Effects of endothelin and vasopressin on cerebral blood vessels

1989 ◽  
Vol 257 (3) ◽  
pp. H799-H803 ◽  
Author(s):  
F. M. Faraci

Endothelin is a recently described peptide which has been suggested to be one type of endothelium-derived contracting factor. The goals of the present study were to examine the effects of endothelin and vasopressin on diameter of cerebral vessels and on permeability of the blood-brain barrier to fluorescein sodium (mol wt of 376). In anesthetized rats, topical suffusion of arginine vasopressin (10(-10) to 10(-7) M) decreased the diameter of pial arterioles, with a reduction of 27 +/- 1% at 10(-7) M in cerebrum and 35 +/- 2% at 10(-8) M for the basilar artery. A low concentration of endothelin (10(-10) M) produced modest (5 +/- 1%) dilatation of pial arterioles. Higher concentrations of endothelin (10(-8) and 10(-7) M) constricted pial arterioles with a reduction in diameter of 22 +/- 5% at 10(-7) M. Dilatation to endothelin was not observed in the basilar artery. The basilar artery constricted to lower doses of vasopressin than endothelin, but vasoconstriction to 10(-7) M endothelin (56 +/- 4%) was greater (P less than 0.05) than that for the same dose of vasopressin. Permeability of the blood-brain barrier to fluorescein sodium was not increased by vasopressin or endothelin. Thus 1) vasopressin produces constriction of brain blood vessels; 2) endothelin produces dilatation of pial arterioles at low doses but constriction at high doses; 3) constrictor responses to both peptides appear to be greater in the brain stem than in the cerebrum; and 4) vasopressin and endothelin do not increase permeability of the blood-brain barrier.

2018 ◽  
Vol 46 ◽  
pp. 3
Author(s):  
Luciana Sonne ◽  
Djeison Lutier Raymundo ◽  
Bianca Santana De Cecco ◽  
Adriana Da Silva Santos ◽  
Caroline Argenta Pescador ◽  
...  

Background: Kernicterus or bilirubin encephalopathy is a condition rarely observed in animal characterized by a yellowish discoloration of the central nervous system. It is a potentially fatal condition due to bilirubin neurotoxic effects caused by the increase of non-conjugated bilirubin pigment, which passes blood brain barrier and has been attributed to an imbalance between albumin and bilirubin levels. Intracellular bilirubin is toxic for cells and can cause decrease in protein synthesis, specially albumin, depression of cell respiration and cellular death. This paper describes kernicterus in a 2-year-old Great Dane female dog.Case: Clinically, the animal showed apathy, lethargy, weight loss and jaundice, which progressed to vomiting and neurological signs characterized by loss of consciousness and eventually coma. Blood parameters were within normal range, except for high levels of alanine aminotransferase (523 U/L), suggesting a liver lesion. The animal was submitted to euthanasia due to the poor prognosis, and at post-mortem examination it showed dehydration and severe jaundice, especially oral, vaginal and ocular mucosas, subcutaneous tissue and blood vessels intima surface. The liver had an accentuated lobular pattern, and the stomach mucosa was reddened. Multiple petechiae were observed in the epicardium, as well as icterus in the blood vessels of the heart. Furthermore, the brain and cerebellum cortex, thalamic region and nuclei region of brainstemshowed extensive icteric areas. Microscopically, the liver presented a mononuclear portal hepatitis, centrilobular necrosis and presence of yellowish pigments. The brain had neuronal necrosis, mild vacuolization of the white matter, perineuronal edema and Alzheimer type II astrocytes, while cerebellum showed Purkinje cells necrosis. Hepatic cooper measurement was within range values, and direct imunofluorescence for the detection of Leptospira sp. was negative.Discussion: Kernicterus pathogenesis has been extensively studied, as the condition is commonly seen in neonatal humans. Diagnosis is based on gross and microscopic lesions in brain, which are consistent with bilirubin encephalopathy caused by the necrosis and degeneration of neurons. This condition is related to cases of intense hyperbilirubinemia, which exceedsthe albumin binding capacity and, therefore, the excess of unconjugated bilirubin that can pass through the blood brain barrier. Liver disease causes deficient production of protein, especially albumin, decreasing the potential binding capacity to bilirubin, and consequently causing hyperbilirubinemia. In this case, the previously detected hepatic lesion suggested by liver enzymes increased, probably led to protein production dysfunction, causing hypoalbuminemia and hyperbilirubinemia. Unfortunately, albumin and bilirubin seric levels could not be measured. Decrease in albumin production along with the excess of unconjugated bilirubin caused the jaundice, and in cases like this one described, the blood brain barrieris compromised and the kernicterus occurs. Unconjugated bilirubin has negative effect in the glutamate uptake causing extracellular accumulation of it, which is consequently neurotoxic, causing necrosis and degeneration leading to a characteristic encephalopathy in animals with kernicterus. In this report, it was not possible to determine the primary hepatic disease, however this caused clinical neurotoxic disease, known as bilirubin encephalopathy.Keywords: kernicterus, icterus, dog.


2021 ◽  
pp. 107385842098583
Author(s):  
Berta Segura-Collar ◽  
Pablo Mata-Martínez ◽  
Aurelio Hernández-Laín ◽  
Pilar Sánchez-Gómez ◽  
Ricardo Gargini

The brain is endowed with a unique cellular composition and organization, embedded within a vascular network and isolated from the circulating blood by a specialized frontier, the so-called blood-brain barrier (BBB), which is necessary for its proper function. Recent reports have shown that increments in the permeability of the blood vessels facilitates the entry of toxic components and immune cells to the brain parenchyma and alters the phenotype of the supporting astrocytes. All of these might contribute to the progression of different pathologies such as brain cancers or neurodegenerative diseases. Although it is well known that BBB breakdown occurs due to pericyte malfunctioning or to the lack of stability of the blood vessels, its participation in the diverse neural diseases needs further elucidation. This review summarizes what it is known about BBB structure and function and how its instability might trigger or promote neuronal degeneration and glioma progression, with a special focus on the role of pericytes as key modulators of the vasculature. Moreover, we will discuss some recent reports that highlights the participation of the BBB alterations in glioma growth. This pan-disease analysis might shed some light into these otherwise untreatable diseases and help to design better therapeutic approaches.


2018 ◽  
Vol 25 (9) ◽  
pp. 1073-1089 ◽  
Author(s):  
Santiago Vilar ◽  
Eduardo Sobarzo-Sanchez ◽  
Lourdes Santana ◽  
Eugenio Uriarte

Background: Blood-brain barrier transport is an important process to be considered in drug candidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, also establishes a restrictive mechanism for the delivery of drugs into the brain. Although there are different and complex mechanisms implicated in drug transport, in this review we focused on the prediction of passive diffusion through the blood-brain barrier. Methods: We elaborated on ligand-based and structure-based models that have been described to predict the blood-brain barrier permeability. Results: Multiple 2D and 3D QSPR/QSAR models and integrative approaches have been published to establish quantitative and qualitative relationships with the blood-brain barrier permeability. We explained different types of descriptors that correlate with passive diffusion along with data analysis methods. Moreover, we discussed the applicability of other types of molecular structure-based simulations, such as molecular dynamics, and their implications in the prediction of passive diffusion. Challenges and limitations of experimental measurements of permeability and in silico predictive methods were also described. Conclusion: Improvements in the prediction of blood-brain barrier permeability from different types of in silico models are crucial to optimize the process of Central Nervous System drug discovery and development.


2020 ◽  
Vol 26 (37) ◽  
pp. 4721-4737 ◽  
Author(s):  
Bhumika Kumar ◽  
Mukesh Pandey ◽  
Faheem H. Pottoo ◽  
Faizana Fayaz ◽  
Anjali Sharma ◽  
...  

Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.


2020 ◽  
Vol 26 (13) ◽  
pp. 1448-1465 ◽  
Author(s):  
Jozef Hanes ◽  
Eva Dobakova ◽  
Petra Majerova

Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The application of potentially effective therapeutics for their successful treatment is hampered by the presence of a naturally occurring brain protection layer called the blood-brain barrier (BBB). BBB represents one of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders, where sufficient BBB penetration is inevitable. BBB is a heavily restricting barrier regulating the movement of molecules, ions, and cells between the blood and the CNS to secure proper neuronal function and protect the CNS from dangerous substances and processes. Yet, these natural functions possessed by BBB represent a great hurdle for brain drug delivery. This review is concentrated on summarizing the available methods and approaches for effective therapeutics’ delivery through the BBB to treat neurodegenerative disorders with a focus on tauopathies. It describes the traditional approaches but also new nanotechnology strategies emerging with advanced medical techniques. Their limitations and benefits are discussed.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 892
Author(s):  
Elisa L. J. Moya ◽  
Elodie Vandenhaute ◽  
Eleonora Rizzi ◽  
Marie-Christine Boucau ◽  
Johan Hachani ◽  
...  

Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a need to develop effective CNS drugs following strategies for delivery to the brain by better selecting them as early as possible during the drug discovery process. The use of in vitro BBB models has proved useful to evaluate the impact of drugs/compounds toxicity, BBB permeation rates and molecular transport mechanisms within the brain cells in academic research and early-stage drug discovery. However, these studies that require biological material (animal brain or human cells) are time-consuming and involve costly amounts of materials and plastic wastes due to the format of the models. Hence, to adapt to the high yields needed in early-stage drug discoveries for compound screenings, a patented well-established human in vitro BBB model was miniaturized and automated into a 96-well format. This replicate met all the BBB model reliability criteria to get predictive results, allowing a significant reduction in biological materials, waste and a higher screening capacity for being extensively used during early-stage drug discovery studies.


Sci ◽  
2021 ◽  
Vol 3 (1) ◽  
pp. 16
Author(s):  
James David Adams

A three-part mechanism is proposed for the induction of Alzheimer’s disease: (1) decreased blood lactic acid; (2) increased blood ceramide and adipokines; (3) decreased blood folic acid. The age-related nature of these mechanisms comes from age-associated decreased muscle mass, increased visceral fat and changes in diet. This mechanism also explains why many people do not develop Alzheimer’s disease. Simple changes in lifestyle and diet can prevent Alzheimer’s disease. Alzheimer’s disease is caused by a cascade of events that culminates in damage to the blood–brain barrier and damage to neurons. The blood–brain barrier keeps toxic molecules out of the brain and retains essential molecules in the brain. Lactic acid is a nutrient to the brain and is produced by exercise. Damage to endothelial cells and pericytes by inadequate lactic acid leads to blood–brain barrier damage and brain damage. Inadequate folate intake and oxidative stress induced by activation of transient receptor potential cation channels and endothelial nitric oxide synthase damage the blood–brain barrier. NAD depletion due to inadequate intake of nicotinamide and alterations in the kynurenine pathway damages neurons. Changes in microRNA levels may be the terminal events that cause neuronal death leading to Alzheimer’s disease. A new mechanism of Alzheimer’s disease induction is presented involving lactic acid, ceramide, IL-1β, tumor necrosis factor α, folate, nicotinamide, kynurenine metabolites and microRNA.


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