RESUMO
Following neurotrauma, secondary degeneration of neurons and glia adjacent to the injury leads to further functional loss. A combination of ion channel inhibitors (lomerizine + oxATP + YM872) has been shown to be effective at limiting structural and functional loss due to secondary degeneration. Here we assess efficacy of the combination where oxATP is replaced with Brilliant Blue G (BBG), a more clinically applicable P2X7 receptor inhibitor. Partial optic nerve transection was used to model secondary degeneration in adult female rats. Animals were treated with combinations of lomerizine + YM872 + oxATP or lomerizine + YM872 + BBG, delivered via osmotic mini-pump directly to the injury site. Outcomes assessed were Iba1 + and ED1 + microglia and macrophages, oligodendroglial cell numbers, node/paranode structure and visual function using the optokinetic nystagmus test. The lomerizine + BBG + YM872 combination was at least as effective at the tested concentrations as the lomerizine + oxATP + YM872 combination at preserving node/paranode structure and visual function when delivered locally. However, neither ion channel inhibitor combination significantly improved microglial/macrophage nor oligodendroglial numbers compared to vehicle-treated controls. In conclusion, a locally delivered combination of ion channel inhibitors incorporating lomerizine + BBG + YM872 is at least as effective at limiting secondary degeneration following partial injury to the optic nerve as the combination incorporating oxATP.
Assuntos
Canais Iônicos/antagonistas & inibidores , Canais Iônicos/metabolismo , Degeneração Neural/tratamento farmacológico , Degeneração Neural/etiologia , Traumatismos do Nervo Óptico/complicações , Animais , Bloqueadores dos Canais de Cálcio/uso terapêutico , Proteínas de Ligação ao Cálcio/metabolismo , Moléculas de Adesão Celular Neuronais , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Quimioterapia Combinada , Ectodisplasinas/metabolismo , Feminino , Imidazóis/uso terapêutico , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologia , Degeneração Neural/patologia , Nistagmo Optocinético/efeitos dos fármacos , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Piperazinas/uso terapêutico , Quinoxalinas/uso terapêutico , Ratos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Corantes de Rosanilina/uso terapêutico , Tubulina (Proteína)/metabolismoRESUMO
Purpose: Retinoic acid (RA) is required for embryonic formation of the anterior segment of the eye and craniofacial structures. The present study further investigated the role of RA in maintaining the function of these neural crest-derived structures in adult zebrafish. Methods: Morphology and histology were analyzed by using live imaging, methylacrylate sections, and TUNEL assay. Functional analysis of vision and aqueous humor outflow were assayed with real-time imaging. Results: Both decreased and increased RA signaling altered craniofacial and ocular structures in adult zebrafish. Exogenous treatment with all-trans RA for 5 days resulted in a prognathic jaw, while inhibition of endogenous RA synthesis through treatment with 4-diethylaminobenzaldehyde (DEAB) decreased head height. In adult eyes, RA activity was localized to the retinal pigment epithelium, photoreceptors, outer plexiform layer, inner plexiform layer, iris stroma, and ventral canalicular network. Exogenous RA increased apoptosis in the iris stroma and canalicular network in the ventral iridocorneal angle, resulting in the loss of these structures and decreased aqueous outflow. DEAB, which decreased RA activity throughout the eye, induced widespread apoptosis, resulting in corneal edema, cataracts, retinal atrophy, and loss of iridocorneal angle structures. DEAB-treated fish were blind with no optokinetic response and no aqueous outflow from the anterior chamber. Conclusions: Tight control of RA levels is required for normal structure and function of the adult anterior segment. These studies demonstrated that RA plays an important role in maintaining ocular and craniofacial structures in adult zebrafish.
Assuntos
Antineoplásicos/farmacologia , Anormalidades Craniofaciais/prevenção & controle , Crista Neural/efeitos dos fármacos , Tretinoína/farmacologia , Visão Ocular/efeitos dos fármacos , Animais , Segmento Anterior do Olho/efeitos dos fármacos , Segmento Anterior do Olho/patologia , Apoptose , Humor Aquoso/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Marcação In Situ das Extremidades Cortadas , Masculino , Nistagmo Optocinético/efeitos dos fármacos , Nistagmo Optocinético/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Visão Ocular/fisiologia , Peixe-ZebraRESUMO
BACKGROUND: Following partial injury to the central nervous system, cells beyond the initial injury site undergo secondary degeneration, exacerbating loss of neurons, compact myelin and function. Changes in Ca2+ flux are associated with metabolic and structural changes, but it is not yet clear how flux through specific ion channels contributes to the various pathologies. Here, partial optic nerve transection in adult female rats was used to model secondary degeneration. Treatment with combinations of three ion channel inhibitors was used as a tool to investigate which elements of oxidative and structural damage related to long term functional outcomes. The inhibitors employed were the voltage gated Ca2+ channel inhibitor Lomerizine (Lom), the Ca2+ permeable AMPA receptor inhibitor YM872 and the P2X7 receptor inhibitor oxATP. RESULTS: Following partial optic nerve transection, hyper-phosphorylation of Tau and acetylated tubulin immunoreactivity were increased, and Nogo-A immunoreactivity was decreased, indicating that axonal changes occurred acutely. All combinations of ion channel inhibitors reduced hyper-phosphorylation of Tau and increased Nogo-A immunoreactivity at day 3 after injury. However, only Lom/oxATP or all three inhibitors in combination significantly reduced acetylated tubulin immunoreactivity. Most combinations of ion channel inhibitors were effective in restoring the lengths of the paranode and the paranodal gap, indicative of the length of the node of Ranvier, following injury. However, only all three inhibitors in combination restored to normal Ankyrin G length at the node of Ranvier. Similarly, HNE immunoreactivity and loss of oligodendrocyte precursor cells were only limited by treatment with all three ion channel inhibitors in combination. CONCLUSIONS: Data indicate that inhibiting any of a range of ion channels preserves certain elements of axon and node structure and limits some oxidative damage following injury, whereas ionic flux through all three channels must be inhibited to prevent lipid peroxidation and preserve Ankyrin G distribution and OPCs.
Assuntos
Canais de Cálcio/metabolismo , Degeneração Neural/metabolismo , Traumatismos do Nervo Óptico/metabolismo , Receptores de AMPA/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Modelos Animais de Doenças , Feminino , Imidazóis/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Degeneração Neural/tratamento farmacológico , Degeneração Neural/etiologia , Degeneração Neural/patologia , Nistagmo Optocinético/efeitos dos fármacos , Nistagmo Optocinético/fisiologia , Traumatismos do Nervo Óptico/complicações , Traumatismos do Nervo Óptico/tratamento farmacológico , Traumatismos do Nervo Óptico/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Piperazinas/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Quinoxalinas/farmacologia , Distribuição Aleatória , Nós Neurofibrosos/efeitos dos fármacos , Nós Neurofibrosos/metabolismo , Nós Neurofibrosos/patologia , Ratos , Receptores de AMPA/antagonistas & inibidoresRESUMO
Cisplatin is a chemotherapeutic agent commonly used for the treatment of solid tumors, and its side-effects include vestibulotoxicity. Previous studies have reported cisplatin-induced vestibulotoxicity in various animal models, but no study has investigated in vivo mouse vestibular dysfunction after cisplatin. The aim of this study was to investigate cisplatin-induced vestibulotoxicity in C57BL/6J mice. Vestibular function was assessed by recording the vestibulo-ocular reflex (VOR). This was done during sinusoidal rotations in the horizontal plane at three frequencies (0.5, 1.0 and 2.5Hz). A high-resolution, high-frequency digital infra-red camera was used with eye-tracking algorithms. Cisplatin at 16mg/kg, but not 8mg/kg, decreased the VOR gain at 2.5Hz compared with the vehicle control. Following 16mg/kg cisplatin treatment, the animals showed no change in the optokinetic nystagmus response, suggesting that no major changes in visual or oculomotor functions had occurred. This mouse model may be useful for studying cisplatin-induced vestibulotoxicity and its treatment.
Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Reflexo Vestíbulo-Ocular/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Movimentos Oculares/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Nistagmo Optocinético/efeitos dos fármacos , Rotação , Testes de Função VestibularRESUMO
Peripheral nerve (PN) grafts can be used to bridge tissue defects in the CNS. Using a PN-to-optic nerve (ON) graft model, we combined gene therapy with pharmacotherapy to promote the long-distance regeneration of injured adult retinal ganglion cells (RGCs). Autologous sciatic nerve was sutured onto the transected ON and the distal end immediately inserted into contralateral superior colliculus (SC). Control rats received intraocular injections of saline or adeno-associated virus (AAV) encoding GFP. In experimental groups, three bi-cistronic AAV vectors encoding ciliary neurotrophic factor (CNTF) were injected into different regions of the grafted eye. Each vector encoded a different fluorescent reporter to assess retinotopic order in the regenerate projection. To encourage sprouting/synaptogenesis, after 6 weeks some AAV-CNTF injected rats received an intravitreal injection of recombinant brain-derived neurotrophic factor (rBDNF) or AAV-BDNF. Four months after surgery, cholera toxin B was used to visualize regenerate RGC axons. RGC viability and axonal regrowth into SC were significantly greater in AAV-CNTF groups. In some cases, near the insertion site, regenerate axonal density resembled retinal terminal densities seen in normal SC. Complex arbors were seen in superficial but not deep SC layers and many terminals were immunopositive for presynaptic proteins vGlut2 and SV2. There was improvement in visual function via the grafted eye with significantly greater pupillary constriction in both AAV-CNTF+BDNF groups. In both control and AAV-CNTF+rBDNF groups the extent of light avoidance correlated with the maximal distance of axonal penetration into superficial SC. Despite the robust regrowth of RGC axons back into the SC, axons originating from different parts of the retina were intermixed at the PN graft/host SC interface, indicating that there remained a lack of order in this extensive regenerate projection.
Assuntos
Comportamento Animal , Encéfalo/anatomia & histologia , Terapia Genética , Nervos Periféricos/transplante , Retina/anatomia & histologia , Vias Visuais/anatomia & histologia , Animais , Axônios/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Fator Neurotrófico Ciliar/metabolismo , Feminino , Neurogênese/efeitos dos fármacos , Nistagmo Optocinético/efeitos dos fármacos , Nervo Óptico/transplante , Ratos , Reflexo Pupilar/efeitos dos fármacos , Células Ganglionares da Retina/efeitos dos fármacos , Nervo Isquiático/transplante , Visão Ocular/efeitos dos fármacosRESUMO
Following neurotrauma, cells beyond the initial trauma site undergo secondary degeneration, with excess Ca2+ a likely trigger for loss of neurons, compact myelin and function. Treatment using inhibitors of specific Ca2+ channels has shown promise in preclinical studies, but clinical trials have been disappointing and combinatorial approaches are needed. We assessed efficacy of multiple combinations of three Ca2+ channel inhibitors at reducing secondary degeneration following partial optic nerve transection in rat. We used lomerizine to inhibit voltage gated Ca2+ channels; oxidised adenosine-triphosphate (oxATP) to inhibit purinergic P2X7 receptors and/or 2-[7-(1H-imidazol-1-yl)-6-nitro-2,3-dioxo-1,2,3,4-tetrahydro quinoxalin-1-yl]acetic acid (INQ) to inhibit Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Only the three Ca2+ channel inhibitors delivered in combination significantly preserved visual function, as assessed using the optokinetic nystagmus visual reflex, at 3 months after injury. Preservation of retinal ganglion cells was partial and is unlikely to have accounted for differential effects on function. A range of the Ca2+ channel inhibitor combinations prevented swelling of optic nerve vulnerable to secondary degeneration. Each of the treatments involving lomerizine significantly increased the proportion of axons with normal compact myelin. Nevertheless, limiting decompaction of myelin was not sufficient for preservation of function in our model. Multiple combinations of Ca2+ channel inhibitors reduced formation of atypical node/paranode complexes; outcomes were not associated with preservation of visual function. However, prevention of lengthening of the paranodal gap that was only achieved by treatment with the three Ca2+ channel inhibitors in combination was an important additional effect that likely contributed to the associated preservation of the optokinetic reflex using this combinatorial treatment strategy.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Degeneração Neural/tratamento farmacológico , Degeneração Neural/etiologia , Traumatismos do Nervo Óptico/complicações , Trifosfato de Adenosina/uso terapêutico , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Modelos Animais de Doenças , Combinação de Medicamentos , Feminino , Espectroscopia de Ressonância Magnética , Degeneração Neural/patologia , Proteínas do Tecido Nervoso/metabolismo , Nistagmo Optocinético/efeitos dos fármacos , Nervo Óptico/patologia , Nervo Óptico/ultraestrutura , Traumatismos do Nervo Óptico/tratamento farmacológico , Traumatismos do Nervo Óptico/patologia , Papiledema/etiologia , Papiledema/prevenção & controle , Piperazinas/uso terapêutico , Nós Neurofibrosos/patologia , Nós Neurofibrosos/ultraestrutura , Ratos , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/ultraestrutura , Tetra-Hidroisoquinolinas/farmacologia , TrítioRESUMO
Acetylcholine is present in and released from starburst amacrine cells in the inner plexiform layer (IPL), but its role in retinal function except, perhaps, in early development, is unclear. Nicotinic acetylcholine receptors are thought to be present on ganglion, amacrine, and bipolar cell processes in the IPL, and it is known that acetylcholine increases the spontaneous and light-evoked responses of retinal ganglion cells. The effects of acetylcholine on bipolar cells are not known, and here we report the effects of nicotine on the b-wave of the electroretinogram in larval zebrafish. The b-wave originates mainly from ON-bipolar cells, and the larval zebrafish retina is cone-dominated. Only small rod responses can be elicited with dim lights in wild-type larval zebrafish retinas, but rod responses can be recorded over a range of intensities in a mutant ( n o optokinetic response f ) fi sh that has no cone function. We fi nd that nicotine strongly enhances cone-driven b-wave response amplitudes but depresses rod driven b-wave response amplitudes without, however, affecting rod- or cone-driven b-wave light sensitivity.
Assuntos
Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Células Fotorreceptoras Retinianas Bastonetes/efeitos dos fármacos , Peixe-Zebra/fisiologia , Acetilcolina/farmacologia , Acetilcolina/fisiologia , Animais , Adaptação à Escuridão/fisiologia , Relação Dose-Resposta à Radiação , Eletrorretinografia , Larva , Mutação/genética , Mutação/fisiologia , Nistagmo Optocinético/efeitos dos fármacos , Nistagmo Optocinético/genética , Nistagmo Optocinético/fisiologia , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/genética , Células Bipolares da Retina/efeitos dos fármacos , Peixe-Zebra/genéticaRESUMO
PURPOSE: CNTF is a neuroprotective agent for retinal degenerations that can cause reduced electroretinogram (ERG) amplitudes. The goal of the present study was to determine the effects of intraocular delivery of CNTF on normal rat visual function. METHODS: Full-field scotopic and photopic ERG amplitudes and spatial frequency thresholds of the optokinetic response (OKR) of adult Long-Evans rats were measured before and after intravitreous injection of CNTF or subretinal delivery of adenoassociated virus-vectored CNTF (AAV-CNTF) into one eye. Visual acuity was also measured by using the Visual Water Task in AAV-CNTF-injected animals. Multiunit luminance thresholds were recorded in the superior colliculus after CNTF injection, and the eyes were examined histologically. RESULTS: In eyes injected with a high dose of CNTF, ERG amplitudes and OKR thresholds measured through CNTF-injected eyes were decreased by 45% to 70% within 6 days after injection. ERG amplitudes had begun to recover by 21 days, whereas OKR thresholds only began to recover after 56 days. Neither OKR thresholds nor ERG amplitudes fully recovered until 90 to 100 days. When measured in the superior colliculus at 2 weeks after CNTF injection, luminance thresholds were elevated by 0.35 log units. In AAV-CNTF-injected eyes, OKR thresholds, and visual acuity were reduced by approximately 50% for at least 6 months, and scotopic and photopic ERG b-waves were reduced by 30% to 50%. Photoreceptor loss occurred in the injected regions in some of the eyes. By contrast, comparison of dose-response analysis with a dose-response study of light damage strongly suggests that therapeutic doses of CNTF exist that do not suppress ERG responses. CONCLUSIONS: Intraocular delivery of CNTF, which preserves photoreceptors in animal models of retinal degeneration, impairs visual function in normal rats at very high doses, but not at lower doses that still provide protection from constant light damage.
Assuntos
Fator Neurotrófico Ciliar/toxicidade , Eletrorretinografia/efeitos dos fármacos , Nistagmo Optocinético/efeitos dos fármacos , Transtornos da Visão/induzido quimicamente , Acuidade Visual/efeitos dos fármacos , Animais , Fator Neurotrófico Ciliar/genética , Dependovirus/genética , Relação Dose-Resposta a Droga , Vetores Genéticos , Injeções , Luz/efeitos adversos , Células Fotorreceptoras de Vertebrados/efeitos da radiação , Lesões Experimentais por Radiação/etiologia , Lesões Experimentais por Radiação/prevenção & controle , Ratos , Ratos Long-Evans , Limiar Sensorial/efeitos dos fármacos , Colículos Superiores/efeitos dos fármacos , Corpo VítreoRESUMO
Nicotine has wellknown, unpleasant side effects, e.g., transient dizziness, nausea, and nicotine-induced nystagmus (NIN). To investigate factors influencing these effects, we addressed three questions: (1) Is the intensity of dizziness, nausea, NIN, and unsteadiness dependent on nicotine dosage? (2) Does the intensity of perceptual, ocular motor, vegetative effects, and postural imbalance correlate? (3) Do visual or vestibular motion stimuli produce and/or aggravate distressing dizziness and nausea? Sixty healthy non-smokers or occasional smokers participated; 40 were tested once before and six times after application of a nicotine nasal spray in doses of 1 mg or 2 mg with or without motion stimulation; 20 received a placebo nasal spray. Plasma nicotine concentrations were significantly related to nicotine dosage. Dizziness, nausea, NIN, and unsteadiness also depended on the nicotine dosage (p < 0.01).Nicotine blood concentration was a better predictor for the temporal dependence of nystagmus than nicotine dosage. Dizziness correlated highly with nausea (R = 0.63, p < 0.001). The degree of nicotine-induced nausea significantly correlated with postural imbalance. The time course of postural sway differed according to nicotine dosage and gender: for women, there was no clear relationship between sway magnitude and nicotine dosage, while men showed increased sway with higher dosage. Motion stimulation increased nicotine-induced dizziness and nausea, but did not significantly influence NIN or postural imbalance. Our data support the view that all measured adverse effects reflect dose-dependent nicotine-induced vestibular dysfunction. Additional motion stimulation aggravates dizziness and nausea, i.e., nicotine increases sensitivity to motion sickness.
Assuntos
Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Transtornos da Percepção , Transtornos de Sensação , Doenças Vestibulares , Administração Intranasal , Adulto , Análise de Variância , Tontura/induzido quimicamente , Tontura/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Movimento (Física) , Náusea/induzido quimicamente , Náusea/fisiopatologia , Nicotina/sangue , Agonistas Nicotínicos/sangue , Nistagmo Optocinético/efeitos dos fármacos , Transtornos da Percepção/induzido quimicamente , Transtornos da Percepção/fisiopatologia , Postura/fisiologia , Distribuição Aleatória , Descanso , Transtornos de Sensação/induzido quimicamente , Transtornos de Sensação/fisiopatologia , Doenças Vestibulares/induzido quimicamente , Doenças Vestibulares/fisiopatologiaRESUMO
Closed-loop and open-loop optokinetic nystagmus (OKN) eye movements were recorded with an electromagnetic scleral search coil in 16 patients with myasthenic ocular palsies, 8 patients with nonmyasthenic ocular palsies, and 4 normal controls. We calculated the summation of fast-phase amplitude per second (SFPAps), mean of fast-phase amplitude (MFPA) and mean of fast-phase peak velocity (MFPV) of OKN before and after administration of neostigmine. Under open-loop conditions, the myasthenic patients group demonstrated distinct increases in three parameters: SFPAps (P < 0.000001), MFPA (P < 0.001) and MFPV (P < 0.001) following neostigmine injection, and the increase in SFPAps was greater than those of MFPA and MFPV (P < 0.02), while the other two groups showed no significant increases. Under closed-loop condition, only five of the myasthenic patients showed significant changes. These results suggest that the change in SFPAps during open-loop OKN before and after neostigmine administration was a specific measurement that differentiated patients with myasthenic ocular palsies from the other groups.
Assuntos
Miastenia Gravis/complicações , Neostigmina/farmacologia , Nistagmo Optocinético/efeitos dos fármacos , Doenças do Nervo Oculomotor/fisiopatologia , Parassimpatomiméticos/farmacologia , Adolescente , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/diagnóstico , Doenças do Nervo Oculomotor/etiologiaRESUMO
Eye growth and refraction are regulated by visual processing in the retina. Until now, the messengers released by the retina to induce these changes are largely unknown. Previously, it was found that glucagon amacrine cells respond to defocus in the retinal image and even to its sign. The expression of the immediate-early gene product ZENK increased in this cell population in eyes wearing plus lenses and decreased in minus lens-treated chicks. Moreover, it was shown that the amount of retinal glucagon mRNA increased during treatment with positive lenses. Therefore, it seems likely that these cells contribute to the visual regulation of ocular growth and that glucagon may act as a stop signal for eye growth. The purpose of the present study was to accumulate further evidence for a role of glucagon in the visual control of eye growth. Chicks were treated with plus and minus lenses after injection of different amounts of the glucagon antagonist des-His1-Glu1-glucagon-amide or the agonist Lys17,18,Glu21-glucagon, respectively. Refractive development and eye growth were recorded by automated infrared photorefraction and A-scan ultrasound, respectively. The glucagon antagonist inhibited hyperopia development, albeit only in a narrow concentration range, and at most by 50%, but not myopia development. In contrast, the agonist inhibited myopia development in a dose-dependent fashion. At high concentrations, it also prevented hyperopia development. The amount of glucagon peptide in the retinae and choroids of lens-treated chicks and its diurnal variation was measured by using a radio-immunoassay. Retinal glucagon content decreased after minus lens treatment and choroidal glucagon content increased after plus lens treatment. No diurnal variation in the retinal amount of glucagon was detected. In addition, using an optokinetic nystagmus paradigm, the effect of glucagon and the antagonist des-His1-Glu9-glucagon-amide on suprathreshold contrast sensitivity was studied. Glucagon reduced contrast sensitivity (which might be linked to a signal for growth inhibition) whereas the antagonist des-His1-Glu9-glucagon-amide increased contrast sensitivity. The results of the study are in line with the hypothesis that glucagon plays a role in the visual control of eye growth in the chick.
Assuntos
Olho/crescimento & desenvolvimento , Glucagon/análogos & derivados , Glucagon/fisiologia , Hiperopia/fisiopatologia , Miopia/fisiopatologia , Análise de Variância , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Galinhas , Corioide/efeitos dos fármacos , Corioide/metabolismo , Ritmo Circadiano/efeitos dos fármacos , Lentes de Contato/efeitos adversos , Sensibilidades de Contraste/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Olho/patologia , Glucagon/agonistas , Glucagon/antagonistas & inibidores , Glucagon/metabolismo , Glucagon/farmacologia , Hiperopia/induzido quimicamente , Hiperopia/metabolismo , Hiperopia/patologia , Imunoensaio/métodos , Miopia/induzido quimicamente , Miopia/metabolismo , Miopia/patologia , Nistagmo Optocinético/efeitos dos fármacos , Peptídeos/metabolismo , Erros de Refração/induzido quimicamente , Erros de Refração/metabolismo , Fatores de Tempo , Corpo Vítreo/efeitos dos fármacosRESUMO
Optokinetic nystagmus (OKN) eye movements of myasthenia gravis (MG) and nonmyasthenic ocular palsies, and normal subjects were examined under closed-loop and open-loop conditions. The open-loop OKN condition was achieved by adding the signal of eye-movement velocity of OKN to the computer-generated signal controlling the stimulus grating moving. The OKN was recorded by means of electromagnetic search scleral coil technique. In MG patients, the open-loop gains of OKN increased significantly after the intramuscular injection of an acetylcholinesterase inhibitor, neostigmine, while the closed-loop OKN gains were not significantly changed. Both the closed-loop and open-loop OKN gains of normal subjects and nonmyasthenic patients were not increased for the administration of neostigmine. The experimental results indicated that the open-loop OKN gain could be sensitive to reflect the changes of the function of neuromuscular junction in MG patients.
Assuntos
Miastenia Gravis/complicações , Nistagmo Optocinético/fisiologia , Transtornos da Motilidade Ocular/etiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/diagnóstico , Miastenia Gravis/fisiopatologia , Neostigmina/farmacologia , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/patologia , Junção Neuromuscular/fisiopatologia , Nistagmo Optocinético/efeitos dos fármacos , Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/fisiopatologia , Músculos Oculomotores/efeitos dos fármacos , Músculos Oculomotores/patologia , Músculos Oculomotores/fisiopatologiaRESUMO
Ocular symptoms of 17 myasthenia gravis (MG) patients were examined by electronystagmographic registration of optokinetic nystagmus. The aim of this study was to replace the subjective methods used previously with a more reliable quantitative technique and thus assess ophthalmoplegia and diplopia, important initial symptoms in MG. Slow phase angular speed values of foveolar type optokinetic nystagmus in the horizontal plane at 10, 20 and 30 degrees/s target speed were determined. Measurements were performed before and after administration of Mestinon, a reversible cholinesterase inhibitor. Twelve healthy volunteers were examined as controls under standard conditions. Results showed significant differences between MG patients and control group. Slow-phase angular speed was significantly larger after Mestinon administration (p < 0.001). It is concluded, that the exhaustion of external ocular muscles in MG can be well characterized by the determination of the slow phase angular speed values of optokinetic nystagmus (OKN). The examination of OKN was also recommended for the evaluation of ocular symptoms in other neurological disorders.
Assuntos
Eletronistagmografia , Miastenia Gravis/diagnóstico , Nistagmo Optocinético , Adulto , Inibidores da Colinesterase , Eletronistagmografia/instrumentação , Eletronistagmografia/métodos , Humanos , Pessoa de Meia-Idade , Debilidade Muscular/diagnóstico , Debilidade Muscular/etiologia , Debilidade Muscular/fisiopatologia , Miastenia Gravis/complicações , Miastenia Gravis/fisiopatologia , Nistagmo Optocinético/efeitos dos fármacos , Músculos Oculomotores/efeitos dos fármacos , Músculos Oculomotores/fisiopatologia , Brometo de PiridostigminaRESUMO
This study details the prevention of gentamicin-induced hearing loss in guinea pig in vivo. The approach is based on our recent demonstrations of a redox-active gentamicin-iron complex in vitro and partial attenuation of gentamicin-induced hearing loss by the iron chelators deferoxamine and 2,3-dihydroxybenzoate. In our study, guinea pigs receiving injections of gentamicin (120 mg/kg body weight daily x 19 days) developed a progressive threshold shift reaching 50 to 70 dB at 18 kHz. Concurrent treatment with different doses of 2,3-dihydroxybenzoate (30-300 mg/kg/day) reduced the threshold shift to 25 to 15 dB. Coinjection of gentamicin with dihydroxybenzoate (100 mg/kg/day) plus mannitol (15 mg/kg/day) yielded complete functional and morphological protection from gentamicin ototoxicity although partial protection was observed with combinations of dihydroxybenzoate and deferoxamine. Dihydroxybenzoate also attenuated gentamicin-induced vestibular toxicity. The iron chelators and radical scavengers affected neither serum levels nor the antimicrobial efficacy of gentamicin against Escherichia coli. These results confirm that iron and free radicals play a crucial role in the toxic side effects of gentamicin. Furthermore, they suggest that iron chelators, which are well-established drugs in clinical therapy, may be promising therapeutic agents to reduce aminoglycoside ototoxicity.