An important task of pharmacology and ophtalmology is to find specific and highly effective agents for correcting retinal ischemia. The objective of this study is to increase the effectiveness of pharmacological correction of retinal ischemia by using new 3-hydroxypyridine derivative–l-isomer of ethylmethylhydroxypyridine malate. A modification to the retinal ischemia-reperfusion model was used, in which an increase in intraocular pressure is carried out by mechanical pressure (110 mmHg) to the front chamber of the eye for 30 min. The protective effects of l-isomer of ethylmethylhydroxypyridine malate in comparison with Emoxipine as pretreatment, with parabulbar injection, based on the model of retinal ischemia-reperfusion, were estimated by the changes in the ratio of the amplitudes of the a- and b-waves of electroretinography (the b/a coefficient) and ophthalmoscopy. The use of l-isomer of ethylmethylhydroxypyridine malate improves the retinal electrophysiological state after 72 h of reperfusion; in the group of rats treated with l-isomer of ethylmethylhydroxypyridine malate, the coefficient b/a was reliably increased by 9.5%, p < 0.05, in comparison with animals treated with Emoxipine, and by 91.7%, p < 0.05, in comparison with the group with no treatment. Furthermore, it prevents the development of ischemic changes in the retina observed in ophthalmoscopy to a greater extent than Emoxipine.
An important task of pharmacology is to find effective agents to improve retinal microcirculation and resistance to ischemia. The purpose of the study is to pharmacologically evaluate the retinoprotective effect of 2-ethyl-3-hydroxy-6-methylpyridine nicotinate in a rat model of retinal ischemia–reperfusion. A retinal ischemia–reperfusion model was used, in which an increase in intraocular pressure (IOP) to 110 mmHg was carried out within 30 min. The retinoprotective effect of 2-ethyl-3-hydroxy-6-methylpyridine nicotinate at a dose of 3.8 mg/kg, in comparison with nicotinic acid at a dose of 2 mg/kg and emoxipine at a dose of 2 mg/kg, was estimated by the changes in the eye fundus during ophthalmoscopy, the retinal microcirculation level with laser Doppler flowmetry (LDF), and electroretinography (ERG) after 72 h of reperfusion. The use of 2-ethyl-3-hydroxy-6-methylpyridine nicotinate prevented the development of ischemic injuries in the fundus and led to an increase in the retinal microcirculation level to 747 (median) (lower and upper quartiles: 693;760) perfusion units (p = 0.0002) in comparison with the group that underwent no treatment. In the group with the studied substance, the b-wave amplitude increased significantly (p = 0.0022), and the b/a coefficient increased reliably (p = 0.0002) in comparison with the group with no treatment. Thus, 2-ethyl-3-hydroxy-6-methylpyridine nicotinate has established itself as a potential retinoprotector.
Preeclampsia is a severe disease of late pregnancy. Etiological factors and a pathogenetic pattern of events still require significant clarification, but it is now recognized that a large role is played by placentation disorders and emerging endothelial dysfunction. The administration of short-chain peptides mimicking the spatial structure of the B erythropoietin chain may become one of the directions of searching for new drugs for preeclampsia prevention and therapy. Simulation of ADMA-like preeclampsia in Wistar rats was performed by the administration of a non-selective NOS blocker L-NAME from the 14th to 20th day of pregnancy. The administration of the pHBSP at the doses of 10 µg/kg and 250 µg/kg corrected the established morphofunctional disorders. The greatest effect was observed at a dose of 250 µg/kg. There was a decrease in systolic and diastolic blood pressure by 31.2 and 32.8%, respectively (p < 0.0001), a decrease in the coefficient of endothelial dysfunction by 48.6% (p = 0.0006), placental microcirculation increased by 82.8% (p < 0.0001), the NOx concentration was increased by 42,6% (p = 0.0003), the greater omentum edema decreased by 11.7% (p = 0.0005) and proteinuria decreased by 76.1% (p < 0.0002). In addition, there was an improvement in the morphological pattern of the fetoplacental complex and the ratio of BAX to Bcl-2 expression which characterizes the apoptotic orientation of the cells.
Исследовано нейропротективное действие агониста имидазолиновых рецепторов типов I и II, 3-(1H-бензимидазол-2-ил)-1,2,2-триметилциклопентанкарбоновой кислоты, в дозе 50 мг/кг в сравнении с пикамилоном в дозе 30 мг/кг на модели ишемической нейропатии зрительного нерва у крыс-самцов линии Wistar. В эксперименте выявлено, что 3-(1H-бензимидазол-2-ил)-1,2,2-триметилциклопентанкарбоновая кислота предотвращает развитие ишемической нейропатии зрительного нерва, вызванной введением неселективного ингибитора NO-синтазы N-нитро-L-аргинин-метилового эфира (L-NAME) в дозе 12,5 мг/кг в течение 28 сут, и однократным повышением внутриглазного давления (ВГД) до 110 мм рт. ст., в большей степени, чем пикамилон. У крыс в группе с коррекцией 3-(1H-бензимидазол-2-ил)-1,2,2-триметилциклопентанкарбоновой кислотой удельное количество ядер нейронов в наружном ядерном слое достоверно выше на 15,0 % (p < 0,05), в сравнении с группой животных с введением пикамилона; на 33,3 % (p < 0,05), в сравнении с группой с моделированием патологии, что свидетельствует о сохранении их жизнеспособности. Обнаруженные протективные эффекты подтверждены результатами офтальмоскопии и гистологических исследований на 29 сут эксперимента.
General aspects of glaucoma: Glaucoma is a heterogeneous multi-factorial disease that is one of the main causes of blindness, along with degeneration of retinal ganglion cells and optic nerve atrophy. Theories of pathogenesis: There are three theories of glaucoma pathogenesis: biomechanical, vascular, and biochemical. Basic theory of the glymphatic system: The classical knowledge of cerebrospinal fluid circulation has been revised, and in 2012 a new concept of glial-perivascular – glymphatic perfusion of the brain parenchyma was introduced. Due to experimental and clinical studies, it is approved by many scientists, especially in relation to Alzheimer’s disease (AD), in which amyloid pathology is the result of dysfunction of the para-/perivascular transport/cleansing pathways. Features of the optic nerve and the cribriform plate: The cribriform plate forms a barrier at the border of intraocular (IOP) and intracranial (ICP) pressures, thus affecting the para-/periarterial flow of cerebrospinal fluid to the optic nerve and retina, as well as the para-/perivenous cleansing outflow. Morphofunctional evidence of an ocular glymphatic system: The presence of an ocular glymphatic system is confirmed by in vivo experiments with the transfer of labeled substances through para-/perivascular structures from the ventricular or subarachnoid space to the optic nerve and by postmortem morphology. Clinical evidence for the glymphatic system hypothesis: There is some clinical, including case-based, and epidemiological evidence for similarities between glaucomatous optic nerve/retinal injuries and AD, since both occur in the form of improper secretion of neurotoxic metabolites, and both are often diagnosed together.
Introduction: Over the past few years, the incidence of retinal ischemic disorders has been increasing, due to a rising prevalence of such socially burdensome diseases as diabetes and hypertension, which ultimately lead to ocular vascular pathology. The identification of new treatment options that would prevent retinal neuron death is a crucial task of modern pharmacology. Materials and methods: The research was carried out on male Wistar rats. Retinopathy was modeled by inducing a 30-min ischemic episode, with a 72-hour period of reperfusion and subsequent administration of Retinalamin and Emoxypine for 10 days. The effectiveness of the drugs was evaluated by electroretinographic, ophthalmoscopic and morphological assessments. Results and discussion: On Day 14 of the experiment, a dose-dependent preservation of the electroretinogram b-wave/a-wave amplitude ratio was observed in the animals treated with Retinalamin depending on a dose (1.39±0.06, 1.46±0.03 and 1.49±0.04 in low (0.214 mg/kg), medium (0.428 mg/kg) and high (0.857 mg/kg) Retinalamin dose groups, respectively). The ophthalmoscopic picture of the fundus oculi also improved following the treatment with Retinalamin (1.42, 1.69 and 1.90 times lower ophthalmoscopic scores compared to placebo-treated animals in low, medium and high dose groups, respectively). The morphologic “coefficient of change” applied to ganglion cell layer was 2.2, 1.7 and 1.6 points in low, medium and high dose Retinalamin groups, respectively. These results are significantly different from both intact and placebo group (p<0.05). Based on the aforementioned experimental findings, we conclude that Retinalamin has a retinoprotective effect and is superior to the drug of comparison (Emoxypine). Conclusion: The greatest neuroprotective effects were shown in the groups receiving Retinalamin. In these groups, the ERG b-wave/a-wave amplitude ratio was preserved, the ophthalmoscopic picture was less pathologic and retinal morphology features were close to those of the intact retina.
Introduction: The retinoprotective effect of the 11-amino acid fragment of darbepoetin PRK-002 on the models of hypertensive retinal angiopathy and hypertensive neuroretinopathy in Wistar rats was investigated in comparison with carbamylated darbepoetin and sulodexide. Materials and methods: The protective effects of the pharmacological agents were assessed using the following criteria: a semi-quantitative assessment of changes in the eye fundus when performing ophthalmoscopy, the retinal blood flow, the b/a coefficient, eNOs expression in retinal vessels, specific number of neuronal nuclei in the inner nuclear layer, and p53 expression in the retina. Results and discussion: A pronounced protective effect, exceeding sulodexide at a dose of 150 LRU/kg and carbamylated darbepoetin at a dose of 300 μg/kg when correcting retinal angiopathy was observed in PRK-002 at a dose of 4 µg/kg, which expressed in adjustment of the retinal vessels’ calibers, removing retinal arterio-venous crossings, reaching the target levels of the retinal microcirculation, the b/a coefficient, and the restoration of eNOs expression in the endothelium of retinal vessels. PRK-002 at a dose of 4 µg/kg has a pronounced neuroprotective effect comparable to carbamylated darbepoetin at a dose of 300 µg/kg in correction of hypertensive neuroretinopathy, which expressed in the normalization of the fundus image, reaching the b/a target values, the specific number of neuronal nuclei in the inner nuclear layer, inhibition of p53 expression in the neurons of the inner nuclear and ganglionic layers. Conclusion: The study revealed angio- and neuroprotective activity of the 11-amino acid fragment of darbepoetin PRK-002 in correction of retinal injury formed on the background of hypertension.
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