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.

Hypertensive encephalopathy mimicking cerebral vasculitis with pontine oedema, cerebellar white matter lesions and multiple cerebral infarctions.

A 47-year-old man with poorly controlled hypertension presented with headaches, right-sided weakness and dysarthria. CT and MRI scans of the brain showed widespread abnormalities including significant pontine oedema, basal ganglia and corona radiata infarctions and cerebellar white matter high signal. Imaging of the intracerebral vasculature also demonstrated wall irregularities. Initially a central nervous system inflammatory disorder was thought to be the most likely diagnosis, possibly acute demyelinating encephalomyelitis or cerebral vasculitis, and the patient was treated with high-dose intravenous steroids. The diagnosis of hypertensive encephalopathy was made because (1) the patient was hypertensive and (2) the patients MRI findings resolved with antihypertensive treatment.Blood pressure treatment was instigated from admission, and the patients symptoms improved with resolution of the radiological abnormalities.

Hypertensive Emergencies in the Emergency Department.

Hypertension affects approximately one-third of Americans. An additional 30% are unaware that they harbor the disease. Significantly increased blood pressure constitutes a hypertensive emergency that could lead to end-organ damage. When organs such as the brain, heart, or kidney are affected, an intervention that will lower the blood pressure in several hours is indicated. Several pharmacologic options are available for treatment, with intravenous antihypertensive therapy being the cornerstone, but there is no standard of care. Careful consideration of each patient's specific complaint, history, and physical examination guides the emergency physician through the treatment algorithm.

[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.

[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.

A case of Liddle's syndrome; unusual presentation with hypertensive encephalopathy.

Liddle's syndrome is a rare cause of secondary hypertension. Identification of this disorder is important because treatment differs from other forms of hypertension. We report an interesting case of a 35-year-old lady, a known diabetic and hypertensive patient, who presented with features of hypertensive encephalopathy. The family history was unremarkable. Past treatment with various combinations of antihypertensive medications including spironolactone, all at high doses, failed to control her blood pressure. Upon evaluation, the patient had hypokalemic alkalosis, low 24-h urine potassium and suppressed plasma renin activity. Although these findings were similar to hyperaldosteronism, plasma aldosterone was lower than the normal range. Blood pressure decreased markedly after administration of amiloride. Along with hyporeninemic hypo-aldosteronism, the non-responsiveness to spironolactone and good response to amiloride established the diagnosis of Liddle's syndrome.

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.

[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.

Hypertension and hypertensive encephalopathy.

The definition of hypertension has continuously evolved over the last 50 years. Hypertension is currently defined as a blood pressure greater than 140/90mmHg. One in every four people in the US has been diagnosed with hypertension. The prevalence of hypertension increases further with age, affecting 75% of people over the age of 70. Hypertension is by far the most common risk factor identified in stroke patients. Hypertension causes pathologic changes in the walls of small (diameter<300 microns) arteries and arterioles usually at short branches of major arteries, which may result in either ischemic stroke or intracerebral hemorrhage. Reduction of blood pressure with diuretics, ß-blockers, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors have all been shown to markedly reduce the incidence of stroke. Hypertensive emergency is defined as a blood pressure greater than 180/120mmHg with end organ dysfunction, such as chest pain, shortness of breath, encephalopathy, or focal neurologic deficits. Hypertensive encephalopathy is believed to be caused by acute failure of cerebrovascular autoregulation. Hypertensive emergency is treated with intravenous antihypertensive agents to reduce blood pressure by 25% within the first hour. Selective inhibition of cerebrovascular blood vessel permeability for the treatment of hypertensive emergency is beginning early clinical trials.

[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.

[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).

[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.

Hypertension crisis in the emergency department.

Hypertensive crises, which include hypertensive emergencies and urgencies, are frequently encountered in the emergency department, and require immediate attention as they can lead to irreversible end-organ damage. Normal blood pressure (BP) regulation is altered during acute rises in BP, leading to end-organ damage. Multiple organs can be injured. Special considerations should be given to hypertensive pregnant patients and patients with postoperative hypertension. Treatment should be individualized to each patient based on the type and extent of end-organ damage, degree of BP elevation, and the specific side effects that each medication could have on a patient's preexisting comorbidities.

Pheochromocytoma: a rare cause of childhood hypertensive encephalopathy.

Pheochromocytomas are rare neuroendocrine tumours of chromaffin tissues. They are catecholamine secreting tumours which cause severe hypertension and other systemic disturbances. Of all the causes of childhood hypertension, pheochromocytoma constitutes less than 1%. We report the case of a 12 years old child who presented with hypertensive encephalopathy, confirmed histologically to be secondary to pheochromocytoma, and cured with meticulous critical care and surgical resection.

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.

Neuroprotection and sex steroid hormones: evidence of estradiol-mediated protection in hypertensive encephalopathy.

Besides their effects on reproduction, estrogens exert neuroprotective effects for brain diseases. Thus, estrogens ameliorate the negative aspects of aging and age-associated diseases in the nervous system, including hypertension. Within the brain, the hippocampus is sensitive to the effects of hypertension, as exemplified in a genetic model, the spontaneously hypertensive rat (SHR). In the dentate gyrus of the hippocampus, SHR present decreased neurogenesis, astrogliosis, low expression of brain derived neurotrophic factor (BDNF), decreased number of neurons in the hilus and increased basal levels of the estrogen-synthesizing enzyme aromatase, with respect to the Wistar Kyoto (WKY) normotensive strain. In the hypothalamus, SHR show increased expression of the hypertensinogenic peptide arginine vasopressin (AVP) and its V1b receptor. From the therapeutic point of view, it was highly rewarding that estradiol treatment decreased blood pressure and attenuated brain abnormalities of SHR, rendering hypertension a suitable model to test estrogen neuroprotection. When estradiol treatment was given for 2 weeks, SHR normalized their faulty brain parameters. This was shown by the enhancement of neurogenesis in the dentate gyrus, according to increased bromodeoxyuridine incorporation and doublecortin labeling, decreased reactive astrogliosis, increased BDNF mRNA and protein expression in the dentate gyrus, increased neuronal number in the hilus of the dentate gyrus and a further hyperexpression of aromatase. The presence of estradiol receptors in hippocampus and hypothalamus suggests the possibility of direct effects of estradiol on brain cells. Successful neuroprotection produced by estradiol in hypertensive rats should encourage the treatment with non-feminizing estrogens and estrogen receptor modulators for age-associated diseases.