Activation of the G Protein-Coupled Estrogen Receptor (GPER) Increases Neurogenesis and Ameliorates Neuroinflammation in the Hippocampus of Male Spontaneously Hypertensive Rats.

It is known that spontaneously hypertensive rats (SHR) present a marked encephalopathy, targeting vulnerable regions such as the hippocampus. Abnormalities of the hippocampus of SHR include decreased neurogenesis in the dentate gyrus (DG), partial loss of neurons in the hilus of the DG, micro and astrogliosis and inflammation. It is also known that 17ß-estradiol (E2) exert neuroprotective effects and prevent hippocampal abnormalities of SHR. The effects of E2 may involve a variety of mechanisms, including intracellular receptors of the ERα and ERß subtypes or membrane-located receptors, such as the G protein-coupled estradiol receptor (GPER). We have now investigated the protective role of GPER in SHR employing its synthetic agonist G1. To accomplish this objective, 5 month-old male SHR received 150 µg/day of G1 during 2 weeks. At the end of this period, we analyzed neuronal progenitors by staining for doublecortin (DCX), and counted the number of glial fibrillary acidic protein (GFAP)-labeled astrocytes and Iba1-stained microglial cells by computerized image analysis. We found that G1 activation of GPER increased DCX+ cells in the DG and reduced GFAP+ astrogliosis and Iba1+ microgliosis in the CA1 region of hippocampus. We also found that the high expression of proinflammatory makers IL1ß and cyclooxygenase 2 (COX2) of SHR was decreased after G1 treatment, which correlated with a change of microglia phenotype from the activated to a resting morphology. Additionally, G1 treatment increased the anti-inflammatory factor TGFß in SHR hippocampus. Altogether, our results suggest that activation of GPER plays a neuroprotective role on the encephalopathy of SHR, an outcome resembling E2 effects but avoiding secondary effects of the natural hormone.

Acute disseminated encephalomyelitis presenting with hypertensive emergency.

We report a 12-year-old girl presenting with acute disseminated encephalomyelitis (ADEM) along with hypertensive emergency. Hypertension persisted for few weeks following recovery and subsided with oral clonidine. Although autonomic instability in ADEM has been reported before, hypertensive emergency was not previously documented as presenting feature of ADEM.

[The influence of citoflavin on molecular mechanisms of hypertensive encephalopathy development in patients with systolic arterial hypertension].

The molecular pharmacological effects of cytoflavin in patients with hypertensive encephalopathy (HE) and isolated systolic arterial hypertension (ISAH) have been investigated using the following methods: assessment of complaints, 24-hour arterial pressure monitoring, ultrasound diagnostics including echocardiography, measurement of lipid profiles and coagulograms, and molecular phenotyping by MALDI-TOF/TOF-MS. A combination of cytoflavin administration with standard therapy of HE and ISAH led to the most expressed return development of clinical symptoms, restoration of the hemodynamic, structural, and geometrical parameters of cardiovascular system, and normalization of the indices of lipid profiles and coagulograms in comparison to patients with HE and ISAH, which accepted only standard therapy. Molecular mechanisms of cytoflavin action have been revealed, which include control of the activity of cellular signaling pathways by means of intermolecular interactions. The optimized therapy of HE and ISAH is recommended for clinical application, which assumes a combined use of standard therapy and cytoflavin and provides a geroprotective action upon the cardiovascular system.

[Efficacy of the energy-modifier cytoflavin in the treatment of patients with hypertensive encephalopathy].

AIM: To evaluate the efficacy of cytoflavin in the treatment of patients with hypertensive encephalopathy (HE). SUBJECTS AND METHODS: One hundred and forty patients aged 39 to 73 years, diagnosed with HE, were examined and randomized to 2 groups. A study group (n = 74) received cytoflavin in a dose of 2 tablets b.i.d. on days 1 to 25 days inclusive during standard basic therapy. A comparison group (n = 66 persons) had standard basic therapy only. A control group consisted of 30 apparently healthy individuals. The investigators studied the frequency of headache, dizziness, and other complaints and the intensity of cephalalgic syndrome, by using a visual analog scale, the quality of life by the Medical Outcomes Study 36-Item Short-Form Health Survey (MOS SF-36) questionnaire, that of sleep by the subjective sleep characteristics questionnaire elaborated at the Moscow City Somnological Center, the level of asthenia by a subjective asthenia rating scale (Multidimensional Fatigue Inventory (MFI-20), and autonomic status, by applying objective and subjective scales on days 1 and 25 of therapy. RESULTS: The study has shown that cytoflavin used in the above dose for 25 days reduces the frequency and magnitude of complaints of headache, dizziness, "venous" complaints, the degree of autonomic and asthenic disorders, and impairments in the quality of sleep and life in the patients with HE at all disease stages. A stepwise discriminant analysis has indicated that the degree of cephalgic syndrome, and autonomic disorders, and worse sleep quality are the most effective points for using the energy-modifier cytoflavin. CONCLUSION: HE treatment based on the current pathogenetic principles may have a preventive impact on the development of HE or slow down the rate of its progression.

[Cytoflavin® effect on endothelium function and cerebral hemodynamics in patients with hypertensive enceplalopathy].

One hundred forty patients (the average age of 46.7 ± 7.7 years) with hypertensive encephalopathy (HE) were observed. 74 patients of the main group received Cytoflavin in a dose of 2 tablets twise a day in the standard basic therapy. 66 patients of the reference group received the basic therapy alone. The arterial endothelium function was estimated and ultrasonic examination of the hemodynamics at five structurally functional levels of the cerebral vascular course was used. All the patients with HE had endothelial dysfunction, bloodstream depression in the arterial course of the brain vascular system, decreased reactivity of the intracranial veins, difficulty in venous outflow. In the course of the therapy with Cytoflavin restotation of the arterial endothelial function in the patients with HE I stage, the linear and volume speed of bloodstream in the main and intracranial cerebral arteries in the patients with HE I-II stages, restoration of the intracranial veins reactivity, the linear speed of bloodstream in intracranial veins in the patients with all three stages of HE, the linear speed of bloodstream in the main veins up to the control values in the patients with I-III stages of HE were observed. Interrelation between the values of the cerebral hemodynamics and the state of the endothelium function was shown.

[Cardiorenal syndrome and prerenal azotemia in patients with acute hypertensive encephalopathy].

AIM: To estimate changes in renal function in patients with acute hypertensive encephalopathy (AHE) during standard inpatient antihypertensive therapy. SUBJECTS AND METHODS: Patients were selected for the trial in the cardiology and admission units of a Perm hospital. The group included 60 patients with AHE. The patients received inpatient antihypertensive therapy for 10-14 days. Within the first 2 hours, enalaprilate 1.25 mg was intravenously injected, by monitoring blood pressure. After 6 hours, the patients were given enalaprilate tablets 20 mg b.i.d. plus hydrochlorothiazide 12.5 mg (Subgroup 1) or nifedipine 60 mg plus hydrochlorothiazide 12.5 mg (Subgroup 2). The laboratory parameters of kidney function were measured twice: on admission to and before discharge from hospital. Plasma creatinine and urea concentrations were estimated. Glomerular filtration rate (GFR) and urea/creatinine ratio were calculated. The patients were found to have proteinurea, low GFR, high plasma creatinine concentrations, and increased urea/creatinine ratio. RESULTS: Transient proteinuria was observed in 25% of the patients with AHE within the first 24 hours of the disease. The proportion of patients with lower GFR was unchanged during a 2-week treatment period (20 and 16%, respectively; p = 0.22). There was a rise in the proportion of patients with higher urea/creatinine ratio (83 and 95%, respectively; p = 0.006). CONCLUSION: The course of AHE is complicated by cardiorenal syndrome (CRS) with transient proteinuria and low GFR, as well as by prerenal azotemia (PRA). The number of patients with PRA increased after 2-week conventional inpatient antihypertensive therapy (enalaprilate + hydrochlorothiazide 12.5 mg or nifedipine + hydrochlorothiazide 12.5 mg).

[Neyromidin in the treatment of stage I hypertensive dyscirculatory encephalopathy].

AIM: To evaluate the efficacy and safety of neyromidin in the treatment of Stage I hypertensive dyscirculatory encephalopathy (HDE) and to analyze long-term treatment results. SUBJECTS AND METHODS: Fifty-seven with Stage I dyscirculatory encephalopathy in the presence of grades 1-2 arterial hypertension were examined. Clinical, psychological, and electrophysiological studies were performed and the efficacy of neyromidin was evaluated using the SANDOS geriatric scale. Neyromidin as monotherapy was used as one tablet (20 mg) b.i.d. during a meal. The duration of course treatment was 3 months. RESULTS: Positive changes in the early manifestations of HDE were observed just on day 45 of therapy. The therapeutic effect of the drug manifested as a reduction in the degree of clinical symptoms. There were positive changes in attention, memory, kinetics, verbal associations, counting. The most noticeable improvement was seen in the values of memory and intellectual processes, suggesting higher working capacity, reduced fatigability, and eliminated sluggishness of intellectual processes. EEG displayed a higher amplitude level, a better response to rhythmic photostimulation, and a total power rise in a- and 8-ranges, which was indicative of the activated effect of neyromidin on the functional state of brain structures. CONCLUSION: Neyromidin (20 mg b.i.d. for 3 months) was shown to be effective and well tolerated. The drug reduced the magnitude of clinical manifestations and improved psychological functions and electrophysiological parameters.

[Cognitive functions and extracranial circulation in patients with hypertonic crisis].

We studied effects of enalaprilate and infedipine therapy on the cognitive functions and extracranial circulation in 60 patients with chronic AH complicated by acute encephalopathy. 10% of them had predemential disorders on day 1 of hospitalization and 90% mild cognitive problems. Half of the patients suffered reduced circulation in the common carotid artery. The contribution of impaired extracranial circulation to cognitive dysfunction in the acute period of hypertonic crisis was higher than that of high SAD and DAD. Antihypertensive therapy improved bloodflow in extracranial vessels, decreased their systolic and diastolic indices but failed to eliminate mild cognitive disorders in 65% of the patients. Visual-spatial orientation was restored more frequently than verbal auditory memory. Enalaprilate and infedipine had similar angio- and cerebroprotective effects but the latter had more pronounced favourable effect on verbal auditory memory than the former. The degree of recovery of cognitive function 2 weeks after hypertonic crisis depended not only on the form of cognitive disorder and therapeutic modality but also on the patient's age. Hemodynamic parameters and age 2 weeks after antihypertensive therapy are predictors of residual cognitive dysfunction soon (2 weeks) after recovery.

Posterior reversible encephalopathy syndrome.

Posterior reversible encephalopathy syndrome (PRES) is characterized by headache, altered mental status, visual disturbances, and seizures. Radiological features typically include edema of the posterior cerebral regions, especially of the parietooccipital lobes. Atypical imaging features, such as involvement of anterior cerebral regions, deep white matter, and the brain stem are also frequently seen. Vasoconstriction is common in vascular imaging. Different conditions have been associated with PRES, but toxemia of pregnancy, solid organ or bone marrow transplantation, immunosuppressive treatment, cancer chemotherapy, autoimmune diseases, and hypertension are most commonly described. The pathophysiology of PRES is unclear and different hypotheses are being discussed. Posterior reversible encephalopathy syndrome is best managed by monitoring and treatment in the setting of a neurointensive care unit. The prognosis is usually benign with complete reversal of clinical symptoms within several days, when adequate treatment is immediately initiated. Treatment of severe hypertension, seizures, and withdrawal of causative agents represent the hallmarks of specific therapy in PRES. Delay in diagnosis and treatment may lead to permanent neurological sequelae. Therefore, awareness of PRES is of crucial importance for the intensivist.

Posterior reversible encephalopathy syndrome in childhood: report of four cases and review of the literature.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a recently described disorder with typical radiological findings of bilateral gray and white matter abnormalities in the posterior regions of the cerebral hemispheres and cerebellum. Its clinical symptoms include headache, decreased alertness, mental abnormalities such as confusion, diminished spontaneity of speech, and changed behavior ranging from drowsiness to stupor, seizures, vomiting, and abnormalities of visual perception such as cortical blindness. In this study, the clinical and radiological findings of 4 children with this syndrome due to a variety of conditions are reported. METHODS: The records of 4 children with a diagnosis of PRES were retrospectively analyzed. RESULTS: PRES is associated with a disorder of cerebrovascular autoregulation of multiple etiologies. Four patients with PRES who had primary diagnoses of severe aplastic anemia, nephritic syndrome, Henoch-Schönlein purpura, and acute poststreptococcal glomerulonephritis are presented. This syndrome has been described in numerous medical conditions, including hypertensive encephalopathy, eclampsia, and with the use of immunosuppressive drugs. CONCLUSIONS: Early recognition of PRES as a complication during different diseases and therapies in childhood may facilitate precise diagnosis and appropriate treatment.

Acute cortical blindness in preeclampsia--a case of reversible posterior encephalopathy syndrome.

BACKGROUND: Cortical blindness is one the most disturbing symptoms of reversible posterior encephalopathy syndrome in preeclamptic and eclamptic patients. The disease has been previously associated with a hypertensive breakthrough in the autoregulation of posterior cerebral arterioles followed by extravasation of the fluid into the brain tissue. CASE: 22-year-old primigravida in the 39th week of gestation diagnosed with gestational diabetes mellitus presented with mild preeclampsia and was admitted to our hospital. Antihypertensive treatment was initiated. Her blood pressure remained between 120/80 to 140/90 mm Hg. Glucose levels were within acceptable range. Before the labor induction she developed acute cortical blindness. Magnetic resonance imaging showed vasogenic edema localized in occipital lobes. Cesarean section was performed and anti-edematous treatment initiated. Blindness resolved by the fifth day postpartum. CONCLUSIONS: Reversible posterior encephalopathy developed in our patient in spite of normalized blood pressure that remained within autoregulation limits. Alternative pathogenesis and precipitating factors are discussed.

Sustained pharmacological inhibition of deltaPKC protects against hypertensive encephalopathy through prevention of blood-brain barrier breakdown in rats.

Hypertensive encephalopathy is a potentially fatal condition associated with cerebral edema and the breakdown of the blood-brain barrier (BBB). The molecular pathways leading to this condition, however, are unknown. We determined the role of deltaPKC, which is thought to regulate microvascular permeability, in the development of hypertensive encephalopathy using deltaV1-1 - a selective peptide inhibitor of deltaPKC. As a model of hypertensive encephalopathy, Dahl salt-sensitive rats were fed an 8% high-salt diet from 6 weeks of age and then were infused s.c. with saline, control TAT peptide, or deltaV1-1 using osmotic minipumps. The mortality rate and the behavioral symptoms of hypertensive encephalopathy decreased significantly in the deltaV1-1-treated group relative to the control-treated group, and BBB permeability was reduced by more than 60%. Treatment with deltaV1-1 was also associated with decreased deltaPKC accumulation in capillary endothelial cells and in the endfeet of capillary astrocytes, which suggests decreased microvasculature disruption. Treatment with deltaV1-1 prevented hypertension-induced tight junction disruption associated with BBB breakdown, which suggests that deltaPKC may specifically act to dysregulate tight junction components. Together, these results suggest that deltaPKC plays a role in the development of hypertension-induced encephalopathy and may be a therapeutic target for the prevention of BBB disruption.

Hypertensive encephalopathy and the blood-brain barrier: is deltaPKC a gatekeeper?

Hypertensive encephalopathy is a life-threatening condition due to elevation of cerebral perfusion pressure beyond the limits of autoregulation. Breakdown of the blood-brain barrier (BBB) leads to cerebral edema and reduced blood flow. In this issue of the JCI, Mochly-Rosen and colleagues demonstrate a novel molecular strategy for preserving the BBB in a model of hypertension-induced encephalopathy (see the related article beginning on page 173). Using a rationally designed peptide inhibitor of deltaPKC, they stabilized the BBB and improved mortality in hypertensive rats. This study highlights the therapeutic potential of deltaPKC inhibitors in hypertensive encephalopathy and provides incentive to elucidate deltaPKC signaling pathways that mediate BBB dysfunction in other disease states.

Posterior reversible encephalopathy syndrome: a case series in patients with eclampsia.

Posterior Reversible Encephalopathy Syndrome (PRES) refers to a clinicoradiologic entity with characteristic features on neuro-imaging and non-specific symptoms comprising headache, confusion, visual disturbances and seizures. The lesions in PRES are thought to be due to vasogenic oedema, predominantly in the posterior cerebral hemispheres, and are reversible with appropriate management. We report 3 cases of acute PRES who had eclampsia and presented with recurrent episodes of seizures and hypertension. Their MRI scan showed diffuse abnormal signal intensities involving predominantly deep white matter of the occipital lobes. Based on the findings the most probable diagnosis of PRES was suggested. They were started on antihypertensive drugs. On follow-up examination after 5-7 weeks, the patients showed marked improvement clinically and on neuro-imaging following which they were discharged in stable condition.

[Impact of antihypertensive therapy on clinical status and quality of life in patients with initial manifestations of hypertensive encephalopathy].

AIM: To study the clinical and instrumental characteristics of hypertensive encephalopathy (HE) in early stages, as well as the time course of their changes during long-term antihypertensive therapy (AHT). SUBJECTS AND METHODS: Prior to and after 9-month AHT, 57 patients aged 50-70 years who had uncomplicated grades 1-2 arterial hypertension (AH) with grades I-II HE underwent comprehensive examination comprising the studies of cognitive functions, quality of life (QL), hemorheology, and hemostasis, duplex scanning of great and intracerebral vessels, echocardiography, 24-hour blood pressure monitoring, magnetic resonance imaging. RESULTS: Early-stage HE was characterized by more cerebral complaints, higher rates of hypertensive crises, a greater degree of psychoautonomic syndrome, and worse QL. Focal brain lesions were detected in 74%; left ventricular hypertrophy (LVH) was diagnosed in 61% of cases. All the patients were observed to have cognitive dysfunctions. AHT (amlodipine, lisinopril) produced a good antihypertensive effect and substantial improvements of the patients' cognitive functions, health status, and QL. LVH regression was achieved. CONCLUSION: HE is a clinical manifestation of damage to the brain as the principal target organ in AH and should be therefore kept in mind in estimating the cardiovascular risk. The diagnosis of HE requires the use of tests to evaluate cognitive functions.

[When should a patient with severe hypertension be referred to the emergency ward?]. / Quand référer aux urgences un patient présentant une elévation sévère de la pression artérielle?

When a severe elevation of blood pressure occurs in conjunction with failure of a target organ, immediate referral of the patient to hospital is an easy decision for the primary care physician. However, when severe elevation of blood pressure is observed in the absence of any significant symptom, it is a much more difficult decision to take. Indeed, if some clinical situations require an immediate and aggressive anti-hypertensive therapy, such a treatment can be clearly deleterious for a number of other cases. This paper attempts to clarify in which situations the primary care physician should refer hypertensive crisis to the emergency department.

Posterior reversible encephalopathy syndrome in intensive care medicine.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a well-recognized clinico-neuroradiological transient condition. Early recognition is of paramount importance for prompt control of blood pressure or removal of precipitating factors and treatment of epileptic seizures or status epilepticus. Delay in the diagnosis and treatment may in fact results in death or in irreversible neurological sequelae. DISCUSSION: PRES is characterized by headache, altered mental status, seizures, and visual disturbances and is associated with a number of different causes, most commonly acute hypertension, preeclampsia/eclampsia, and immunosuppressive agents. Clinical symptoms and neuroradiological findings are typically indistinguishable among the cases of PRES, regardless of underlying cause. Magnetic resonance studies typically show edema involving the white matter of cerebral posterior regions, especially parieto-occipital lobes but frontal and temporal lobes, and other encephalic structures may be involved. CONCLUSIONS: Intensivists and other physicians involved in the evaluation of patients with presumed PRES must be aware of the clinical spectrum of the associated conditions, the diagnostic modalities, and the correct treatment.

Hyperperfusion syndromes: insight into the pathophysiology and treatment of hypertensive encephalopathy.

Hypertensive encephalopathy is one of the manifestations of a hypertensive crisis. It is not the absolute value of the blood pressure that causes the encephalopathy, rather the presence of an abrupt rise in pressure. In terms of clinical and radiographic findings, there are many similarities among a group of entities, including hypertensive encephalopathy, eclampsia, and immunosuppressant neurotoxicity. Hyperperfusion syndromes may represent these clinical disease states that may share the same pathophysiology. Magnetic resonance imaging fluid attenuated inversion recovery sequences have recognized the prominent cortical involvement of the disease that had been previously missed on computed tomography. Studies have found cortical involvement in 94% of their patients, particularly in mild cases. Animal models demonstrate endothelial damage and enhanced pinocytosis in the cortex as reasons why edema may begin in that region of the brain. Patients diagnosed with hypertensive encephalopathy should be diagnosed and treated promptly in order to avoid further neurological complications. The mean arterial pressure should be lowered by 20% to 25% within the first hour of patient presentation, followed by further gradual reduction in blood pressure over the following 24 hours. Hypertensive emergency in acute ischemic stroke should be managed with more caution. According to the 2003 American Stroke Association treatment guidelines, for patients with ischemic stroke not eligible for thrombolytic therapy, target blood pressures are a diastolic blood pressure <120 mmHg and systolic blood pressure <220 mmHg. The systolic pressure must be <185 mmHg and diastolic pressure <110 mmHg at all times if eligible for thrombolytic therapy.

Brainstem involvement in hypertensive encephalopathy: a report of two cases and literature review.

The cerebral hemispheres show prominent involvement in hypertensive encephalopathy far more frequently than the brainstem. Two patients with severe paroxysmally accelerated hypertension associated with brainstem hyperintensity in T2-weighted magnetic resonance images are presented. Both present hyperintense lesions improved dramatically in appearance after stabilization of blood pressure. Extreme acceleration of hypertension may be essential for breakdown of autoregulation in the brainstem circulation. The marked clinicoradiologic dissociation ruled out major brainstem infarction and made tumor unlikely.