Implications of high homocysteine levels in migraine pain: An experimental study of the excitability of peripheral meningeal afferents in rats with hyperhomocysteinemia.

OBJECTIVES: Investigation of chronic homocysteine action on the excitability and N-methyl-D-aspartate (NMDA) sensitivity of the peripheral trigeminovascular system of rats. BACKGROUND: Migraine is a neurological disease that affects 15%-20% of the general population. Epidemiological observations show that an increase of the sulfur-containing amino acid homocysteine in plasma-called hyperhomocysteinemia-is associated with a high risk of migraine, especially migraine with aura. In animal studies, rats with hyperhomocysteinemia demonstrated mechanical allodynia, photophobia, and anxiety, and higher sensitivity to cortical spreading depression. In addition, rats with hyperhomocysteinemia were more sensitive in a model of chronic migraine induced by nitroglycerin which indicated the involvement of peripheral nociceptive mechanisms. The present work aimed to analyze the excitability of meningeal afferents and neurons isolated from the trigeminal ganglion of rats with prenatal hyperhomocysteinemia. METHODS: Experiments were performed on male rats born from females fed with a methionine-rich diet before and during pregnancy. The activity of meningeal afferents was recorded extracellularly in hemiskull preparations ex vivo and action potentials were characterized using cluster analysis. The excitability of trigeminal ganglion neurons was assessed using whole-cell patch clamp recording techniques and calcium imaging studies. Meningeal mast cells were stained using toluidine blue. RESULTS: The baseline extracellular recorded electrical activity of the trigeminal nerve was higher in the hyperhomocysteinemia group with larger amplitude action potentials. Lower concentrations of KCl caused an increase in the frequency of action potentials of trigeminal afferents recorded in rat hemiskull ex vivo preparations. In trigeminal ganglion neurons of rats with hyperhomocysteinemia, the current required to elicit at least one action potential (rheobase) was lower, and more action potentials were induced in response to stimulus of 2 × rheobase. In controls, short-term application of homocysteine and its derivatives increased the frequency of action potentials of the trigeminal nerve and induced Ca2+ transients in neurons, which are associated with the activation of NMDA receptors. At the same time, in rats with hyperhomocysteinemia, we did not observe an increased response of the trigeminal nerve to NMDA. Similarly, the parameters of Ca2+ transients induced by NMDA, homocysteine, and its derivatives were not changed in rats with hyperhomocysteinemia. Acute incubation of the meninges in homocysteine and homocysteinic acid did not change the state of the mast cells, whereas in the model of hyperhomocysteinemia, an increased degranulation of mast cells in the meninges was observed. CONCLUSIONS: Our results demonstrated higher excitability of the trigeminal system of rats with hyperhomocysteinemia. Together with our previous finding about the lower threshold of generation of cortical spreading depression in rats with hyperhomocysteinemia, the present data provide evidence of homocysteine as a factor that increases the sensitivity of the peripheral migraine mechanisms, and the control of homocysteine level may be an important strategy for reducing the risk and/or severity of migraine headache attacks.

Voluntary Exercise Attenuates Hyperhomocysteinemia, But Does not Protect Against Hyperhomocysteinemia-Induced Testicular and Epididymal Disturbances.

The hyperhomocysteinemia (HHcy) is toxic to the cells and associated with several diseases. Clinical studies have shown changes in plasma concentrations of Hcy after physical exercise. This study aimed to assess the effect of HHcy on testis, epididymis and sperm quality and to investigate whether voluntary exercise training protects this system against damage caused by HHcy in Swiss mice. In this study, 48 mice were randomly distributed in the control, HHcy, physical exercise, and HHcy combined with physical exercise groups. HHcy was induced by daily administration of dl-homocysteine thiolactone via gavage throughout the experimental period. Physical exercise was performed through voluntary running on the exercise wheels. The plasma concentrations of homocysteine (Hcy) and testosterone were determined. The testes and epididymis were used to assess the sperm count, histopathology, lipoperoxidation, cytokine levels, testicular cholesterol, myeloperoxidase, and catalase activity. Spermatozoa were analyzed for morphology, acrosome integrity, mitochondrial activity, and motility. In the testes, HHcy increased the number of abnormal seminiferous tubules, reduced the tubular diameter and the height of the germinal epithelium. In the epididymis, there was tissue remodeling in the head region. Ultimately, voluntary physical exercise training reduced plasma Hcy concentration but did not attenuate HHcy-induced testicular and epididymal disturbances.

Effect of long-term chronic hyperhomocysteinemia on retinal structure and function in the cystathionine-ß-synthase mutant mouse.

Elevated levels of the excitatory amino acid homocysteine (Hcy) have been implicated in retinal diseases in humans including glaucoma and macular degeneration. It is not clear whether elevated Hcy levels are pathogenic. Models of hyperhomocysteinemia (Hhcy) have proven useful in addressing this including mice with deficiency in the enzyme cystathionine ß-synthase (CBS). Cbs+/- mice have a ∼two-fold increase in plasma and retinal Hcy levels. Previous studies of visual function and structure in Cbs+/- mice during the first 10 months of life revealed mild ganglion cell loss, but minimal electrophysiological alterations. It is not clear whether extended, chronic exposure to moderate Hhcy elevation will lead to visual function loss and retinal pathology. The present study addressed this by performing comprehensive analyses of retinal function/structure in 20 month Cbs+/- and Cbs+/+ (WT) mice including IOP, SD-OCT, scotopic and photopic ERG, pattern ERG (pERG), and visual acuity. Eyes were harvested for histology and immunohistochemical analysis of Brn3a (ganglion cells), dihydroethidium (oxidative stress) and GFAP (gliosis). The analyses revealed no difference in IOP between groups for age/strain. Visual acuity measured ∼0.36c/d for mice at 20 months in Cbs+/- and WT mice; contrast sensitivity did not differ between groups at either age. Similarly SD-OCT, scotopic/photopic ERG and pERG revealed no differences between 20 month Cbs+/- and WT mice. There was minimal disruption in retinal structure when eyes were examined histologically. Morphometric analysis revealed no significant differences in retinal layers. Immunohistochemistry revealed ∼5 RGCs/100 µm retinal length in both Cbs+/- and WT mice at 20 months. While there was greater oxidative stress and gliosis in older (20 month) mice versus young (4 month) mice, there was no difference in these parameters between the 20 month Cbs+/- and WT mice. We conclude that chronic, moderate Hhcy (at least due to deficiency of Cbs) is not accompanied by retinal structural/functional changes that differ significantly from age-matched WT littermates. Despite considerable evidence that severe Hhcy is toxic to retina, moderate Hhcy appears tolerated by retina suggesting compensatory cellular survival mechanisms.

Hyperhomocysteinemia: Metabolic Role and Animal Studies with a Focus on Cognitive Performance and Decline-A Review.

Disturbances in the one-carbon metabolism are often indicated by altered levels of the endogenous amino acid homocysteine (HCys), which is additionally discussed to causally contribute to diverse pathologies. In the first part of the present review, we profoundly and critically discuss the metabolic role and pathomechanisms of HCys, as well as its potential impact on different human disorders. The use of adequate animal models can aid in unravelling the complex pathological processes underlying the role of hyperhomocysteinemia (HHCys). Therefore, in the second part, we systematically searched PubMed/Medline for animal studies regarding HHCys and focused on the potential impact on cognitive performance and decline. The majority of reviewed studies reported a significant effect of HHCys on the investigated behavioral outcomes. Despite of persistent controversial discussions about equivocal findings, especially in clinical studies, the present evaluation of preclinical evidence indicates a causal link between HHCys and cognition-related- especially dementia-like disorders, and points out the further urge for large-scale, well-designed clinical studies in order to elucidate the normalization of HCys levels as a potential preventative or therapeutic approach in human pathologies.

Late-onset methylmalonic acidemia and homocysteinemia / Acidemia metilmalónica y homocisteinemia de inicio tardío

Introduction: cobalamin C (Cbl C) deficiency is the most common defect in intracellular cobalamin metabolism, associated with methylmalonic acidemia and homocystinuria. Its late clinical presentation is heterogeneous and may lead to a diagnostic delay. Case report: we report the case of a 45-year-old man with a 20-year history of chronic kidney disease and recently diagnosed spastic paraparesis, both of unknown origin. Metabolic studies revealed elevated levels of homocysteine and methylmalonic acid in the blood and urine. A genetic study confirmed cobalamin C deficiency. Treatment with hydroxocobalamin, betaine, carnitine, and folic acid was started. The patient eventually received a kidney transplant. Discussion: early diagnosis and appropriate treatment improve the clinical evolution of patients with Cbl C deficiency. Determination of homocysteine, organic acids, and other amino acids should be included in the differential diagnosis of patients with nephrological-neurological symptoms without a clear etiology. (AU)

Introducción: la deficiencia de cobalamina C (Cbl C) es el defecto más común en el metabolismo intracelular de la cobalamina, asociado a acidemia metilmalónica y homocistinuria. Su presentación clínica tardía es heterogénea y puede llevar a un retraso en el diagnóstico. Caso clínico: presentamos el caso de un varón de 45 años con 20 años de evolución de enfermedad renal crónica y paraparesia espástica de reciente diagnóstico, ambos de origen desconocido. Los estudios metabólicos revelaron niveles elevados de homocisteína y ácido metilmalónico en sangre y orina. El estudio genético confirmó el déficit de cobalamina C. Se inició tratamiento con hidroxocobalamina, betaína, carnitina y ácido fólico. El paciente pudo recibir un trasplante renal. Discusión: el establecimiento de un diagnóstico precoz y un tratamiento adecuado mejora la evolución clínica de los pacientes con déficit de Cbl C. La determinación de homocisteína, ácidos orgánicos y otros aminoácidos debe incluirse en el diagnóstico diferencial de los pacientes con síntomas nefrológico-neurológicos sin una etiología clara. (AU)

Late-onset methylmalonic acidemia and homocysteinemia.

INTRODUCTION: Introduction: cobalamin C (Cbl C) deficiency is the most common defect in intracellular cobalamin metabolism, associated with methylmalonic acidemia and homocystinuria. Its late clinical presentation is heterogeneous and may lead to a diagnostic delay. Case report: we report the case of a 45-year-old man with a 20-year history of chronic kidney disease and recently diagnosed spastic paraparesis, both of unknown origin. Metabolic studies revealed elevated levels of homocysteine and methylmalonic acid in the blood and urine. A genetic study confirmed cobalamin C deficiency. Treatment with hydroxocobalamin, betaine, carnitine, and folic acid was started. The patient eventually received a kidney transplant. Discussion: early diagnosis and appropriate treatment improve the clinical evolution of patients with Cbl C deficiency. Determination of homocysteine, organic acids, and other amino acids should be included in the differential diagnosis of patients with nephrological-neurological symptoms without a clear etiology.

INTRODUCCIÓN: Introducción: la deficiencia de cobalamina C (Cbl C) es el defecto más común en el metabolismo intracelular de la cobalamina, asociado a acidemia metilmalónica y homocistinuria. Su presentación clínica tardía es heterogénea y puede llevar a un retraso en el diagnóstico. Caso clínico: presentamos el caso de un varón de 45 años con 20 años de evolución de enfermedad renal crónica y paraparesia espástica de reciente diagnóstico, ambos de origen desconocido. Los estudios metabólicos revelaron niveles elevados de homocisteína y ácido metilmalónico en sangre y orina. El estudio genético confirmó el déficit de cobalamina C. Se inició tratamiento con hidroxocobalamina, betaína, carnitina y ácido fólico. El paciente pudo recibir un trasplante renal. Discusión: el establecimiento de un diagnóstico precoz y un tratamiento adecuado mejora la evolución clínica de los pacientes con déficit de Cbl C. La determinación de homocisteína, ácidos orgánicos y otros aminoácidos debe incluirse en el diagnóstico diferencial de los pacientes con síntomas nefrológico-neurológicos sin una etiología clara.

Mild hyperhomocysteinemia induces blood-brain barrier dysfunction but not neuroinflammation in the cerebral cortex and hippocampus of wild-type mice.

This study explored the potential effects of mild hyperhomocysteinemia (HHcy) on the blood-brain barrier (BBB) and neuroinflammation. Seven-week-old male wild-type C57BL/6 mice were fed normal mouse chow (the control group) or a methionine-enriched diet (the HHcy group) for 14 weeks. Mice in the HHcy group exhibited a slight increase in serum Hcy levels (13.56 ± 0.61 µmol/L). Activation of the ERK signaling pathway, up-regulation of matrix metalloproteinase-9 (MMP-9), and degradation of tight junction proteins (occludin and claudin-5) were observed in both the cerebral cortex and hippocampus of mice with mild HHcy. However, microglia were not activated and the levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were not changed in either the cerebral cortex or hippocampus of mice with mild HHcy. Moreover, the signaling activity of STAT3 also did not differ significantly between the two groups. These findings demonstrate that the BBB is highly vulnerable to homocysteine insult. Even a slight increase in serum homocysteine levels up-regulates MMP-9 expression and disrupts the BBB integrity. Meanwhile, microglia activation or the STAT3 pathway might not contribute to the effects of mild HHcy on the brain.

Arterial Blood Pressure Variability and Other Vascular Factors Contribution to the Cognitive Decline in Parkinson's Disease.

Dementia is one of the most disabling non-motor symptoms in Parkinson's disease (PD). Unlike in Alzheimer's disease, the vascular pathology in PD is less documented. Due to the uncertain role of commonly investigated metabolic or vascular factors, e.g., hypertension or diabetes, other factors corresponding to PD dementia have been proposed. Associated dysautonomia and dopaminergic treatment seem to have an impact on diurnal blood pressure (BP) variability, which may presumably contribute to white matter hyperintensities (WMH) development and cognitive decline. We aim to review possible vascular and metabolic factors: Renin-angiotensin-aldosterone system, vascular endothelial growth factor (VEGF), hyperhomocysteinemia (HHcy), as well as the dopaminergic treatment, in the etiopathogenesis of PD dementia. Additionally, we focus on the role of polymorphisms within the genes for catechol-O-methyltransferase (COMT), apolipoprotein E (APOE), vascular endothelial growth factor (VEGF), and for renin-angiotensin-aldosterone system components, and their contribution to cognitive decline in PD. Determining vascular risk factors and their contribution to the cognitive impairment in PD may result in screening, as well as preventive measures.

Hyperhomocysteinemia alters cytokine gene expression, cytochrome c oxidase activity and oxidative stress in striatum and cerebellum of rodents.

AIMS: Homocysteine has been linked to neurodegeneration and motor function impairments. In the present study, we evaluate the effect of chronic mild hyperhomocysteinemia on the motor behavior (motor coordination, functional performance, and muscular force) and biochemical parameters (oxidative stress, energy metabolism, gene expression and/or protein abundance of cytokine related to the inflammatory pathways and acetylcholinesterase) in the striatum and cerebellum of Wistar male rats. MAIN METHODS: Rodents were submitted to one injection of homocysteine (0.03 µmol Hcy/g of body weight) between 30th and 60th postnatal days twice a day. After hyperhomocysteinemia induction, rats were submitted to horizontal ladder walking, beam balance, suspension, and vertical pole tests and/or euthanized to brain dissection for biochemical and molecular assays. KEY FINDINGS: Chronic mild hyperhomocysteinemia did not alter motor function, but induced oxidative stress and impaired mitochondrial complex IV activity in both structures. In the striatum, hyperhomocysteinemia decreased TNF-α gene expression and increased IL-1ß gene expression and acetylcholinesterase activity. In the cerebellum, hyperhomocysteinemia increased gene expression of TNF-α, IL-1ß, IL-10, and TGF-ß, while the acetylcholinesterase activity was decreased. In both structures, hyperhomocysteinemia decreased acetylcholinesterase protein abundance without altering total p-NF-κB, NF-κB, Nrf-2, and cleaved caspase-3. SIGNIFICANCE: Chronic mild hyperhomocysteinemia compromises several biochemical/molecular parameters, signaling pathways, oxidative stress, and chronic inflammation in the striatum and cerebellum of rats without impairing motor function. These alterations may be related to the mechanisms in which hyperhomocysteinemia has been linked to movement disorders later in life and neurodegeneration.

Evaluation of H-type hypertension prevalence and its influence on the risk of increased carotid intima-media thickness among a high-risk stroke population in Hainan Province, China.

H-type hypertension, defined as a combination of hypertension and hyperhomocysteinemia (Hhcy), is associated with atherosclerosis and, therefore, increased stroke risk. However, the role of hypertension and Hhcy in high-risk stroke populations has not been studied. The present study investigated the prevalence of H-type hypertension in a high-risk stroke population of Hainan Province, China and to assess possible joint effects between hypertension and Hhcy for increased carotid intima-media thickness (CIMT). In this community-based cross-sectional study, 959 high-risk stroke subjects (age, 65.8 ±â€Š10.8 years; 46.6% men) were recruited from Hainan Province, China. The demographic and clinical characteristics were collected, and blood samples were obtained. Analysis of variance or chi-square tests were performed to compare variates among groups based on both homocysteine levels and blood pressure status. The associations of hypertension and Hhcy with increased CIMT were evaluated through logistic regression. The prevalence of H-type hypertension was 34.8% in this population, with a higher ratio of H-type hypertension in men than in women. Compared with the normotension and normal homocysteine subgroup, the risk of increased CIMT was significantly higher in the subgroup with hypertension and Hhcy (odds ratio [OR] = 2.639; 95% confidence interval [CI], 1.690-4.091) after adjusting for age and sex. Increased CIMT was affected by an additive synergetic interaction between Hhcy and hypertension (synergy index = 1.105). It emphasized the clinical importance of anti-hypertension and lowering Hhcy in the high-risk stroke population.

Implication of Hyperhomocysteinemia in Blood Retinal Barrier (BRB) Dysfunction.

Elevated plasma homocysteine (Hcy) level, known as hyperhomocysteinemia (HHcy) has been linked to different systemic and neurological diseases, well-known as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD) and has been identified as a risk factor for several ocular disorders, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Different mechanisms have been proposed to explain HHcy-induced visual dysfunction, including oxidative stress, upregulation of inflammatory mediators, retinal ganglion cell apoptosis, and extracellular matrix remodeling. Our previous studies using in vivo and in vitro models of HHcy have demonstrated that Hcy impairs the function of both inner and outer blood retinal barrier (BRB). Dysfunction of BRB is a hallmark of vision loss in DR and AMD. Our findings highlighted oxidative stress, ER stress, inflammation, and epigenetic modifications as possible mechanisms of HHcy-induced BRB dysfunction. In addition, we recently reported HHcy-induced brain inflammation as a mechanism of blood-brain barrier (BBB) dysfunction and pathogenesis of Alzheimer's disease (AD). Moreover, we are currently investigating the activation of glutamate receptor N-methyl-d-aspartate receptor (NMDAR) as the molecular mechanism for HHcy-induced BRB dysfunction. This review focuses on the studied effects of HHcy on BRB and the controversial role of HHcy in the pathogenesis of aging neurological diseases such as DR, AMD, and AD. We also highlight the possible mechanisms for such deleterious effects of HHcy.

Anti-Oxidant and Anti-Endothelial Dysfunctional Properties of Nano-Selenium in vitro and in vivo of Hyperhomocysteinemic Rats.

PURPOSE: Elevation of blood homocysteine (Hcy) level (hyperhomocysteinemia) is a risk factor for cardiovascular disorders and is closely associated with endothelial dysfunction. The present study aims to investigate the protective effect and underlying mechanism of nanoscale selenium (Nano-Se) in Hcy-mediated vascular endothelial cell dysfunction in vitro and in vivo. MATERIALS AND METHODS: By incubating vascular endothelial cells with exogenous Hcy and generating hyperhomocysteinemic rat model, the effects of Nano-Se on hyperhomocysteinemia-mediated endothelial dysfunction and its essential mechanisms were investigated. RESULTS: Nano-Se inhibited Hcy-induced mitochondrial oxidative damage and apoptosis by preventing the downregulation of glutathione peroxidase enzyme 1 and 4 (GPX1, GPX4) in the vascular endothelial cells, thus effectively prevented the vascular damage in vitro and in vivo in the hyperhomocysteinemic rats. Nano-Se possessed similar protective effects but lower toxicity against Hcy in vascular endothelial cells when compared with other forms of Se. CONCLUSION: The application of Nano-Se could serve as a novel promising strategy against Hcy-mediated vascular dysfunction with reduced risk of Se toxicity.

Associations of MTRR A66G polymorphism and promoter methylation with ischemic stroke in patients with hyperhomocysteinemia.

BACKGROUND: Patients with hyperhomocysteinemia (HHcy) have a higher risk of developing ischemic stroke (IS). The association between MTRR A66G polymorphism and promoter methylation with IS in patients with HHcy is also uncertain. The present study aimed to investigate the association between the MTRR polymorphism and methylation with IS in HHcy patients. METHODS: This case-control study included a total of 304 HHcy patients (95 with IS and 209 without IS). Multivariate logistic regression analyses were applied to explore the association between MTRR polymorphism and classical atherothrombotic risk factors with the risk of IS. RESULTS: The log-additive and dominant models were markedly different in participants with IS compared to the control group (p = 0.031 and 0.016, respectively). The log-additive and dominant showed a significant association with IS in the low level plasma homocysteine groups (p = 0.024 and 0.014, respectively). No significant difference of methylation between IS and without IS group (p > 0.05). Patients with high plasma homocysteine had a 4.041-4.941 fold higher risk of IS (p = 0.01, 0.016 and 0.041, respectively) compared to the low plasma homocysteine group. Age, diabetes, hypertension and plasma homocysteine were the risk factors for IS in patients with HHcy (p = 0.033, 0.000, 0.001 and 0.038, respectively). CONCLUSIONS: MTRR A66G polymorphism and an elevated plasma plasma homocysteine level were significantly associated with an increased risk of IS in patients with HHcy. Age, diabetes, hypertension and Hcy were all found to be associated with IS.

Association of Hyperhomocysteinemia with Increased Coronary Microcirculatory Resistance and Poor Short-Term Prognosis of Patients with Acute Myocardial Infarction after Elective Percutaneous Coronary Intervention.

BACKGROUND: This study aims to investigate the coronary microcirculatory resistance and prognosis of patients with acute myocardial infarction (AMI) concomitant with hyperhomocysteinemia (HHcy) after an elective percutaneous coronary intervention (PCI). METHODS: A total of 101 patients that underwent elective PCI between May 2015 and July 2018 due to AMI were consecutively enrolled in this study. Patients were divided into a HHcy group (53) and a normal Hcy group (control; 48) based on their plasma homocysteine concentration. The characteristics of coronary angiography, the index of microcirculatory resistance (IMR) of infarct-related vessels (IRV), changes in left ventricular end diastolic diameter (LVEDd) and left ventricular ejection fraction (LVEF) before and after PCI, and the incidence of major adverse cardiovascular events (MACE) three months after PCI were compared between these groups. RESULTS: Compared to the results from the Hcy group, the HHcy group had a higher IMR. The HHcy group had significantly higher LVEDd and a lower LVEF than the Hcy group 3 months after PCI. Additionally, the incidence of MACE at three months after PCI was higher in the HHcy group than in the Hcy group. Pearson correlation analysis revealed a positive correlation with IMR in the HHcy group. Furthermore, there was a difference in the LVEDd measured at one day after PCI and at three months after PCI in the HHcy group. CONCLUSION: AMI patients concomitant with HHcy that undergo elective PCI are prone to coronary microcirculatory dysfunction and have a poor cardiac function and poor prognosis at three months after PCI.

Genes and genetics in hyperhomocysteinemia and the "1-carbon metabolism": implications for retinal structure and eye functions.

Homocysteine (Hcy), a sulfur-containing nonproteinogenic amino acid, is generated as a metabolic intermediate. Hcy constitutes an important part of the "1-carbon metabolism" during methionine turnover. Elevated levels of Hcy known as hyperhomocysteinemia (HHcy) results from vitamin B deficiency, lack of exercise, smoking, excessive alcohol intake, high-fat and methionine-rich diet, and the underlying genetic defects. These factors directly affect the "1-carbon metabolism (methionine-Hcy-folate)" of a given cell. In fact, the Hcy levels are determined primarily by dietary intake, vitamin status, and the genetic blueprint of the susceptible individual. Although Hcy performs an important role in cellular functions, genetic alterations in any of the key enzymes responsible for the "1-carbon metabolism" could potentially upset the metabolic cycle, thus causing HHcy environment in susceptible people. As such, HHcy relates to several clinical conditions like atherosclerosis, myocardial infarction, stroke, cognitive impairment, dementia, Parkinson's disease, multiple sclerosis, epilepsy, and ocular disorders, among others. This article summarizes the findings from our laboratory and public database regarding genetics of HHcy and its effects on ocular disorders, their respective management during dysregulation of the 1-carbon metabolism.

[Hyperhomocysteinemia and endothelial dysfunction in patients with cerebral vascular and autoimmune diseases]. / Gipergomotsisteinemiia i éndotelial'naia disfunktsiia pri sosudistykh i autoimmunnykh zabolevaniiakh golovnogo mozga.

Endothelial dysfunction today is recognized as one of the leading factors in the pathogenesis of diseases of the central nervous system of various etiologies. Numerous studies have shown the role of hyperhomocysteinemia in the development of endothelial dysfunction and prothrombogenic state. The most important condition in the development of multiple sclerosis (MS) is dysregulation of the blood-brain barrier (BBB) and transendothelial leukocyte migration. It has been proven that homocysteine also contributes to the damage of neurons by the mechanism of excitotoxicity and induction of apoptosis of neurons. These processes can be one of the factors of neurodegenerative brain damage, which plays a leading role in the progression of MS. This review describes the pleiotropic effect of homocysteine on these processes and its role in the pathogenesis of MS.

CHANGES IN ARTERIOLE REACTIVITY TO NORADRENALINE UNDER CONDITIONS OF HYPERHOMOCYSTEINEMIA.

The aim of the research was the experimental study of one of the possible mechanisms performing contractile activity of arterioles in hyperhomocysteinemic animals. Moderate hyperhomocysteinemia was induced in male rats (120-160 g., n=12) by adding L-methionine to the drinking water during 4 weeks. Control animals (n=12) administered the normal water without limitation. The experiments were performed on the isolated arterioles of first line of the rat's soft muscle (Gracilis). Reactions were studied on normal and deendothelized segments of arterioles. Increased homocysteine has been found to be associated with noradrenaline-induced vascular constriction and decreased endothelium-dependent dilatation in the arterioles of the muscle. It has been suggested that the increased reactivity of blood to noradrenaline in animals in the group of hyperhomocysteinemia must have been due to impaired endothelial nitric oxide synthesis.

Model of Moderate Hyperhomocisteinemia Associated with Mechanical Injury: Dynamics of Morphometric Parameters of Microcirculatory Vessels.

A model of moderate hyperhomocysteinemia associated with mechanical injury of the musculoskeletal system was developed and experimentally substantiated. The adequacy of this model for studies of morphological and functional regularities is verified. This model can be used for the development of a new concept of evaluation of thrombotic complications of mechanical injury.

Effect of Intensive Blood Pressure Control on Carotid Morphology and Hemodynamics in Chinese Patients with Hyperhomocysteinemia-Type Hypertension and High Risk of Stroke.

BACKGROUND Different blood pressure targets should be formulated for different groups of people. This study aimed to assess the effectiveness of intensive blood control in improving the carotid morphology and hemodynamics in Chinese patients with hyperhomocysteinemia-type hypertension and high risk of stroke. MATERIAL AND METHODS Chinese hypertensive patients with high risk of stroke were randomized to intensive (n=187) and standard (n=192; controls) blood pressure management groups. Systolic blood pressure (SBP) targets were 100< SBP ≤120 and 120< SBP ≤140 mmHg, respectively. All patients received folic acid 0.8 mg/d and atorvastatin 20 mg/d. Calcium antagonist was first used. If blood pressure was still uncontrolled, angiotensin-converting enzyme inhibitor or angiotensin receptor antagonist, ß-receptor blocker, and diuretics were added successively. Follow-up was 12 months. Carotid features, hemodynamics, and adverse events were examined. RESULTS There were no differences in sex, age, body mass index, blood lipids, baseline carotid parameters, and histories of smoking, diabetes, statin use, and stroke between the 2 groups. Carotid plaques after 12 months of treatment were 19.4±2.1 and 23.6±3.1 cm² for the intensive and control groups, respectively (P=0.038). Plaque scores were lower in the intensive group (1.75±0.52 vs. 2.45±0.47, P=0.023). Compared with controls, intensive management resulted in relatively higher Vd and significantly lower Vs/Vd, PI, and RI (all P<0.05). Major adverse events such as hypotension (n=5 (2.7%) vs. 3 (1.6%), P=0.020) and dizziness (n=20 (10.7%) vs. 16 (8.3%), P=0.041) were more frequent in the intensive group. CONCLUSIONS Intensive blood pressure management could be beneficial for Chinese patients with hyperhomocysteinemia-type hypertension and high risk of stroke.