.23 mm, and 4.97 ±â€Š0.24 mm vs 5.15 ±â€Š0.28 mm, all P <.001). ONSDs at T2, T3, and T4 were significantly increased compared to T1 in both groups. Hemodynamic and respiratory variables, except heart rate, did not significantly differ between the 2 groups. The bradycardia and atropine administration were not significantly different between the 2 groups. CONCLUSION: Dexmedetomidine attenuates the increase of ONSD during RALP, suggesting that intraoperative dexmedetomidine administration may effectively attenuate the ICP increase during pneumoperitoneum in the Trendelenburg position.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Dexmedetomidina/farmacologia , Hipertensão Intracraniana/prevenção & controle , Pressão Intracraniana/efeitos dos fármacos , Nervo Óptico/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Idoso , Dexmedetomidina/administração & dosagem , Método Duplo-Cego , Decúbito Inclinado com Rebaixamento da Cabeça , Humanos , Período Intraoperatório , Laparoscopia , Masculino , Nervo Óptico/diagnóstico por imagem , Prostatectomia , Procedimentos Cirúrgicos Robóticos , Resultado do Tratamento
6.
EMBO Mol Med ; 11(8): e10291, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31318166

RESUMO

Optic nerve atrophy represents the most common form of hereditary optic neuropathies leading to vision impairment. The recently described Bosch-Boonstra-Schaaf optic atrophy (BBSOA) syndrome denotes an autosomal dominant genetic form of neuropathy caused by mutations or deletions in the NR2F1 gene. Herein, we describe a mouse model recapitulating key features of BBSOA patients-optic nerve atrophy, optic disc anomalies, and visual deficits-thus representing the only available mouse model for this syndrome. Notably, Nr2f1-deficient optic nerves develop an imbalance between oligodendrocytes and astrocytes leading to postnatal hypomyelination and astrogliosis. Adult heterozygous mice display a slower optic axonal conduction velocity from the retina to high-order visual centers together with associative visual learning deficits. Importantly, some of these clinical features, such the optic nerve hypomyelination, could be rescued by chemical drug treatment in early postnatal life. Overall, our data shed new insights into the cellular mechanisms of optic nerve atrophy in BBSOA patients and open a promising avenue for future therapeutic approaches.


Assuntos
Fator I de Transcrição COUP/genética , Haploinsuficiência , Fibras Nervosas Mielinizadas/ultraestrutura , Atrofia Óptica Autossômica Dominante/genética , Nervo Óptico/ultraestrutura , Animais , Astrócitos/metabolismo , Astrócitos/ultraestrutura , Comportamento Animal , Fator I de Transcrição COUP/deficiência , Modelos Animais de Doenças , Predisposição Genética para Doença , Heterozigoto , Humanos , Aprendizagem , Camundongos Knockout , Miconazol/farmacologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/metabolismo , Condução Nervosa , Oligodendroglia/metabolismo , Oligodendroglia/ultraestrutura , Atrofia Óptica Autossômica Dominante/tratamento farmacológico , Atrofia Óptica Autossômica Dominante/metabolismo , Atrofia Óptica Autossômica Dominante/patologia , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/metabolismo , Percepção Visual
7.
BMC Pharmacol Toxicol ; 20(1): 40, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277705

RESUMO

BACKGROUND: We aimed to determine the protective effects of thiamine pyrophosphate on ethanol induced optic neuropathy in an experimental model. METHODS: The rats were assigned into 4 groups, with 6 rats in each group as follows: healthy controls (HC group), only ethanol administered group (EtOH group), ethanol + thiamine pyrophosphate (20 mg/kg) administered group (TEt-20 group), and only thiamine pyrophosphate (20 mg/kg) (TPG group) administered group. To the rats in TEt-20 and TPG groups, 20 mg/kg thiamine pyrophosphate was administered via intraperitoneal route. To the rats in HC and EtOH groups, the same volume (0.5 ml) of distilled water as solvent was applied in the same manner. To the rats in TEt-20 and EtOH groups, one hour after application of thiamine pyrophosphate or distilled water, 32% ethanol with a dose of 5 g/kg was administered via oral gavage. This procedure was repeated once a day for 6 weeks. From the blood samples and tissues obtained from the rats, Malondialdehyde (MDA), reduced glutathione (GSH), interleukin 1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) levels were studied. Histopathological evaluations were performed to the optic nerve tissue. RESULTS: Serum and tissue IL-1ß, TNF-α and MDA levels were the highest in EtOH group which were significantly lower in thiamine pyrophosphate administered group (TEt-20 group) (p: 0.001). Serum and tissue reduced GSH levels were the lowest in EtOH group which were also significantly higher in TEt-20 group (p:0.001). In histopathological evaluations, in EtOH group there was obvious destruction and edema with hemorrhage and dilated blood vessels which were not present in any other groups. CONCLUSIONS: There was an apparent destruction in ethanol administered group in histopathological analyses with an augmented level of oxidative stress markers and all those alterations were prevented with concomitant thiamine pyrophosphate administration. These protective effects of thiamine pyrophosphate are extremely important in chronic ethanol consumption. Clinical studies are warranted to define the exact role of thiamine pyrophosphate in prevention of ethanol induced optic neuropathy.


Assuntos
Etanol/toxicidade , Traumatismos do Nervo Óptico/induzido quimicamente , Traumatismos do Nervo Óptico/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Tiamina Pirofosfato/uso terapêutico , Animais , Glutationa/metabolismo , Interleucina-1beta/metabolismo , Masculino , Malondialdeído/metabolismo , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/metabolismo , Nervo Óptico/patologia , Traumatismos do Nervo Óptico/metabolismo , Substâncias Protetoras/farmacologia , Ratos Wistar , Tiamina Pirofosfato/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
8.
Exp Eye Res ; 186: 107710, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31254512

RESUMO

Quantifying the number of axons in the optic nerve is of interest in many research questions. Here, we show that a stereological method allows simple, efficient, precise and unbiased determination of the total axon number in the murine optic nerve. Axons in semi-thin optic nerve cross sections from untreated eyes (n = 21) and eyes subjected to retinal damage by intravitreous NMDA injections (n = 32) or PBS controls (n = 5) were manually identified, counted and digitally labeled by hand. A stereological procedure was empirically tested with systematic combinations of different sampling methods (simple random sampling without replacement, systematic uniform random sampling, stratified random sampling) and sampling parameters. Extensive numerical Monte Carlo experiments were performed to evaluate their large-sample properties. Our results demonstrate reliable determination of total axon number and superior performance compared to other methods at a small fraction of the time required for a full manual count. We specify suitable sampling parameters for the adoption of an efficient stereological sampling scheme, give empirical estimates of the additionally introduced sampling variance to facilitate experimental planning, and offer AxonCounter, an easy-to-use plugin implementing these stereological methods for the multi-platform image processing application NIH ImageJ.


Assuntos
Contagem de Células/métodos , Técnicas Citológicas , Nervo Óptico/citologia , Animais , Agonistas de Aminoácidos Excitatórios/farmacologia , Processamento de Imagem Assistida por Computador/métodos , Camundongos , Camundongos Endogâmicos BALB C , N-Metilaspartato/farmacologia , Nervo Óptico/efeitos dos fármacos
9.
Acta Biomater ; 94: 219-231, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31176841

RESUMO

Investigation of neurodegeneration in glaucoma, a leading cause of irreversible blindness worldwide, has been obfuscated by the lack of an efficient model that provides chronic, mild to moderate elevation of intraocular pressure (IOP) with preservation of optical media clarity for long term, in vivo interrogation of the structural and functional integrity of the retinal ganglion cells (RGCs). Here, we designed and formulated an injectable hydrogel based on in situ cross-linking of hyaluronic acid functionalized with vinyl sulfone (HA-VS) and thiol groups (HA-SH). Intracameral injection of HA-VS and HA-SH in C57BL/6J mice exhibited mild to moderate elevation of IOP with daily mean IOP ranged between 14 ±â€¯3 and 24 ±â€¯3 mmHg, which led to progressive, regional loss of RGCs evaluated with in vivo, time-lapse confocal scanning laser ophthalmoscopy; a reduction in fractional anisotropy in the optic nerve and the optic tract projected from the eye with increased IOP in diffusion tensor magnetic resonance imaging; a decrease in positive scotopic threshold response in electroretinography; and a decline in visual acuity measured with an optokinetic virtual reality system. The proportion of RGC loss was positively associated with the age of the animals, and the levels and the duration of IOP elevation. The new glaucoma model recapitulates key characteristics of human glaucoma which is pertinent to the development and pre-clinical testing of neuroprotective and neuroregenerative therapies. STATEMENT OF SIGNIFICANCE: A new model to study chronic neurodegeneration in glaucoma has been developed via intracameral injection of a specifically designed hyaluronic acid functionalized with vinyl sulfone and thiol groups for cross-linking. Intracameral injection of the chemically cross-linked hydrogel generates mild to moderate IOP elevation, resulting in progressive degeneration of the retinal ganglion cells, optic nerve, and optic tract, and a decline in visual function. The model recapitulates the key features of neurodegeneration in human glaucoma, which will facilitate and expedite the development of neuroprotective and neuroregenerative therapies.


Assuntos
Reagentes para Ligações Cruzadas/química , Glaucoma/metabolismo , Ácido Hialurônico/química , Hidrogéis/química , Doenças Neurodegenerativas/metabolismo , Fatores Etários , Animais , Modelos Animais de Doenças , Elasticidade , Eletrorretinografia , Hidrogéis/administração & dosagem , Hidrogéis/metabolismo , Injeções , Injeções Intraoculares , Pressão Intraocular/efeitos dos fármacos , Cinética , Imagem por Ressonância Magnética , Camundongos Endogâmicos C57BL , Doenças Neurodegenerativas/complicações , Nervo Óptico/efeitos dos fármacos , Células Ganglionares da Retina/efeitos dos fármacos , Compostos de Sulfidrila/química , Sulfonas/química , Viscosidade
10.
BMC Ophthalmol ; 19(1): 124, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174513

RESUMO

BACKGROUND: To analyze the clinical features and prognosis of the visual loss resulted from inhalational methanol poisoning in 8 Chinese patients. METHODS: Eight consecutive patients seen at the Beijing Tongren Hospital of Capital Medical University, Beijing, China between January 2003 to August 2017, with complains of vision loss in both eyes, identified as inhalational methanol poisoning. Detailed medical history was extracted. All patients underwent optic nerve and brain magnetic resonance imaging (MRI) scan, laboratory tests, and visual function analysis. Treatment protocols were large dosage of methylprednisolone and B vitamins over 3 months. Patients were seen at 3-month intervals until a year. RESULTS: Eight patients with optic neuropathy caused by inhalation toxicity of methanol were under observation, whose methanol-contact time spans were form 4 days to 5 years for occupational exposure. All the patients had acute onset, transient systemic symptoms on early stage, both eyes involved with severe visual impairment (visual acuity 0.1 or even worse). Retrobulbar optic nerves (ONs) were the major sites involved. Optic nerve MRI scan showed increased signal of bilateral ONs in the orbit and the canal parts, with enhancement. After treatment, the visual function of these patients got improved in different degree in a year follow-up, but not satisfactorily. CONCLUSIONS: Inhalational methanol toxicity may lead to serious damage to ON in a process of chronic intoxication with acute attack, and with poor prognosis.


Assuntos
Metanol/envenenamento , Nervo Óptico/efeitos dos fármacos , Transtornos da Visão/induzido quimicamente , Acuidade Visual/fisiologia , Doença Aguda , Administração por Inalação , Adulto , Encéfalo/diagnóstico por imagem , Doença Crônica , Feminino , Seguimentos , Humanos , Imagem por Ressonância Magnética , Masculino , Metanol/administração & dosagem , Pessoa de Meia-Idade , Nervo Óptico/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Solventes/envenenamento , Transtornos da Visão/diagnóstico , Transtornos da Visão/fisiopatologia , Acuidade Visual/efeitos dos fármacos , Adulto Jovem
11.
Medicine (Baltimore) ; 98(22): e15749, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31145289

RESUMO

RATIONALE: Glioblastoma (GBM) is the most aggressive malignant brain tumor in adults. The first choice for GBM is surgery, and followed by a combination of radiotherapy and chemotherapy. There are limited treatments for patients with recurrent GBM. Relapsed patients usually have a worse prognosis, and with a median survival time of <6 months. Anlotinib is a novel small molecule multi-target tyrosine kinase inhibitor that can inhibit tumor angiogenesis and inhibit tumor cell growth. This drug has been used to treat advanced lung cancer. PATIENT CONCERNS: We present a case of recurrent GBM was treated with anlotinib in this report. The patient was diagnosed with GBM in August 2016 and treated with surgery and temozolomide (TMZ) chemotherapy. She was diagnosed with recurrence in February 2017 following which she was treated with gamma knife and TMZ chemotherapy. In November 2017, the patient presented with decreased vision in left eye. She was given radiation and her left eye vision returned to normal after radiation. On May23, 2018, the patient reported a decrease in left visual acuity again. DIAGNOSES: Brain magnetic resonance imaging (MRI) showed progression of the disease, and the tumor invaded the left optic nerve. INTERVENTIONS: This patient was administer anlotinib 12 mg po qd (d1-14, 21days as a cycle). Three cycles anlotinib were given to this patient. OUTCOMES: The patient reported her left visual acuity increased over 10 days after first cycle of anlotinib treatment. MRI scan revealed tumor volume shrinks, especially the part that invades the left optic nerve shrinks significantly at 26 days after anlotinib treatment on August 11, 2018. However, the tumor progressed in 2 months after using of anlotinib. From the beginning of the application of anlotinib to death, her survival time was 110 days. LESSONS: Anlotinib treatment with mild side effects may be a new option for the patients with recurrent glioblastoma.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Indóis/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Quinolinas/uso terapêutico , Neoplasias Encefálicas/patologia , Evolução Fatal , Feminino , Glioblastoma/patologia , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/patologia
12.
Mol Neurobiol ; 56(11): 7458-7472, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31044366

RESUMO

Neuroinflammatory diseases are characterized by blood-brain barrier disruption (BBB) and leukocyte infiltration. We investigated the involvement of monocyte recruitment in visual pathway damage provoked by primary optic neuritis (ON) induced by a microinjection of bacterial lipopolysaccharide (LPS) into the optic nerve from male Wistar rats. Increased Evans blue extravasation and cellularity were observed at 6 h post-LPS injection. In WT-GFPþ/WT chimeric rat optic nerves, the presence of GFP(+) neutrophils and GFP(+) monocytes, and in wild-type rat optic nerves, an increase in CD11b+CD45low and CD11b+CD45high cell number, were observed at 24 h post-LPS. Gamma-irradiation did not affect the increase in BBB permeability, but significantly lessened the decrease in pupil light reflex (PLR), and retinal ganglion cell (RGC) number induced by LPS. At 6 h post-LPS, an increase in chemokine (C-C motif) ligand 2 (CCL2) immunoreactivity co-localized with neutrophils (but not microglia/macrophages or astrocytes) was observed, while at 24 h post-injection, an increase in Iba-1-immunoreactivity and its co-localization with CCL2 became evident. The co-injection of LPS with bindarit (a CCL2 synthesis inhibitor) lessened the effect of LPS on PLR, and RGC loss. The treatment with etoposide or gadolinium chloride that significantly decreased peripheral monocyte (but not neutrophil or lymphocyte) percentage decreased the effect of LPS on PLR, and RGC number. Moreover, a negative correlation between PRL and monocyte (but not lymphocyte or neutrophil) percentage was observed at 7 days post-LPS. Taken together, these results support that monocytes are key players in the initial events that take place during primary ON.


Assuntos
Monócitos/patologia , Nervo Óptico/patologia , Neurite Óptica/patologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Quimiocina CCL2/metabolismo , Indazóis/administração & dosagem , Indazóis/farmacologia , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/farmacologia , Masculino , Monócitos/efeitos dos fármacos , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/efeitos da radiação , Permeabilidade , Propionatos/administração & dosagem , Propionatos/farmacologia , Ratos Wistar , Proteínas Recombinantes/farmacologia , Ativador de Plasminogênio Tecidual/farmacologia
13.
Technol Health Care ; 27(S1): 357-365, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31045553

RESUMO

Dexamethasone (DEX) is associated with many inflammation and metabolic diseases. We analyzed the effects of DEX on the expression of estrogen metabolism enzyme 17ß-HSD1 at the optic nerve. Rats were treated with different concentrations of intraperitoneal DEX. Western Blot analysis showed that 17ß-HSD protein was expressed in the optic nerve tissue. The enzyme was detected by immunohistochemistry on the terminal foot of Muller cells from the ganglion cell layer of rat retina. ELISA analysis showed that the 17ß-HSD1 protein expression of DEX-treated group is 2.4 fold comparing to the control group. The results indicated that DMXS sodium phosphate might modulate the expression of 17ß-HSD1 protein in optic tissue. This study sheds light on understanding of the relationship among DEX, 17ß-HSD presence and distribution of visual neural systems. At the same time, DEX treatment affects the athletic ability and memory of the animals. Compared with the control group, the experimental group showed slow response to stimulation, inertia, depression, cowardice and lack of appetite. The results of ethology experiments showed that all the parameters decreased by 15-30%.


Assuntos
17-Hidroxiesteroide Desidrogenases/efeitos dos fármacos , Dexametasona/farmacologia , Nervo Óptico/efeitos dos fármacos , Animais , Western Blotting , Dexametasona/administração & dosagem , Ensaio de Imunoadsorção Enzimática , Ratos , Ratos Sprague-Dawley
14.
Invest Ophthalmol Vis Sci ; 60(6): 1987-1995, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31063183

RESUMO

Purpose: To investigate the potential neuroprotective effect of sildenafil on the ocular circulation in mice with/without optic nerve crush (ONC). Methods: Male adult mice (n = 63) were treated with intravitreal (IVT) sildenafil 24 µg/3 µL, intraperitoneal (IP) sildenafil 24 µg/300 µL, or IP saline immediately before right ONC induction (ONC group). A second group (n = 123) received the same treatments without ONC induction (naïve group). Evaluations included fluorescein angiography (naïve group; day 0), molecular studies (days 1 and 3), and retinal and optic nerve histology (day 21). Results: Maximal retinal vessel dilatation and increased choroidal effusion were detected within 30 minutes of sildenafil injection. In the ONC group, moderate retinal ganglion cell (RGC) loss was noted at 21 days. However, molecular studies showed increased stress induced gene expression (IP superoxide dismutase [SOD]-1: 3.1-fold; heme oxygenase [HO]-1: 5.8-fold; IVT SOD-1: 1.47-fold), proapoptotic gene expression (IP BAX/B-cell lymphoma [BCL]-2 10.8-/2.3-fold), and glial gene expression (IP glial fibrillary acidic protein [GFAP]: 2.8- and myelin basic protein [MBP]: 2.5-fold). In the naïve group, IVT sildenafil was not associated with RGC loss or optic nerve stroke on histology, although in two samples, molecular parameters were compatible with stroke, showing increased gene expression of HO-1 (3.8-fold) and BCL-2 (2.5-fold). In the IP sildenafil subgroup, optic neuropathy was observed in 6/120 optic nerves, including 3 cyan fluorescence protein (CFP)-Thy-1 mice. Levels of antiapoptosis and anti-ischemia genes were decreased (<0.5-fold) except for three outliers. Conclusions: Sildenafil affects retinal and choroidal perfusion in mice. When injected immediately before ONC, molecular parameters showed a preconditioning neuroprotective effect while histologic studies did not. In the absence of ONC, it is associated with neuropathy, possibly dose-dependent.


Assuntos
Traumatismos do Nervo Óptico/tratamento farmacológico , Nervo Óptico/patologia , Citrato de Sildenafila/administração & dosagem , Animais , Apoptose , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Angiofluoresceinografia , Fundo de Olho , Injeções Intravítreas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nervo Óptico/efeitos dos fármacos , Traumatismos do Nervo Óptico/patologia , Inibidores da Fosfodiesterase 5/administração & dosagem , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia
15.
Cutan Ocul Toxicol ; 38(3): 290-293, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31010341

RESUMO

Purpose: Carvone (CVN) is a natural monoterpene found in essential oils of many aromatic plant species. In this study, we investigated the protective effect of CVN against paclitaxel (PTX)-induced retinal and optic nerve cytotoxicity in rats. Methods: Twenty-four male adult Wistar albino rats (250-400 g) were randomized into four equal groups comprising six animals in each. Group 1 (control group) received intraperitoneal (i.p.) saline solution (0.5 mL/200 g) weekly for 4 weeks. Group 2 received i.p. CVN [(S)-(+)- CVN, (5S)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one, C10H14, 25 mg/kg], while Group 3 received i.p. PTX (5 mg/kg) weekly for 4 weeks. Group 4 received i.p. CVN (25 mg/kg) 30 min after i.p. PTX (5 mg/kg) weekly for 4 weeks. At the end of the experimental period, retinal and optic nerve tissues were evaluated histopathologically. Results: All retinal specimens in control and CVN groups were histopathologically normal. In PTX group all eyes (6/6) demonstrated increased retinal vascularity and rosette-like structures in the outer nuclear layer, while in PTX-CVN group all eyes (6/6) demonstrated normal retinal vascularity and absence of rosette-like structures. All optic nerve specimens in control and CVN groups were histopathologically normal. In PTX group all eyes (6/6) demonstrated severe vacuolization and decrease in the number of astrocytes and oligodendrocytes, while 3 eyes (3/6) demonstrated marked single cell necrosis. In PTX-CVN group, 4 eyes (4/6) demonstrated moderate vacuolization while, 2 eyes (2/6) had none. Compared with PTX group, 1 eye (1/6) in PTX-CVN group demonstrated a decrease in numbers of astrocytes and oligodendrocytes while 5 eyes (5/6) were normal. No remarkable single cell necrosis was observed in PTX-CVN group. Conclusions: Our histopathological findings demonstrated the potential protective role of CVN against PTX-induced retinal and optic nerve cytotoxicity. CVN might be a promising molecule in counteracting oxidative stress-based cytotoxicity in the field of retinal and optic nerve disorders.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Monoterpenos Cicloexânicos/uso terapêutico , Nervo Óptico/efeitos dos fármacos , Paclitaxel/efeitos adversos , Substâncias Protetoras/uso terapêutico , Retina/efeitos dos fármacos , Animais , Masculino , Nervo Óptico/patologia , Ratos Wistar , Retina/patologia
16.
Oncol Res Treat ; 42(3): 123-127, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799422

RESUMO

BACKGROUND: Mixed adenoneuroendocrine carcinomas (MANECs) are rare malignancies with both neuroendocrine and non-neuroendocrine components. To date, the prognosis of gastroenteropancreatic MANECs remains dismal, and treatment options are mainly based on guidelines for the treatment of pure neuroendocrine carcinomas or small cell lung cancer. Established first-line therapy in the metastatic situation is cisplatin and etoposide. Platinum derivatives are known to cause a variety of side effects also involving the visual system. Severe orbital and optic nerve toxicities have been described mainly after intracarotid infusion of cisplatin. CASE REPORT: Herein we report a rare case of a 60-year-old male patient suffering from MANEC of the gastroesophageal junction with HER2/neu overexpression who developed severe orbital and ocular neurotoxicity (grade 3 according to CTCAE v4.03) after intravenous cisplatin. CONCLUSION: We discuss diagnostic approaches and differential diagnoses in this clinical situation. Before starting treatment with intravenous and topical steroids, it is crucial to rule out meningeal and cerebral spread as well as paraneoplastic and endocrine syndromes.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/efeitos adversos , Carcinoma Neuroendócrino/tratamento farmacológico , Cisplatino/efeitos adversos , Neoplasias Esofágicas/tratamento farmacológico , Exoftalmia/induzido quimicamente , Adenocarcinoma/patologia , Administração Intravenosa/efeitos adversos , Carcinoma Neuroendócrino/patologia , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/patologia , Exoftalmia/diagnóstico por imagem , Exoftalmia/tratamento farmacológico , Glucocorticoides/uso terapêutico , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculos Oculomotores/diagnóstico por imagem , Músculos Oculomotores/efeitos dos fármacos , Nervo Óptico/diagnóstico por imagem , Nervo Óptico/efeitos dos fármacos , Receptor ErbB-2/metabolismo
17.
PLoS One ; 14(2): e0212588, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30789966

RESUMO

Acetozolamide-ACZ, carbonic anhydrase inhibitor- is still the most effective systemic drug for glaucoma treatment. Due to its limited ocular bioavailability, topical formulations are not available yet. This study introduces within the framework of nanotechnology three nanopreparations of acetozolamide for topical application, one of them is liposomal phospholipid vehicle and the other two preparations are propolis and Punica granatum (pomegranate). The hypotensive effect of these different nanopreparations in lowering the increased intraocular pressure that was induced in experimental rabbits is monitored for 130 hrs. Structural characteristics of the optic nerve dissected from all involved groups were studied by Fourier transfrom infrared spectroscopy. The obtained results indicate the impact of the topically applied acetozolamide nanopreparations in lowering the intraocular pressure to its normotensive control value. On the other hand, the optic nerve characteristics were found to be dependent on the way acetozolamide introduced. Glaucoma affects structural components that contain OH group and increases ß-turns of the protein secondary structure while, reducing the content of both α-helix and Turns. In the same context, liposomal-acetozolamide and propolis nanopreparations protecting the optic nerve protein secondary structure from these changes associated with glaucoma.


Assuntos
Acetazolamida/administração & dosagem , Inibidores da Anidrase Carbônica/administração & dosagem , Glaucoma/tratamento farmacológico , Nervo Óptico/efeitos dos fármacos , Acetazolamida/uso terapêutico , Administração Tópica , Animais , Inibidores da Anidrase Carbônica/uso terapêutico , Modelos Animais de Doenças , Portadores de Fármacos/química , Feminino , Glaucoma/patologia , Pressão Intraocular/efeitos dos fármacos , Lipossomos/química , Lythraceae/química , Masculino , Nervo Óptico/patologia , Própole/química , Coelhos
18.
Hum Exp Toxicol ; 38(5): 610-615, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30744420

RESUMO

The objective of the present study was to perform histological and stereological examination of alcohol-induced changes in the optic nerve, considered an extension of white matter of the brain, in rats. This study included 20 male Wistar albino rats aged 60 days and weighing 190-220 g. The rats were divided into three groups: ethanol ( n = 7), maltodextrin ( n = 7), and control ( n = 6) groups. The ethanol group was administered ethanol at a dose of 6.4% (v/v) instead of water for 18 days; the maltodextrin group received maltodextrin for the same time period, and the control group was the sham group. At the end of the experiment, a 0.5-mm long section of the optic nerve starting from the optic chiasma was dissected and examined with routine microscopic histological examination methods. The modified Cavalieri method was used for stereological measurement. Total tissue area ratios were calculated with a point grid provided by the Shtereom 1.5 software package. The statistical comparison of the groups revealed that the ethanol group had a significant reduction in the number of axons and sheath area of the optic nerve compared to the control and maltodextrin groups ( p < 0.017, p < 0.022, respectively). These results indicate the toxic effects of ethanol on the optic nerve.


Assuntos
Depressores do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Nervo Óptico/efeitos dos fármacos , Animais , Masculino , Nervo Óptico/patologia , Polissacarídeos/farmacologia , Ratos Wistar
19.
Mol Neurobiol ; 56(2): 1056-1069, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29869196

RESUMO

Retinal ganglion cell (RGC) degeneration occurs within 2 weeks following optic nerve crush (ONC) as a consequence of reduced retro-transport of growth factors including nerve growth factor (NGF). The hypothesis that intravitreal (ivt) and eye drop (ed) administration of recombinant human NGF (rhNGF) might counteract ONC in adult rats is explored in this study. We found that both ivt- and ed-rhNGF reduced RGC loss and stimulated axonal regrowth. Chiefly, survival and regenerative effects of rhNGF were associated with a reduction of cells co-expressing Nogo-A/p75NTR at crush site borders, which contribute to glia scar formation following nerve injury, and induce further degeneration. We also found that ocular application of rhNGF reduced p75NTR and proNGF and enhanced phosphorylation of TrkA and its intracellular signals at retina level. Nogo-R and Rock2 expression was also normalized by ed-rhNGF treatment in both ONC and contralateral retina. Our findings that ocular applied NGF reaches and exerts biological actions on posterior segment of the eye give a further insight into the neurotrophin diffusion/transport through eye structures and/or their trafficking in optic nerve. In addition, the use of a highly purified NGF form in injury condition in which proNGF/p75NTR binding is favored indicates that increased availability of mature NGF restores the balance between TrkA and p75NGF, thus resulting in RGC survival and axonal growth. In conclusion, ocular applied NGF is confirmed as a good experimental paradigm to study mechanisms of neurodegeneration and regeneration, disclose biomarkers, and time windows for efficacy treatment following cell or nerve injury.


Assuntos
Fator de Crescimento Neural/farmacologia , Traumatismos do Nervo Óptico/induzido quimicamente , Nervo Óptico/efeitos dos fármacos , Células Ganglionares da Retina/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Masculino , Modelos Teóricos , Proteínas Nogo/metabolismo , Traumatismos do Nervo Óptico/tratamento farmacológico , Ratos Long-Evans , Retina/metabolismo , Células Ganglionares da Retina/metabolismo
20.
Mol Neurobiol ; 56(6): 4322-4345, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30315478

RESUMO

Glaucomatous neurodegeneration represents one of the major causes of irreversible blindness worldwide. Yet, the detailed molecular mechanisms that initiate optic nerve damage and retinal ganglion cell (RGC) loss are not fully understood. Members of the protein tyrosine phosphatase (PTP) superfamily are key players in numerous neurodegenerative diseases. In order to investigate the potential functional relevance of the PTP megakaryocyte 2 (Meg2) in retinal neurodegeneration, we analyzed Meg2 knockout (KO) and heterozygous (HET)-synonym protein-tyrosine phosphatase non-receptor type 9 (Ptpn9)-mice. Interestingly, via global microarray and quantitative real-time PCR (RT-qPCR) analyses of Meg2 KO and HET retinae, we observed a dysregulation of several candidate genes that are highly associated with retinal degeneration and intraocular pressure (IOP) elevation, the main risk factor for glaucoma. Subsequent IOP measurements in Meg2 HET mice verified progressive age-dependent IOP elevation. Ultrastructural analyses and immunohistochemistry showed severe optic nerve degeneration accompanied by a dramatic loss of RGCs. Additionally, HET mice displayed reactive micro-/macrogliosis and early activation of the classical complement cascade with pronounced deposition of the membrane attack complex (MAC) in the retina and optic nerve. When treated with latanoprost, significant IOP lowering prevented RGC loss and microglial invasion in HET mice. Finally, electroretinogram (ERG) recordings revealed reduced a- and b-wave amplitudes, indicating impaired retinal functionality in Meg2 HET mice. Collectively, our findings indicate that the heterozygous loss of Meg2 in mice is sufficient to cause IOP elevation and glaucomatous neurodegeneration. Thus, Meg2 HET mice may serve as a novel animal model to study the pathomechanism involved in the onset and progression of glaucoma.


Assuntos
Progressão da Doença , Glaucoma/complicações , Glaucoma/fisiopatologia , Pressão Intraocular , Proteínas Tirosina Fosfatases não Receptoras/deficiência , Degeneração Retiniana/complicações , Degeneração Retiniana/fisiopatologia , Animais , Ativação do Complemento/efeitos dos fármacos , Regulação para Baixo/genética , Glaucoma/genética , Glaucoma/patologia , Gliose/complicações , Gliose/patologia , Heterozigoto , Pressão Intraocular/efeitos dos fármacos , Latanoprosta/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Fármacos Neuroprotetores/farmacologia , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/patologia , Nervo Óptico/ultraestrutura , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Degeneração Retiniana/genética , Degeneração Retiniana/patologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Regulação para Cima/genética
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