RESUMO
Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.
Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/prevenção & controle , Lesões Encefálicas Traumáticas/complicações , Neuroproteção , Proteínas tau/metabolismo , Acetilação , Doença de Alzheimer/metabolismo , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Biomarcadores/sangue , Biomarcadores/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Linhagem Celular , Diflunisal/uso terapêutico , Feminino , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora) , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Salicilatos/uso terapêutico , Sirtuína 1/metabolismo , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Fatores de Transcrição de p300-CBP/metabolismo , Proteínas tau/sangueRESUMO
Traumatic brain injury (TBI) caused by acoustic blast overpressure (ABO) is frequently associated with chronic visual deficits in military personnel and civilians. In this study, we characterized retinal gliotic response in adult male rats following a single ABO exposure directed to one side of the head. Expression of gliosis markers and intermediate filaments was assessed at 48 h and 1 wk post-ABO exposure, in comparison to age-matched non-exposed control retina. In response to a single ABO exposure, type III IF, glial fibrillary acidic protein (GFAP) was variably induced in a subpopulation of retinal Müller glia in ipsilateral eyes. ABO-exposed eyes exhibited radial Müller glial GFAP filament extension through the inner plexiform layer (IPL) and the inner nuclear layer (INL) through the retina in both the nasal quadrant and juxta-optic nerve head (jONH) eye regions at 1 wk post-ABO. We observed an â¼6-fold increase (p ≤ 0.05) in radial glial GFAP immunolabeling in the IPL in both eye regions, in comparison to regionally matched controls. Similarly, GFAP extension through the INL into the outer retina was elevated â¼3-fold, p ≤ 0.05 in the nasal retina, but exhibited wider variability in the jONH retina. In contrast, constitutive type III IF vimentin exhibited greater remodeling in retinal Müller glia through the jONH retina compared to the nasal retina in response to ABO. We observed areas of lateral vimentin remodeling through the Müller glial end-feet, and greater mid-outer retinal radial vimentin IF extension in a subpopulation of glia at 1 wk post-ABO. We also observed a significant increase in total retinal levels of the type III IF desmin in ABO-exposed retina vs. controls (â¼1.6-fold, p ≤ 0.01). In addition, ABO-exposure elicited varied glial induction of developmentally regulated type VI family IFs (nestin and synemin) in subpopulations of Müller cells at 48 h and 1 wk post-ABO. We demonstrate that multiple glial phenotypes emerge in the rat retina following a single ABO exposure, rather than a global homogeneous retinal glial response, involving less well characterized IF protein forms which warrant further investigation in the context of ABO-induced retinal gliosis.
Assuntos
Gliose , Filamentos Intermediários , Masculino , Ratos , Animais , Vimentina/metabolismo , Gliose/metabolismo , Filamentos Intermediários/metabolismo , Retina/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Neuroglia/metabolismoRESUMO
Glaucoma is the leading cause of irreversible blindness worldwide, and women represent roughly 60% of the affected population. Early menopause and estrogen signaling defects are risk factors for glaucoma. Recently, we found that surgical menopause exacerbated visual dysfunction in an ocular hypertension model of glaucoma. Here, we investigated if surgical menopause exacerbated visual dysfunction in a model of direct retinal ganglion cell (RGC) damage via optic nerve crush (ONC). Female Long Evans rats (n = 12) underwent ovariectomy (OVX) to induce surgical menopause or Sham surgery. Eight weeks post-surgery, baseline visual function was assessed via optomotor response. Afterwards, rats underwent monocular ONC. Visual function was assessed at 4, 8, and 12 weeks post-ONC. At 12 weeks, retinal function via electroretinography and retinal nerve fiber layer (RNFL) thickness via optical coherence tomography were measured. Visual acuity was reduced after ONC (p < 0.001), with surgical menopausal animals having 31.7% lower visual acuity than Sham animals at 12 weeks (p = 0.01). RNFL thinning (p < 0.0001) and decreased RGC function (p = 0.0016) occurred at 12 weeks in ONC groups. Surgical menopause worsens visual acuity after direct RGC damage using an ONC model. This demonstrates that surgical menopause plays a role in visual function after injury.
Assuntos
Fibras Nervosas/fisiologia , Traumatismos do Nervo Óptico/fisiopatologia , Ovariectomia , Retina/fisiopatologia , Células Ganglionares da Retina/fisiologia , Transtornos da Visão/fisiopatologia , Animais , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Compressão Nervosa , Ratos , Ratos Long-Evans , Tomografia de Coerência Óptica , Acuidade Visual/fisiologiaRESUMO
High fat diets (HFD) have been utilized in rodent models of visual disease for over 50 years to model the effects of lipids, metabolic dysfunction, and diet-induced obesity on vision and ocular health. HFD treatment can recapitulate the pathologies of some of the leading causes of blindness, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) in rodent models of visual disease. However, there are many important factors to consider when using and interpreting these models. To synthesize our current understanding of the importance of lipid signaling, metabolism, and inflammation in HFD-driven visual disease processes, we systematically review the use of HFD in mouse and rat models of visual disease. The resulting literature is grouped into three clusters: models that solely focus on HFD treatment, models of diabetes that utilize both HFD and streptozotocin (STZ), and models of AMD that utilize both HFD and genetic models and/or other exposures. Our findings show that HFD profoundly affects vision, retinal function, many different ocular tissues, and multiple cell types through a variety of mechanisms. We delineate how HFD affects the cornea, lens, uvea, vitreous humor, retina, retinal pigmented epithelium (RPE), and Bruch's membrane (BM). Furthermore, we highlight how HFD impairs several retinal cell types, including glia (microglia), retinal ganglion cells, bipolar cells, photoreceptors, and vascular support cells (endothelial cells and pericytes). However, there are a number of gaps, limitations, and biases in the current literature. We highlight these gaps and discuss experimental design to help guide future studies. Very little is known about how HFD impacts the lens, ciliary bodies, and specific neuronal populations, such as rods, cones, bipolar cells, amacrine cells, and retinal ganglion cells. Additionally, sex bias is an important limitation in the current literature, with few HFD studies utilizing female rodents. Future studies should use ingredient-matched control diets (IMCD), include both sexes in experiments to evaluate sex-specific outcomes, conduct longitudinal metabolic and visual measurements, and capture acute outcomes. In conclusion, HFD is a systemic exposure with profound systemic effects, and rodent models are invaluable in understanding the impacts on visual and ocular disease.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Doenças Retinianas/etiologia , Transtornos da Visão/etiologia , Animais , Degeneração Macular/etiologia , Camundongos , Obesidade/etiologia , RatosRESUMO
Diabetic retinopathy is a leading cause of vision loss. Treatment options for early retinopathy are sparse. Exercise protects dying photoreceptors in models of retinal degeneration, thereby preserving vision. We tested the protective effects of exercise on retinal and cognitive deficits in a type 1 diabetes model and determined whether the TrkB pathway mediates this effect. Hyperglycaemia was induced in Long Evans rats via streptozotocin injection (STZ; 100 mg/kg). Following confirmed hyperglycaemia, both control and diabetic rats underwent treadmill exercise for 30 min, 5 days/week at 0 m/min (inactive groups) or 15 m/min (active groups) for 8 weeks. A TrkB receptor antagonist (ANA-12), or vehicle, was injected 2.5 h before exercise training. We measured spatial frequency and contrast sensitivity using optokinetic tracking biweekly post-STZ; retinal function using electroretinography at 4 and 8 weeks; and cognitive function and exploratory behaviour using Y-maze at 8 weeks. Retinal neurotrophin-4 was measured using ELISA. Compared with non-diabetic controls, diabetic rats showed significantly reduced spatial frequency and contrast sensitivity, delayed electroretinogram oscillatory potential and flicker implicit times and reduced cognitive function and exploratory behaviour. Exercise interventions significantly delayed the appearance of all deficits, except for exploratory behaviour. Treatment with ANA-12 significantly reduced this protection, suggesting a TrkB-mediated mechanism. Despite this, no changes in retinal neurotrohin-4 were observed with diabetes or exercise. Exercise protected against early visual and cognitive dysfunction in diabetic rats, suggesting that exercise interventions started after hyperglycaemia diagnosis may be a beneficial treatment. The translational potential is high, given that exercise treatment is non-invasive, patient controlled and inexpensive.
Assuntos
Disfunção Cognitiva , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Retinopatia Diabética , Terapia por Exercício , Comportamento Exploratório/fisiologia , Fatores de Crescimento Neural/metabolismo , Condicionamento Físico Animal , Receptor trkB/antagonistas & inibidores , Transtornos da Visão , Animais , Azepinas/farmacologia , Comportamento Animal/fisiologia , Benzamidas/farmacologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/terapia , Sensibilidades de Contraste/fisiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 1/terapia , Retinopatia Diabética/complicações , Retinopatia Diabética/metabolismo , Retinopatia Diabética/fisiopatologia , Retinopatia Diabética/terapia , Eletrorretinografia , Masculino , Aprendizagem em Labirinto/fisiologia , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Long-Evans , Receptor trkB/metabolismo , Transtornos da Visão/etiologia , Transtornos da Visão/metabolismo , Transtornos da Visão/fisiopatologia , Transtornos da Visão/terapiaRESUMO
Purpose: Electroretinography (ERG) is used to assess retinal function in ophthalmology clinics and animal models of ocular disease; however, analyzing ERG waveforms can be a time-intensive process with interobserver variability. We developed ERGAssist, an automated approach, to perform non-subjective and repeatable feature identification ("marking") of the ERG waveform. Methods: The automated approach denoised the recorded waveforms and then located the b-wave after applying a lowpass filter. If an a-wave was present, the lowpass filter wave was also used to help locate the a-wave, which was considered the initial large negative response after the flash stimuli. Oscillatory potentials (OPs) were found using a bandpass filter on the denoised waveform. We used two cohorts. One was a Coherence cohort that consisted of ERGs with eight dark-adapted and three light-adapted stimuli in Brown Norway rats (-6 to 1.5 log cd·s/m2). The Verification cohort consisted of control and diabetic (DM) Long Evans rats. We examined retinal function using a five-step dark-adapted protocol (-3 to 1.9 log cd·s/m2). Results: ERGAssist showed a strong correlation with manual markings of ERG features in our Coherence dataset, including the amplitudes (a-wave: r2 = 0.99; b-wave: r2 = 0.99; OP: r2 = 0.92) and implicit times (a-wave: r2 = 0.96; b-wave: r2 = 0.90; OP: r2 = 0.96). In the Verification cohort, both approaches detected differences between control and DM animals and found longer OP implicit times (P < 0.0001) in DM animals. Conclusions: These results provide verification of ERGAssist to identify features of the full-field ERG. Translational Relevance: This ERG analysis approach can increase the rigor of basic science studies designed to investigate retinal function using full-field ERG. To aid the community, we have developed an open-source graphical user interface (GUI) implementing the methods presented.
Assuntos
Eletrorretinografia , Retina , Humanos , Ratos , Animais , Ratos Long-Evans , Ratos Endogâmicos BNRESUMO
Purpose: Limited research exists on the time course of long-term retinal and cerebral deficits in diabetic rodents. Previously, we examined short term (4-8 weeks) deficits in the Goto-Kakizaki (GK) rat model of Type II diabetes. Here, we investigated the long-term (1-8 months) temporal appearance of functional deficits (retinal, cognitive, and motor), retinal vascular pathology, and retinal dopamine levels in the GK rat. Methods: In GK rats and Wistar controls, retinal neuronal function (electroretinogram), cognitive function (Y-maze), and motor function (rotarod) were measured at 1, 2, 4, 6, and 8 months of age. In addition, we evaluated retinal vascular function (functional hyperemia) and glucose and insulin tolerance. Retinas from rats euthanized at ≥8 months were assessed for vascular pathology. Dopamine and DOPAC levels were measured via HPLC in retinas from rats euthanized at 1, 2, 8, and 12 months. Results: Goto-Kakizaki rats exhibited significant glucose intolerance beginning at 4 weeks and worsening over time (p < 0.001). GK rats also showed significant delays in flicker and oscillatory potential implicit times (p < 0.05 to p < 0.001) beginning at 1 month. Cognitive deficits were observed beginning at 6 months (p < 0.05), but no motor deficits. GK rats showed no deficits in functional hyperemia and no increase in acellular retinal capillaries. Dopamine levels were twice as high in GK vs. Wistar retinas at 1, 2, 8, and 12 months (p < 0.001). Conclusion: As shown previously, retinal deficits were detectable prior to cognitive deficits in GK rats. While retinal neuronal function was compromised, retinal vascular pathology was not observed, even at 12+ months. High endogenous levels of dopamine in the GK rat may be acting as an anti-angiogenic and providing protection against vascular pathology.
RESUMO
Purpose: L-DOPA treatment initiated at the start of hyperglycemia preserves retinal and visual function in diabetic rats. Here, we investigated a more clinically relevant treatment strategy in which retinal and visual dysfunction designated the beginning of the therapeutic window for L-DOPA treatment. Methods: Spatial frequency thresholds using optomotor response and oscillatory potential (OP) delays using electroretinograms were compared at baseline, 3, 6, and 10 weeks after streptozotocin (STZ) between diabetic and control rats. L-DOPA/carbidopa treatment (DOPA) or vehicle was delivered orally 5 days per week beginning at 3 weeks after STZ, when significant retinal and visual deficits were measured. At 10 weeks after STZ, retinas were collected to measure L-DOPA, dopamine, and 3,4-dihydroxyphenylacetic acid (DOPAC) levels using high-performance liquid chromatography. Results: Spatial frequency thresholds decreased at 6 weeks in diabetic vehicle rats (28%), whereas diabetic DOPA rats had stable thresholds (<1%) that maintained to 10 weeks, creating significantly higher thresholds compared with diabetic vehicle rats (P < 0.0001). OP2 implicit times in response to dim, rod-driven stimuli were decreased in diabetic compared with control rats (3 weeks, P < 0.0001; 10 weeks, P < 0.01). With L-DOPA treatment, OP2 implicit times recovered in diabetic rats to be indistinguishable from control rats by 10 weeks after STZ. Rats treated with L-DOPA showed significantly increased retinal L-DOPA (P < 0.001) and dopamine levels (P < 0.05). Conclusions: L-DOPA treatment started after the detection of retinal and visual dysfunction showed protective effects in diabetic rats. Translational Relevance: Early retinal functional deficits induced by diabetes can be used to identify an earlier therapeutic window for L-DOPA treatment which protects from further vision loss and restores retinal function.
Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Animais , Diabetes Mellitus Experimental/complicações , Retinopatia Diabética/tratamento farmacológico , Eletrorretinografia , Levodopa , Neuroproteção , RatosRESUMO
Diabetes has been demonstrated to be one of the strongest predictors of risk for postoperative delirium and functional decline in older patients undergoing surgery. Exercise is often prescribed as a treatment for diabetic patients and regular physical activity is hypothesized to decrease the risk of postoperative cognitive impairments. Prior studies suggest that anesthetic emergence trajectories and recovery are predictive of risk for later postoperative cognitive impairments. Therapeutic strategies aimed at improving emergence and recovery from anesthesia may therefore be beneficial for diabetic patients. Wistar (n = 32) and Goto-Kakizaki (GK) type 2 diabetic (n = 32) rats between 3-4 months old underwent treadmill exercise for 30 min/day for ten days or remained inactive. Pre-anesthesia spontaneous alternation behavior was recorded with a Y-maze. Rats then received a 2-h exposure to 1.5-2 % isoflurane or oxygen only. The time to reach anesthetic emergence and post-anesthesia recovery behaviors was recorded for each rat. Postsynaptic density protein-95 (PSD-95), an important scaffolding protein required for synaptic plasticity, protein levels were quantified from hippocampus using western blot. Spontaneous alternation behavior (p = 0.044) and arm entries (p < 0.001) were decreased in GK rats. There was no difference between groups in emergence times from isoflurane, but exercise hastened the recovery time (p = 0.008) for both Wistar and GK rats. Following 10 days of exercise, both Wistar and GK rats show increased levels of PSD-95 in the hippocampus. Prehabilitation with moderate intensity exercise, even on a short timescale, is beneficial for recovery from isoflurane in rats, regardless of metabolic disease status.
Assuntos
Anestésicos Inalatórios/efeitos adversos , Recuperação Demorada da Anestesia/prevenção & controle , Diabetes Mellitus Experimental/fisiopatologia , Isoflurano/efeitos adversos , Condicionamento Físico Animal/métodos , Animais , Diabetes Mellitus Experimental/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Hipocampo/metabolismo , Masculino , Exercício Pré-Operatório , Ratos , Ratos WistarRESUMO
Blast-induced traumatic brain injury is the signature injury of modern military conflicts. To more fully understand the effects of blast exposure, we placed rats in different holder configurations, exposed them to blast overpressure, and assessed the degree of eye and brain injury. Anesthetized Long-Evans rats received blast exposures directed at the head (63 kPa, 195 dB-SPL) in either an "open holder" (head and neck exposed; n = 7), or an "enclosed holder" (window for blast exposure to eye; n = 15) and were compared to non-blast exposed (control) rats (n = 22). Outcomes included optomotor response (OMR), electroretinography (ERG), and spectral domain optical coherence tomography (SD-OCT) at 2, 4, and 6 months post-blast, and cognitive function (Y-maze) at 3 months. Spatial frequency and contrast sensitivity were reduced in ipsilateral blast-exposed eyes in both holders (p < 0.01), while contralateral eyes showed greater deficits with the enclosed holder (p < 0.05). Thinner retinas (p < 0.001) and reduced ERG a- and b- wave amplitudes (p < 0.05) were observed for both ipsilateral and contralateral eyes with the enclosed, but not the open, holder. Rats in the open holder showed cognitive deficits compared to rats in the enclosed holder (p < 0.05). Overall, the animal holder configuration used in blast exposure studies can significantly affect outcomes. Enclosed holders may cause secondary damage to the contralateral eye by concussive injury or blast wave reflection off the holder wall. Open holders may damage the brain via rapid head movement (contrecoup injury). These results highlight additional factors to be considered when evaluating patients with blast exposure or developing models of blast injury.
Assuntos
Explosões , Roedores , Animais , Cognição , Modelos Animais de Doenças , Humanos , Ratos , Ratos Long-Evans , RetinaRESUMO
Spectral-domain optical coherence tomography (SD-OCT) is useful for visualizing retinal and ocular structures in vivo. In research, SD-OCT is a valuable tool to evaluate and characterize changes in a variety of retinal and ocular disease and injury models. In light induced retinal degeneration models, SD-OCT can be used to track thinning of the photoreceptor layer over time. In glaucoma models, SD-OCT can be used to monitor decreased retinal nerve fiber layer and total retinal thickness and to observe optic nerve cupping after inducing ocular hypertension. In diabetic rodents, SD-OCT has helped researchers observe decreased total retinal thickness as well as decreased thickness of specific retinal layers, particularly the retinal nerve fiber layer with disease progression. In mouse models of myopia, SD-OCT can be used to evaluate axial parameters, such as axial length changes. Advantages of SD-OCT include in vivo imaging of ocular structures, the ability to quantitatively track changes in ocular dimensions over time, and its rapid scanning speed and high resolution. Here, we detail the methods of SD-OCT and show examples of its use in our laboratory in models of retinal degeneration, glaucoma, diabetic retinopathy, and myopia. Methods include anesthesia, SD-OCT imaging, and processing of the images for thickness measurements.
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Oftalmopatias/diagnóstico por imagem , Olho/diagnóstico por imagem , Olho/patologia , Tomografia de Coerência Óptica , Animais , Comprimento Axial do Olho , Modelos Animais de Doenças , Feminino , Processamento de Imagem Assistida por Computador , Masculino , Camundongos Endogâmicos BALB C , Miopia/diagnóstico por imagem , Miopia/patologia , Células Fotorreceptoras de Vertebrados/patologia , Ratos , Retina/diagnóstico por imagem , Retina/patologiaRESUMO
The optomotor response and the Y-maze are behavioral tests useful for assessing visual and cognitive function, respectively. The optomotor response is a valuable tool to track changes in spatial frequency (SF) and contrast sensitivity (CS) thresholds over time in a number of retinal disease models, including diabetic retinopathy. Similarly, the Y-maze can be used to monitor spatial cognition (as measured by spontaneous alternation) and exploratory behavior (as measured by a number of entries) in a number of disease models that affect the central nervous system. Advantages of the optomotor response and the Y-maze include sensitivity, speed of testing, the use of innate responses (training is not needed), and the ability to be performed on awake (non-anesthetized) animals. Here, protocols are described for both the optomotor response and the Y-maze and examples of their use shown in models of Type I and Type II diabetes. Methods include preparation of rodents and equipment, performance of the optomotor response and the Y-maze, and post-test data analysis.
Assuntos
Cognição , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Aprendizagem em Labirinto/fisiologia , Visão Ocular/fisiologia , Animais , Comportamento Animal , Masculino , RatosRESUMO
Diabetic retinopathy (DR) is diagnosed clinically by directly viewing retinal vascular changes during ophthalmoscopy or through fundus photographs. However, electroretinography (ERG) studies in humans and rodents have revealed that retinal dysfunction is demonstrable prior to the development of visible vascular defects. Specifically, delays in dark-adapted ERG oscillatory potential (OP) implicit times in response to dim-flash stimuli (<-1.8 log cd · s/m2) occur prior to clinically recognized DR. Animal studies suggest that retinal dopamine deficiency underlies these early functional deficits. In this study, we randomized individuals with diabetes, without clinically detectable retinopathy, to treatment with either low- or high-dose Sinemet (levodopa plus carbidopa) for 2 weeks and compared their ERG findings with those of control subjects (no diabetes). We assessed dim-flash-stimulated OP delays using a novel handheld ERG system (RETeval) at baseline and 2 and 4 weeks. RETeval recordings identified significant OP implicit time delays in individuals with diabetes without retinopathy compared with age-matched control subjects (P < 0.001). After 2 weeks of Sinemet treatment, OP implicit times were restored to control values, and these improvements persisted even after a 2-week washout. We conclude that detection of dim-flash OP delays could provide early detection of DR and that Sinemet treatment may reverse retinal dysfunction.
Assuntos
Carbidopa/uso terapêutico , Retinopatia Diabética/tratamento farmacológico , Eletrorretinografia/métodos , Levodopa/uso terapêutico , Adulto , Idoso , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/fisiopatologia , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Purpose: To investigate the temporal appearance of retinal, cognitive, and motor deficits in Goto-Kakizaki (GK) rats, a spontaneously occurring, polygenic model of type II diabetes. GK rats develop impaired insulin secretion at 2 weeks and fasting hyperglycemia at 4 weeks. Methods: In male and female GK rats and Wistar controls, glucose tolerance test (hyperglycemia) and electroretinogram (ERG, retinal function) were performed at 4 and 8 weeks of age. Spectral domain-optical coherence tomography (retinal structure) was assessed at 6 weeks. Spatial alternation (cognitive function) and number of entries (exploratory behavior) were assessed via Y-maze at 4, 5, 6, 7, and 8 weeks. Rotarod (motor function) was performed at 4, 6, and 8 weeks. Results: By 4 weeks, the GK rats exhibited significant glucose intolerance (P < 0.001) and retinal deficits, including delays in ERG implicit times (flicker, P < 0.01; oscillatory potentials, P < 0.001). In addition, the GK rats showed greater ERG amplitudes (P < 0.001) and thinner retinas (P < 0.001). At 7 weeks, the GK rats showed deficits in cognitive function (P < 0.001) and exploratory behavior (P < 0.01). However, no motor function deficits were observed by 8 weeks. Interestingly, the male GK rats showed greater hyperglycemia (P < 0.05), but the female rats showed greater ERG delays (P < 0.001). Conclusions: In GK rats, retinal function deficits developed prior to cognitive or motor deficits. Future studies will investigate common mechanistic links, long-term functional and vascular changes, and whether early retinal deficits can predict cognitive dysfunction or late-stage retinal disease.
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Transtornos Cognitivos/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Retinopatia Diabética/diagnóstico , Modelos Animais de Doenças , Transtornos Motores/diagnóstico , Animais , Glicemia/metabolismo , Transtornos Cognitivos/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Retinopatia Diabética/fisiopatologia , Eletrorretinografia , Comportamento Exploratório/fisiologia , Feminino , Teste de Tolerância a Glucose , Hiperglicemia/diagnóstico , Hiperglicemia/fisiopatologia , Masculino , Transtornos Motores/fisiopatologia , Ratos , Ratos Mutantes , Ratos Wistar , Retina/fisiopatologia , Tomografia de Coerência ÓpticaRESUMO
Diseases that affect the eye, including photoreceptor degeneration, diabetic retinopathy, and glaucoma, affect 11.8 million people in the US, resulting in vision loss and blindness. Loss of sight affects patient quality of life and puts an economic burden both on individuals and the greater healthcare system. Despite the urgent need for treatments, few effective options currently exist in the clinic. Here, we review research on promising neuroprotective strategies that promote neuronal survival with the potential to protect against vision loss and retinal cell death. Due to the large number of neuroprotective strategies, we restricted our review to approaches that we had direct experience with in the laboratory. We focus on drugs that target survival pathways, including bile acids like UDCA and TUDCA, steroid hormones like progesterone, therapies that target retinal dopamine, and neurotrophic factors. In addition, we review rehabilitative methods that increase endogenous repair mechanisms, including exercise and electrical stimulation therapies. For each approach, we provide background on the neuroprotective strategy, including history of use in other diseases; describe potential mechanisms of action; review the body of research performed in the retina thus far, both in animals and in humans; and discuss considerations when translating each treatment to the clinic and to the retina, including which therapies show the most promise for each retinal disease. Despite the high incidence of retinal diseases and the complexity of mechanisms involved, several promising neuroprotective treatments provide hope to prevent blindness. We discuss attractive candidates here with the goal of furthering retinal research in critical areas to rapidly translate neuroprotective strategies into the clinic.
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Fármacos Neuroprotetores , Doenças Retinianas/terapia , Animais , Morte Celular/efeitos dos fármacos , Terapia por Estimulação Elétrica , Terapia por Exercício , Humanos , Fatores de Crescimento Neural/farmacologia , Fatores de Crescimento Neural/uso terapêutico , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Retina/efeitos dos fármacos , Ácido Tauroquenodesoxicólico/farmacologia , Ácido Tauroquenodesoxicólico/uso terapêutico , Ácido Ursodesoxicólico/análogos & derivados , Ácido Ursodesoxicólico/farmacologia , Ácido Ursodesoxicólico/uso terapêutico , Transtornos da Visão/prevenção & controleRESUMO
Acoustic blast overpressure (ABO) injury in military personnel and civilians is often accompanied by delayed visual deficits. However, most animal model studies dealing with blast-induced visual defects have focused on short-term (≤1 month) changes. Here, we evaluated long-term (≤8 months) retinal structure and function deficits in rats with ABO injury. Adult male Long-Evans rats were subjected to ABO from a single blast (approximately 190 dB SPL, â¼63 kPa, @80 psi), generated by a shock tube device. Retinal function (electroretinography; ERG), visual function (optomotor response), retinal thickness (spectral domain-optical coherence tomography; SD-OCT), and spatial cognition/exploratory motor behavior (Y-maze) were measured at 2, 4, 6, and 8 months post-blast. Immunohistochemical analysis of glial fibrillary acidic protein (GFAP) in retinal sections was performed at 8 months post-blast. Electroretinogram a- and b-waves, oscillatory potentials, and flicker responses showed greater amplitudes with delayed implicit times in both eyes of blast-exposed animals, relative to controls. Contrast sensitivity (CS) was reduced in both eyes of blast-exposed animals, whereas spatial frequency (SF) was decreased only in ipsilateral eyes, relative to controls. Total retinal thickness was greater in both eyes of blast-exposed animals, relative to controls, due to increased thickness of several retinal layers. Age, but not blast exposure, altered Y-maze outcomes. GFAP was greatly increased in blast-exposed retinas. ABO exposure resulted in visual and retinal changes that persisted up to 8 months post-blast, mimicking some of the visual deficits observed in human blast-exposed patients, thereby making this a useful model to study mechanisms of injury and potential treatments.
Assuntos
Traumatismos por Explosões/patologia , Traumatismos Oculares/patologia , Olho/patologia , Perda Auditiva Provocada por Ruído/patologia , Animais , Traumatismos por Explosões/complicações , Traumatismos por Explosões/diagnóstico por imagem , Eletrorretinografia , Olho/diagnóstico por imagem , Traumatismos Oculares/diagnóstico por imagem , Proteína Glial Fibrilar Ácida/metabolismo , Perda Auditiva Provocada por Ruído/complicações , Perda Auditiva Provocada por Ruído/diagnóstico por imagem , Masculino , Aprendizagem em Labirinto , Músculos Oculomotores/fisiopatologia , Ratos , Ratos Long-Evans , Retina/patologia , Transtornos da Visão/etiologiaRESUMO
BACKGROUND/OBJECTIVE: To determine whether inflammation increases in retina as it does in brain following middle cerebral artery occlusion (MCAO), and whether the neurosteroid progesterone, shown to have protective effects in both retina and brain after MCAO, reduces inflammation in retina as well as brain. METHODS: MCAO rats treated systemically with progesterone or vehicle were compared with shams. Protein levels of cytosolic NF-κB, nuclear NF-κB, phosphorylated NF-κB, IL-6, TNF-α, CD11b, progesterone receptor A and B, and pregnane X receptor were assessed in retinas and brains at 24 and 48âh using western blots. RESULTS: Following MCAO, significant increases were observed in the following inflammatory markers: pNF-κB and CD11b at 24âh in both brain and retina, nuclear NF-κB at 24âh in brain and 48âh in retina, and TNF-α at 24âh in brain.Progesterone treatment in MCAO animals significantly attenuated levels of the following markers in brain: pNF-κB, nuclear NF-κB, IL-6, TNF-α, and CD11b, with significantly increased levels of cytosolic NF-κB. Retinas from progesterone-treated animals showed significantly reduced levels of nuclear NF-κB and IL-6 and increased levels of cytosolic NF-κB, with a trend for reduction in other markers. Post-MCAO, progesterone receptors A and B were upregulated in brain and downregulated in retina. CONCLUSION: Inflammatory markers increased in both brain and retina after MCAO, with greater increases observed in brain. Progesterone treatment reduced inflammation, with more dramatic reductions observed in brain than retina. This differential effect may be due to differences in the response of progesterone receptors in brain and retina after injury.
Assuntos
Encéfalo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Fármacos Neuroprotetores/uso terapêutico , Progesterona/uso terapêutico , Receptores de Progesterona/metabolismo , Retina/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Receptor 1 de Sinal de Orientação para Peroxissomos/metabolismo , Ratos , Ratos Sprague-Dawley , Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de TempoRESUMO
PURPOSE: To determine whether the neurosteroid progesterone, shown to have protective effects in animal models of traumatic brain injury, stroke, and spinal cord injury, is also protective in ocular ischemia animal models. METHODS: Progesterone treatment was tested in two ocular ischemia models in rats: a rodent anterior ischemic optic neuropathy (rAION) model, which induces permanent monocular optic nerve stroke, and the middle cerebral artery occlusion (MCAO) model, which causes transient ischemia in both the retina and brain due to an intraluminal filament that blocks the ophthalmic and middle cerebral arteries. Visual function and retinal histology were assessed to determine whether progesterone attenuated retinal injury in these models. Additionally, behavioral testing and 2% 2,3,5-triphenyltetrazolium chloride (TTC) staining in brains were used to compare progesterone's neuroprotective effects in both retina and brain using the MCAO model. RESULTS: Progesterone treatment showed no effect on visual evoked potential (VEP) reduction and retinal ganglion cell loss in the permanent rAION model. In the transient MCAO model, progesterone treatment reduced (1) electroretinogram (ERG) deficits, (2) MCAO-induced upregulation of glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP), and (3) retinal ganglion cell loss. As expected, progesterone treatment also had significant protective effects in behavioral tests and a reduction in infarct size in the brain. CONCLUSIONS: Progesterone treatment showed protective effects in the retina following MCAO but not rAION injury, which may result from mechanistic differences with injury type and the therapeutic action of progesterone.
Assuntos
Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Neuropatia Óptica Isquêmica/tratamento farmacológico , Progesterona/uso terapêutico , Animais , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Eletrorretinografia/efeitos dos fármacos , Eletrorretinografia/métodos , Potenciais Evocados Visuais/efeitos dos fármacos , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/fisiopatologia , Isquemia/etiologia , Isquemia/patologia , Isquemia/fisiopatologia , Isquemia/prevenção & controle , Masculino , Neuropatia Óptica Isquêmica/complicações , Neuropatia Óptica Isquêmica/fisiopatologia , Ratos Sprague-Dawley , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Vasos Retinianos/patologiaRESUMO
PURPOSE: In vivo methods for detecting oxidative stress in the eye would improve screening and monitoring of the leading causes of blindness: diabetic retinopathy, glaucoma, and age-related macular degeneration. METHODS: To develop an in vivo biomarker for oxidative stress in the eye, we tested the efficacy of a reactive oxygen species (ROS)-activated, near-infrared hydrocyanine-800CW (H-800CW) fluorescent probe in light-induced retinal degeneration (LIRD) mouse models. After intravitreal delivery in LIRD rats, fluorescent microscopy was used to confirm that the oxidized H-800CW appeared in the same retinal layers as an established ROS marker (dichlorofluorescein). RESULTS: Dose-response curves of increasing concentrations of intravenously injected H-800CW demonstrated linear increases in both intensity and total area of fundus hyperfluorescence in LIRD mice, as detected by scanning laser ophthalmoscopy. Fundus hyperfluorescence also correlated with the duration of light damage and functional deficits in vision after LIRD. In LIRD rats with intravitreal injections of H-800CW, fluorescent labeling was localized to photoreceptor inner segments, similar to dichlorofluorescein. CONCLUSIONS: Hydrocyanine-800CW detects retinal ROS in vivo and shows potential as a novel biomarker for ROS levels in ophthalmic diseases.
Assuntos
Corantes Fluorescentes , Oftalmoscopia/métodos , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Degeneração Retiniana/metabolismo , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Corantes Fluorescentes/metabolismo , Camundongos , Microscopia de Fluorescência , Ratos , Ratos Long-EvansRESUMO
Middle cerebral artery occlusion (MCAO) using the intraluminal suture technique is a common model used to study cerebral ischemia in rodents. Due to the proximity of the ophthalmic artery to the middle cerebral artery, MCAO blocks both arteries, causing both cerebral ischemia and retinal ischemia. While previous studies have shown retinal dysfunction at 48h post-MCAO, we investigated whether these retinal function deficits persist until 9days and whether they correlate with central neurological deficits. Rats received 90min of transient MCAO followed by electroretinography at 2 and 9days to assess retinal function. Retinal damage was assessed with cresyl violet staining, immunohistochemistry for glial fibrillary acidic protein (GFAP) and glutamine synthetase, and TUNEL staining. Rats showed behavioral deficits as assessed with neuroscore that correlated with cerebral infarct size and retinal function at 2days. Two days after surgery, rats with moderate MCAO (neuroscore <5) exhibited delays in electroretinogram implicit time, while rats with severe MCAO (neuroscore ≥5) exhibited reductions in amplitude. Glutamine synthetase was upregulated in Müller cells 3days after MCAO in both severe and moderate animals; however, retinal ganglion cell death was only observed in MCAO retinas from severe animals. By 9days after MCAO, both glutamine synthetase labeling and electroretinograms had returned to normal levels in moderate animals. Early retinal function deficits correlated with behavioral deficits. However, retinal function decreases were transient, and selective retinal cell loss was observed only with severe ischemia, suggesting that the retina is less susceptible to MCAO than the brain. Temporary retinal deficits caused by MCAO are likely due to ischemia-induced increases in extracellular glutamate that impair signal conduction, but resolve by 9days after MCAO.