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BACKGROUND: Elevated serum vascular endothelial growth factor (VEGF) levels are associated with diabetic retinopathy (DR). Serum VEGF levels correlate with vitreous levels. Neuroretinal changes occur even before the appearance of vascular signs in DR. Role of VEGF as a biomarker for DR has not been assessed. Serum VEGF as a biomarker for severity of DR, was evaluated for the first time. METHODS: Consecutive cases of type 2 diabetes mellitus [without DR, (no DR, n = 38); non-proliferative DR, (NPDR, n = 38); proliferative DR, (PDR, n = 40)] and healthy controls (n = 40) were included. Serum VEGF was measured using enzyme linked immunosorbent assay. Accuracy of VEGF as a biomarker for severity of retinopathy was measured using the area under the receiver operator characteristic (ROC) curve. RESULTS: Serum VEGF levels in controls, No DR, NPDR and PDR groups showed significant incremental trend from 138.96 ± 63.37 pg/ml (controls) to 457.18 ± 165.69 pg/ml (PDR) (F = 48.47; p < 0.001). Serum VEGF levels were observed to be significantly elevated even before DR had set in clinically. ROC for serum VEGF levels was significant in discriminating between the cases and the controls and had good accuracy in discerning between subjects with and without retinopathy. The area under curve (AUC ± SE) for discrimination was significant: (a) cases and controls (n = 156): AUC = 0.858 ± 0.029, p < 0.001; (b) DR (NPDR + PDR) and No DR (n = 116): AUC = 0.791 ± 0.044, p < 0.001; and (c) NPDR and PDR (n = 78): AUC = 0.761 ± 0.056, p < 0.001, with over 90% projected sensitivity and specificity at various cut off values. CONCLUSION: Serum VEGF level is a simple, effective laboratory investigative test in predicting the onset of DR in eyes showing no evidence of DR and serves as a reliable biomolecular biomarker for severity of DR.
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Memory loss is one of the most tragic symptoms of Alzheimer's disease. Our laboratory has recently demonstrated that 'i-Extract' of Ashwagandha (Withania somnifera) restores memory loss in scopolamine (SC)-induced mice. The prime target of i-Extract is obscure. We hypothesize that i-Extract may primarily target muscarinic subtype acetylcholine receptors that regulate memory processes. The present study elucidates key target(s) of i-Extract via cellular, biochemical, and molecular techniques in a relevant amnesia mouse model and primary hippocampal neuronal cultures. Wild type Swiss albino mice were fed i-Extract, and hippocampal cells from naïve mice were treated with i-Extract, followed by muscarinic antagonist (dicyclomine) and agonist (pilocarpine) treatments. We measured dendritic formation and growth by immunocytochemistry, kallikrein 8 (KLK8) mRNA by reverse transcription polymerase chain reaction (RT-PCR), and levels of KLK8 and microtubule-associated protein 2, c isoform (MAP2c) proteins by western blotting. We performed muscarinic receptor radioligand binding. i-Extract stimulated an increase in dendrite growth markers, KLK8 and MAP2. Scopolamine-mediated reduction was significantly reversed by i-Extract in mouse cerebral cortex and hippocampus. Our study identified muscarinic receptor as a key target of i-Extract, providing mechanistic evidence for its clinical application in neurodegenerative cognitive disorders.
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Memória/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Receptor Muscarínico M1/efeitos dos fármacos , Withania/química , Animais , Western Blotting , Dendritos/efeitos dos fármacos , Dendritos/fisiologia , Diciclomina/farmacologia , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Pilocarpina/farmacologia , Receptor Muscarínico M1/agonistas , Receptor Muscarínico M1/antagonistas & inibidores , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Escopolamina/farmacologiaRESUMO
The original version of this article unfortunately contained errors in Fig. 4a. Representative image of b-actin of brain region were copied incorrectly during the preparation of the figures.
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The original version of this article unfortunately contained a mistake. The acknowledgment published was incomplete.
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Extensive use of synthetic pyrethroids has resulted in serious human health issues. Induction of oxidative stress is an important mechanism of action of most pesticides including pyrethroids. In the present study, we have elucidated the possible role of oxidative stress in bifenthrin-induced neurotoxicity. Adult male Wistar rats were administered bifenthrin (3.5 and 7 mg per kg body weight p.o.) for 30 days. Behavioral studies were conducted on a set of randomly selected rats from each treatment group after completion of treatment. Neurochemical parameters were assessed 24 h after the last dose was administered. The selected behavioral and neurochemical endpoints were also assessed 15 days after cessation of exposure to reveal whether the neurobehavioral changes produced by bifenthrin were temporary or permanent. Deficits in motor activity, motor incoordination, and cognitive impairment were observed after exposure to bifenthrin. Levels of biogenic amines viz. dopamine (DA) and its metabolites, i.e. 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), epinephrine (EPN), norepinephrine (NE), and serotonin (5-HT) altered in the frontal cortex, corpus striatum, and hippocampus of bifenthrin-treated rats. A decrease in the activity of acetylcholinesterase (AChE) occurred in all regions of the brain. Both doses of bifenthrin significantly induced lipid peroxidation (LPO) and increased protein carbonyl levels in the frontal cortex, corpus striatum, and hippocampus of rats. The activities of antioxidant enzymes, i.e. catalase, superoxide dismutase, and glutathione peroxidase, were also suppressed in all selected regions of the brain. A trend of recovery was, however, observed in all the behavioral and neurochemical endpoints 15 days after withdrawal of exposure. Oxidative stress seems to play an important role in bifenthrin-induced neurotoxicity. Our study suggests that long-term exposure to these compounds can produce detrimental effects.
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Protective efficacy of curcumin in arsenic induced NMDA receptor dysfunctions and PI3K/Akt/ GSK3ß signalling in hippocampus has been investigated in vivo and in vitro. Exposure to sodium arsenite (in vivo - 20â¯mg/kg, body weight p.o. for 28 days; in vitro - 10⯵M for 24â¯h) and curcumin (in vivo - 100â¯mg/kg body weight p.o. for 28 days; in vitro - 20⯵M for 24â¯h) was carried out alone or simultaneously. Treatment with curcumin ameliorated sodium arsenite induced alterations in the levels of NMDA receptors, its receptor subunits and synaptic proteins - pCaMKIIα, PSD-95 and SynGAP both in vivo and in vitro. Decreased levels of BDNF, pAkt, pERK1/2, pGSK3ß and pCREB on sodium arsenite exposure were also protected by curcumin. Curcumin was found to decrease sodium arsenite induced changes in hippocampus by modulating PI3K/Akt/GSK3ß neuronal survival pathway, known to regulate various cellular events. Treatment of hippocampal cultures with pharmacological inhibitors for ERK1/2, GSK3ß and Akt individually inhibited levels of CREB and proteins associated with PI3K/Akt/GSK3ß pathway. Simultaneous treatment with curcumin was found to improve sodium arsenite induced learning and memory deficits in rats assessed by water maze and Y-maze. The results provide evidence that curcumin exercises its neuroprotective effect involving PI3K/Akt pathway which may affect NMDA receptors and downstream signalling through TrKß and BDNF in arsenic induced cognitive deficits in hippocampus.
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Arsênio/toxicidade , Curcumina/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/metabolismo , Fármacos Neuroprotetores/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Aprendizagem Espacial/efeitos dos fármacos , Aprendizagem Espacial/fisiologiaRESUMO
Proteomic studies were carried out in immature (3 week), adult (18 week) and aged (48 week) rats to understand the age dependent vulnerability to lindane induced neurodegeneration. 2-D and western blot analysis of protein extracts of hippocampus and substantia-nigra isolated from lindane treated rats (2.5â¯mg/kg; p.o. X 21 days) revealed marked dysregulation in the expression of proteins related to ubiquitin proteasome pathway, antioxidant activity, chaperones, energy metabolism, calcium homeostasis and proteins involved in neurodegeneration. These alterations were associated with marked increase in reactive oxygen species formation, lipid peroxidation, reduced glutathione content and antioxidant enzyme activities in lindane treated rats. Aged rats, in particular showed higher magnitude of alteration in these proteins when compared to immature or adult rats. Proteins involved in apoptosis and autophagy also showed marked alterations in their expression, particularly in the aged rats. Ultrastructural analysis revealed greater number of autophagic vesicle in hippocampus and substantia-nigra in treated aged rats. The data suggest that proteomic approaches could be used to investigate the vulnerability to lindane induced neurodegeneration in rats.
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Hexaclorocicloexano/toxicidade , Hipocampo/efeitos dos fármacos , Inseticidas/toxicidade , Proteômica , Substância Negra/efeitos dos fármacos , Fatores Etários , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Western Blotting , Eletroforese em Gel Bidimensional , Glutationa/metabolismo , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Microscopia Eletrônica de Transmissão , Chaperonas Moleculares/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Substância Negra/metabolismo , Substância Negra/ultraestruturaRESUMO
Given increasing risk of cadmium-induced neurotoxicity, the study was conducted to delineate the molecular mechanisms associated with cadmium-induced motor dysfunctions and identify targets that govern dopaminergic signaling in the brain involving in vivo, in vitro, and in silico approaches. Selective decrease in dopamine (DA)-D2 receptors on cadmium exposure was evident which affected the post-synaptic PKA/DARPP-32/PP1α and ß-arrestin/Akt/GSK-3ß signaling concurrently in rat corpus striatum and PC12 cells. Pharmacological inhibition of PKA and Akt in vitro demonstrates that both pathways are independently modulated by DA-D2 receptors and associated with cadmium-induced motor deficits. Ultrastructural changes in the corpus striatum demonstrated neuronal degeneration and loss of synapse on cadmium exposure. Further, molecular docking provided interesting evidence that decrease in DA-D2 receptors may be due to direct binding of cadmium at the competitive site of dopamine on DA-D2 receptors. Treatment with quercetin resulted in the alleviation of cadmium-induced behavioral and neurochemical alterations. This is the first report demonstrating that cadmium-induced motor deficits are associated with alteration in postsynaptic dopaminergic signaling due to a decrease in DA-D2 receptors in the corpus striatum. The results further demonstrate that quercetin has the potential to alleviate cadmium-induced dopaminergic dysfunctions.
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Antioxidantes/farmacologia , Cádmio/toxicidade , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Dopamina/metabolismo , Transtornos dos Movimentos , Quercetina/farmacologia , Receptores de Dopamina D2/metabolismo , Animais , Antioxidantes/uso terapêutico , Corpo Estriado/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Masculino , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/prevenção & controle , Células PC12 , Proteína Fosfatase 1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quercetina/uso terapêutico , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/patologia , Transmissão Sináptica/efeitos dos fármacos , beta-Arrestinas/metabolismoRESUMO
Earlier, protective role of curcumin in arsenic-induced dopamine (DA)-D2 receptor dysfunctions in corpus striatum has been demonstrated by us. In continuation to that, the present study is focused to decipher the molecular mechanisms associated with alterations in dopaminergic signaling on arsenic exposure in corpus striatum and assess the protective efficacy of curcumin. Exposure to arsenic (20 mg/kg, body weight p.o. for 28 days) in rats resulted to decrease the expression of presynaptic proteins-tyrosine hydroxylase and VMAT2 while no effect was observed on the expression of DAT in comparison to controls. A significant decrease in the expression of DA-D2 receptors associated with alterations in the expression of PKA, pDARPP32 (Thr 34), and PP1 α was clearly evident on arsenic exposure. Expression of BDNF and pGSK3ß in corpus striatum was found decreased in arsenic-exposed rats. Simultaneous treatment with curcumin (100 mg/kg, body weight p.o. for 28 days) resulted to protect arsenic-induced alterations in the expression of DA-D2 receptors, PKA, pDARPP32, pCREB, and pPP1α. Neuroprotective efficacy of curcumin can possibly be attributed to its antioxidant potential which significantly protected arsenic-induced mitochondrial dysfunctions by modulating the ROS generation and apoptosis. Modulation in the expression of BDNF and pGSK3ß in corpus striatum by curcumin exhibits the importance of neuronal survival pathway in arsenic-induced dopaminergic dysfunctions. Interestingly, curcumin was also found to protect arsenic-induced ultrastructural changes in corpus striatum. The results exhibit that curcumin modulates BDNF/DARPP32/CREB in arsenic-induced alterations in dopaminergic signaling in rat corpus striatum.
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Arsênio/toxicidade , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corpo Estriado/patologia , Curcumina/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Dopamina/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Corpo Estriado/ultraestrutura , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores Dopaminérgicos/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
The present study is focused to decipher the molecular mechanisms associated with dopaminergic alterations in corpus striatum of developing rats exposed prenatally to lambda-cyhalothrin (LCT), a new generation type II synthetic pyrethroid. There was no significant change in the mRNA and protein expression of DA-D1 receptors at any of the doses of LCT (0.5, 1 and 3mg/kg body weight) in corpus striatum of developing rats exposed prenatally to LCT on PD22 and PD45. Prenatal exposure to LCT (1 and 3mg/kg body weight) resulted to decrease the levels of mRNA and protein of DA-D2 receptors in corpus stratum of developing rats on PD22 as compared to controls. Decrease in the binding of 3H-Spiperone in corpus striatum, known to label DA-D2 receptors was also distinct in developing rats on PD22. These rats also exhibited decrease in the expression of proteins - TH, DAT and VMAT2 involved in pre-dopaminergic signaling. Further, decrease in the expression of DARPP-32 and pCREB associated with increased expression of PP1α was evident in developing rats on PD22 as compared to controls. Interestingly, a trend of recovery in the expression of these proteins was observed in developing rats exposed to LCT at moderate dose (1.0mg/kg body weight) while alteration in the expression of these proteins continued to persist in those exposed at high dose (3.0mg/kg body weight) on PD45 as compared to respective controls. No significant change in the expression of any of these proteins was observed in corpus striatum of developing rats prenatally exposed to LCT at low dose (0.5mg/kg body weight) on PD22 and PD45 as compared to respective controls. The results provide interesting evidence that alterations in dopaminergic signaling on LCT exposure are due to selective changes in DA-D2 receptors in corpus striatum of developing rats. Further, these changes could be attributed to impairment in spontaneous motor activity on LCT exposure in developing rats.
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Encéfalo/efeitos dos fármacos , Dopamina/metabolismo , Inseticidas/administração & dosagem , Nitrilas/administração & dosagem , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Piretrinas/administração & dosagem , Animais , Encéfalo/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Feminino , Inseticidas/toxicidade , Atividade Motora/efeitos dos fármacos , Nitrilas/toxicidade , Gravidez , Piretrinas/toxicidade , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Effect of prenatal exposure to lambda-cyhalothrin (LCT) has been assessed on the integrity of NMDA receptors and associated post-synaptic signalling in hippocampus of developing rats. Decrease in the binding of [3H]-MK 801, known to label NMDA receptors was observed in hippocampus of rats prenatally exposed to LCT (1 and 3mg/kg body weight) on PD22, compared to controls. Consistent with this, decrease in the mRNA and protein expression of NR1 and NR2B subunits of NMDA receptors was evident in rats prenatally exposed to LCT (1 and 3mg/kg body weight) on PD22. There was no change in mRNA and protein expression of NR2A subunit of NMDA receptors. Prenatal exposure to LCT (1 and 3mg/kg body weight) decreased the expression of positive regulators (PSD95, pERK1/2, CaMKIIα & pCREB) and increased the expression of negative regulators (Cdk5 & SynGAP) associated with NMDA receptor dependent synaptic plasticity in hippocampus and impaired learning and memory of rats on PD22. The neurobehavioral changes continued to persist in rats exposed to LCT at high dose (3mg/kg body weight) while exhibited trend of recovery in those exposed at moderate dose (1mg/kg body weight) on PD45, compared to controls. No change in any of the neurobehavioral endpoint was observed in developing rats prenatally exposed to LCT at low dose (0.5mg/kg body weight) on PD22 and PD45. The results exhibit that alterations in NMDA receptors on prenatal exposure to LCT may affect postsynaptic signalling associated with impaired learning and memory in developing rats.
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Hipocampo , Transtornos da Memória/etiologia , Nitrilas/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Piretrinas/toxicidade , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Fatores Etários , Animais , Animais Recém-Nascidos , Maleato de Dizocilpina/farmacologia , Feminino , Fungicidas Industriais/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ensaio Radioligante , Ratos , Ratos Wistar , Sinapses/fisiologiaRESUMO
With the increasing evidences of cadmium-induced cognitive deficits associated with brain cholinergic dysfunctions, the present study aimed to decipher molecular mechanisms involved in the neuroprotective efficacy of quercetin in rats. A decrease in the binding of cholinergic-muscarinic receptors and mRNA expression of cholinergic receptor genes (M1, M2, and M4) was observed in the frontal cortex and hippocampus on exposure of rats to cadmium (5.0 mg/kg body weight, p.o.) for 28 days compared to controls. Cadmium exposure resulted to decrease mRNA and protein expressions of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) and enhance reactive oxygen species (ROS) generation associated with mitochondrial dysfunctions, ultrastructural changes, and learning deficits. Enhanced apoptosis, as evidenced by alterations in key proteins involved in the pro- and anti-apoptotic pathway and mitogen-activated protein (MAP) kinase signaling, was evident on cadmium exposure. Simultaneous treatment with quercetin (25 mg/kg body weight, p.o.) resulted to protect cadmium-induced alterations in cholinergic-muscarinic receptors, mRNA expression of genes (M1, M2, and M4), and expression of ChAT and AChE. The protective effect on brain cholinergic targets was attributed to the antioxidant potential of quercetin, which reduced ROS generation and protected mitochondrial integrity by modulating proteins involved in apoptosis and MAP kinase signaling. The results exhibit that quercetin may modulate molecular targets involved in brain cholinergic signaling and attenuate cadmium neurotoxicity.
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Encéfalo/enzimologia , Encéfalo/fisiopatologia , Cádmio/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/farmacologia , Quercetina/farmacologia , Receptores Muscarínicos/metabolismo , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/ultraestrutura , Colina O-Acetiltransferase/metabolismo , Citocromos c/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/fisiopatologia , Hipocampo/ultraestrutura , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Memória/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Proteína Quinase C beta/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoRESUMO
Experimental studies have been carried out on rats to understand the influence of immobilization stress (IMS), a psychological stressor and forced swim stress (FSS), a physical stressor in the neurotoxicity of lambda-cyhalothrin (LCT), a new generation type II synthetic pyrethroid with extensive applications. No significant change in plasma corticosterone levels and blood brain barrier (BBB) permeability was observed in rats subjected to IMS (one session of 15min/day), FSS (one session of 3min/day) for 28days or LCT treatment (3.0mg/kg body weight, p.o. suspended in groundnut oil) for 3days (26th, 27th and 28th day) as compared to controls. Marginal changes in the levels of biogenic amines and their metabolites (NE, EPN, DA, HVA, DOPAC, 5-HT) in hypothalamus, frontal cortex, hippocampus, and corpus striatum were observed in rats subjected to IMS or FSS or LCT alone as compared to controls. It was interesting to note that pre-exposure to IMS or FSS followed by LCT treatment for 3days caused a marked increase in plasma corticosterone levels associated with disruption in the BBB permeability as compared to rats exposed to IMS or FSS or LCT alone. Pre-exposure to IMS or FSS followed by LCT treatment for 3days resulted to alter the levels of biogenic amines and their metabolites in hypothalamus, frontal cortex, hippocampus, and corpus striatum as compared to rats exposed to IMS or FSS or LCT alone. Although neurochemical changes were more intense in rats pre-exposed to IMS as compared to those subjected to FSS on LCT treatment, the results indicate that both psychological and physical stress could be important influencing factors in the neurotoxicity of LCT.
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Aminas Biogênicas/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Inseticidas/toxicidade , Nitrilas/toxicidade , Piretrinas/toxicidade , Estresse Psicológico/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corticosterona/sangue , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Ratos Wistar , Restrição Física , Estresse FisiológicoRESUMO
PURPOSE: To study the correlation between serum levels of vitamin B12, folic acid, and homocysteine and the severity of diabetic retinopathy and the correlation with retinal nerve fiber layer (RNFL) thinning on spectral domain optical coherence tomography (SD-OCT). METHODS: In a tertiary care center-based prospective cross-sectional study, 60 consecutive cases and 20 healthy controls in the age group of 40-65 years were included. The eyes of the cases were divided into three groups according to Early Treatment Diabetic Retinopathy Study (ETDRS) classification: diabetes mellitus without retinopathy (n = 20), non-proliferative diabetic retinopathy with macular edema (n = 20), and proliferative diabetic retinopathy with macular edema (n = 20). The serum levels of vitamin B12 and folic acid were measured using a standard protocol. The serum homocysteine assay was performed using an enzyme-linked immunosorbent assay (ELISA) kit. Average RNFL thickness was measured using SD-OCT. Statistical analysis was used to assess the correlations between the study variables. RESULTS: Increased severity of diabetic retinopathy was found to correlate with an increase in the serum levels of homocysteine (F = 53.79; p<0.001). The mean serum levels of vitamin B12 and folic acid were found to be within the normal reference range. A positive correlation was found between retinal nerve fiber layer thinning and serum levels of homocysteine (p<0.001). CONCLUSIONS: This study, for the first time, demonstrated a correlation between increased homocysteine with a decrease in RNFL thickness and increased severity of diabetic retinopathy.
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Retinopatia Diabética/sangue , Retinopatia Diabética/diagnóstico , Homocisteína/sangue , Fibras Nervosas/patologia , Células Ganglionares da Retina/patologia , Adulto , Idoso , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Ácido Fólico/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tomografia de Coerência Óptica , Vitamina B 12/sangueRESUMO
BACKGROUND: To evaluate the role of thiobarbituric acid reactive substance (TBARS) and nitric oxide (NO) as biochemical biomarkers and central subfield (CST) and cube average thickness (CAT) as biomarkers for medical imaging in diabetic retinopathy. METHODS: Forty consecutive cases of diabetic retinopathy and 20 healthy controls were included. Cases were divided into two groups: non proliferative diabetic retinopathy (n = 20) and proliferative diabetic retinopathy (n = 20) according to ETDRS classification. LogMAR visual acuity was documented. Plasma levels of TBARS, NO and glycated hemoglobin (HbA1c) were measured using standard protocol. CST and CAT were analyzed on spectral domain optical coherence tomography. Data was analyzed statistically. RESULTS: Increased severity of diabetic retinopathy was associated with an increase in plasma levels of TBARS (F = 10.92; p < 0.001), NO (F = 21.8; p < 0.001) and HbA1c (F = 5.87; p = 0.001). Increase in CST (F = 61.51; p < 0.001) and CAT (F = 60.84; p < 0.001) was also found to be associated with increased severity of diabetic retinopathy. Pearson's correlation analysis revealed a positive correlation of TBARS with CST (r = 0.29; p = 0.038) and CAT (r = 0.31; p = 0.04). A positive correlation of NO with CST (r = 0.27; p = 0.03) and CAT (r = 0.7; p = 0.001) was also observed. On univariate analysis with logMAR visual acuity as dependent variable, a significant increase in visual acuity was observed with increase in independent variables TBARS (B = 0.22; p = 0.004), NO (B = 0.006; p < 0.001), CST (B = 0.005; p < 0.001) and CAT (B = 0.005; p < 0.001). On multivariate linear regression analysis with logMAR visual acuity as dependent variable and adjusting for other factors like duration of diabetes and HbA1c, it was observed that increase in independent variables TBARS (B = 0.07), NO (B = 0.001) and CST (B = 0.004) independently predict increase in logMAR visual acuity (p < 0.001). CONCLUSION: Thiobarbituric acid reactive substance and nitric oxide serve as potential biochemical markers whereas central subfield and cube average thickness serve as potential biomarkers for medical imaging for severity of diabetic retinopathy. In a clinical retinal setting, CAT and CST will help in early recognition of increase in severity of diabetic retinopathy.
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Role of immobilization stress (IMS), a psychological stressor and forced swim stress (FSS), a physical stressor was investigated on the neurobehavioral toxicity of lambda-cyhalothrin (LCT), a new generation type-II synthetic pyrethroid. Pre-exposure of rats to IMS (15 min/day) or FSS (3 min/day) for 28 days on LCT (3.0 mg/kg body weight, p.o.) treatment for 3 days resulted to decrease spatial learning and memory and muscle strength associated with cholinergic-muscarinic receptors in frontal cortex and hippocampus as compared to those exposed to IMS or FSS or LCT alone. Decrease in acetylcholinesterase activity, protein expression of ChAT and PKC-ß1 associated with decreased mRNA expression of CHRM2, AChE and ChAT in frontal cortex and hippocampus was also evident in rats pre-exposed to IMS or FSS on LCT treatment, compared to rats exposed to IMS or FSS or LCT alone. Interestingly, changes both in behavioral and neurochemical endpoints were marginal in rats subjected to IMS or FSS for 28 days or those exposed to LCT for 3 days alone, compared to controls. The results suggest that stress is an important contributor in LCT induced cholinergic deficits.
Assuntos
Encéfalo/metabolismo , Imobilização , Nitrilas/administração & dosagem , Piretrinas/administração & dosagem , Receptores Colinérgicos/metabolismo , Estresse Fisiológico , Natação , Animais , Comportamento Animal , Masculino , Ratos , Ratos WistarRESUMO
PURPOSE: To correlate serum levels of N-epsilon-carboxy methyl lysine (N(ε)-CML) with severity of retinopathy, in vivo macular edema and disruption of external limiting membrane (ELM) and photoreceptor ellipsoid zone in type 2 diabetes mellitus (DM). METHODS: Consecutive cases of type 2 DM [diabetes mellitus with no retinopathy (No DR) (n=20); non- proliferative diabetic retinopathy (NPDR) with diabetic macular edema (n=20); proliferative diabetic retinopathy with diabetic macular edema (PDR) (n=20)] and healthy controls (n=20) between the ages of 40 and 65 years were included (power of study=93.8%). In vivo histology of retinal layers was assessed using spectral domain optical coherence tomography. Every study subject underwent macular thickness analysis using the macular cube 512×128 feature. Disruption of ELM and photoreceptor ellipsoid zone was graded: grade 0, no disruption of ELM and ellipsoid zone; grade 1, ELM disrupted and ellipsoid zone intact; grade 2, both ELM and ellipsoid zone disrupted. Data were statistically analyzed. RESULTS: The mean levels of N(ε)-CML were 31.34±21.23 ng/ml, 73.88±35.01 ng/ml, 91.21±66.65 ng/ml, and 132.08±84.07 ng/ml in control, No DR, NPDR and PDR respectively. N(ε)-CML level was significantly different between the study groups (control, No DR, NPDR and PDR) (p<0.001). Mean logMAR visual acuity decreased with increased levels of N(ε)-CML (p<0.001). The association of N(Æ)CML with the grades of disruption was found to be statistically significant (F value=18.48, p<0.001). Univariate analysis was done with N(Æ)-CML as a dependent variable. The values of N(Æ)-CML were normalized (log10) and were subjected to univariate analysis with fasting blood glucose level, glycosylated hemoglobin, central subfield macular thickness and cube average thickness among the diseased groups (NPDR and PDR) that act as confounders. It was found that none of the variables had significant effect on N(Æ)-CML (fasting blood glucose p=0.12, HBA1c p=0.65, central subfield macular thickness p=0.13, cube average thickness p=0.19). N(Æ)-CML tends to be a significant and important predictor of grade of ELM and ellipsoid zone disruption in diabetic retinopathy. CONCLUSIONS: Increased N(ε)-CML levels are associated with increased severity of diabetic retinopathy, macular edema and structural changes in macula that is ELM and ellipsoid zone disruption, which serves as a prognosticator of visual outcome.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/sangue , Lisina/análogos & derivados , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Retinopatia Diabética/patologia , Feminino , Humanos , Lisina/sangue , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
Human exposure to monocrotophos, an organophosphate pesticide, could occur due to its high use in agriculture to protect crops. Recently, we found that postlactational exposure to monocrotophos impaired cholinergic mechanisms in young rats and such changes persisted even after withdrawal of monocrotophos exposure. In continuation to this, the effect of monocrotophos on noncholinergic targets and role of oxidative stress in its neurotoxicity has been studied. Exposure of rats from postnatal day (PD)22 to PD49 to monocrotophos (0.50 or 1.0 mg kg(-1) body weight, perorally) significantly impaired motor activity and motor coordination on PD50 as compared to controls. A significant decrease in the binding of (3)H-spiperone to striatal membrane (26%, p < 0.01; 30%, p < 0.05) in rats exposed to monocrotophos at both the doses and increase in the binding of (3)H-ketanserin to frontocortical membrane (14%, p > 0.05; 37%, p < 0.05) in those exposed at a higher dose, respectively, was observed on PD50 compared with the controls. Alterations in the binding persisted even after withdrawal of monocrotophos exposure on PD65. Increased oxidative stress in brain regions following exposure of rats to monocrotophos was also observed on PD50 that persisted 15 days after withdrawal of exposure on PD65. The results suggest that monocrotophos exerts its neurobehavioral toxicity by affecting noncholinergic functions involving dopaminergic and serotonergic systems associated with enhanced oxidative stress. The results also exhibit vulnerability of developing brain to monocrotophos as most of the changes persisted even after withdrawal of its exposure.
Assuntos
Encéfalo/efeitos dos fármacos , Monocrotofós/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Animais , Comportamento Animal , Feminino , Ratos , Ratos WistarRESUMO
Beta-cyfluthrin (CYF) is a commonly used synthetic pyrethroid having both agricultural and domestic applications. The present study aimed to evaluate the neurobehavioural effects of beta-cyfluthrin in adult rats administered at doses 25 mg/kg body weight/day and 12.5 mg/kg body weight/day for a period of 30 days. Motor coordination and spatial memory were found to be impaired by beta-cyfluthrin. Levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), epinephrine (EPN), and serotonin (5-HT) decreased in frontal cortex, corpus striatum and hippocampus of treated rats. At the same time, significantly elevated levels of homovanillic acid (HVA) and nor-epinephrine (NE) were measured. Beta-cyfluthrin inhibited the activity of acetylcholinesterase (AChE) in all the regions of the brain. Hippocampal choline acetyltransferase (ChAT) expression was reduced 3.1 and 4.7 fold by the two doses respectively. Impairment of the antioxidant defense system, evident by decrease in the levels of antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) was seen in the treated rats. The neurochemical alterations manifested were more pronounced in the high dose group as the effects persisted even after withdrawal of exposure.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Inseticidas/toxicidade , Nitrilas/toxicidade , Piretrinas/toxicidade , Memória Espacial/efeitos dos fármacos , Acetilcolinesterase/análise , Acetilcolinesterase/metabolismo , Animais , Encéfalo/metabolismo , Catalase/análise , Catalase/metabolismo , Dopamina/análise , Dopamina/metabolismo , Feminino , Glutationa Peroxidase/análise , Glutationa Peroxidase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Serotonina/análise , Serotonina/metabolismo , Superóxido Dismutase/análise , Superóxido Dismutase/metabolismoRESUMO
Correlation of increased levels of serum urea and creatinine with retinal nerve fibre layer (RNFL) thinning on spectral domain optical coherence tomography (SD-OCT) was studied in diabetic retinopathy (DR). Sixty consecutive cases and 20 healthy controls were included. Cases were divided into three groups: without DR, non-proliferative DR with macular oedema and proliferative DR with oedema. Serum urea and creatinine were measured using a standard protocol. Average (RNFL) was measured using SD-OCT. Increased severity of DR was associated with decrease in levels of serum urea and serum creatinine levels. RNFL thinning correlated positively with increase in serum urea and creatinine levels.