Blood-brain barrier Recent developments and clinical correlations
Department of Neurology, Mayo Clinic, Rochester, MN, USA.Neurology (Impact Factor: 8.29). 04/2012; 78(16):1268-76. DOI: 10.1212/WNL.0b013e318250d8bc
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- "This homeostasis of brain microenvironment is maintained by the blood-brainbarrier (BBB), which represents a dynamic and highly complex interface between the vascular and central nervous systems . The BBB plays a key role in brain homeostasis by tightly controling the exchange between blood and brain compartments  . However, both aging and ADrelated pathology increases the permeability of the BBB  . "
ABSTRACT: Alzheimer's disease (AD) represents the most prevalent form of dementia in the elderly. However, the pathological mechanisms underlying the development and progression of AD are only partially understood. To date, the accumulated clinical and experimental evidence indicate that the locus coeruleus (LC), the main source of brain's norepinephrine, represents "the epicenter" of pathology leading to the development of AD. Evidence for this includes observations that neurons of the LC modulate several processes that are altered in brains of AD patients, including synaptic plasticity, neuroinflammation, neuronal metabolism, and blood-brain-barrier permeability. Moreover, the LC undergoes significant degeneration in the brains of AD patients and is considered a source of the prion-like spreading of tau pathology to forebrain structures innervated by the noradrenergic neurons of the LC. Furthermore, lesions of the LC exaggerate AD-related pathology, while augmentation of the brain's noradrenergic neurotransmission reduces both neuroinflammation and cognitive decline. We hypothesize that better understanding the role of the LC neurons in AD pathogenesis may lead to development of new strategies for the treatment of AD.
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- "Na/H exchange in the blood–brain barrier is prominently sensitive to amiloride and MIA (Murphy and Johanson, 1990; Sipos et al., 2005; Pedersen et al., 2006) and a high binding capacity of MIA has been demonstrated in cerebral microvessels (Kalaria et al., 1998). The endothelial isoforms of Na/H exchangers are located on the luminal side of endothelial cells (Crone, 1986; Goldstein et al., 1986; Redzic, 2011; Benarroch, 2012), and therefore , they are easily accessible to systemically applied Na/H exchange inhibitors, regardless of the drug permeability across the blood–brain barrier. Amiloride is poorly permeable in the blood– brain barrier (Sipos and Brem, 2000; Fisher, 2002; Liu et al., 2010), and notably, our present study shows that amiloride is as effective as MIA in abolishing post-asphyxia seizures. "
ABSTRACT: Birth asphyxia is often associated with a high seizure burden that is predictive of poor neurodevelopmental outcome. The mechanisms underlying birth asphyxia seizures are unknown. Using an animal model of birth asphyxia based on 6-day-old rat pups, we have recently shown that the seizure burden is linked to an increase in brain extracellular pH that consists of the recovery from the asphyxia-induced acidosis, and of a subsequent plateau level well above normal extracellular pH. In the present study, two-photon imaging of intracellular pH in neocortical neurons in vivo showed that pH changes also underwent a biphasic acid-alkaline response, resulting in an alkaline plateau level. The mean alkaline overshoot was strongly suppressed by a graded restoration of normocapnia after asphyxia. The parallel post-asphyxia increase in extra- and intracellular pH levels indicated a net loss of acid equivalents from brain tissue that was not attributable to a disruption of the blood-brain barrier, as demonstrated by a lack of increased sodium fluorescein extravasation into the brain, and by the electrophysiological characteristics of the blood-brain barrier. Indeed, electrode recordings of pH in the brain and trunk demonstrated a net efflux of acid equivalents from the brain across the blood-brain barrier, which was abolished by the Na/H exchange inhibitor, N-methyl-isobutyl amiloride. Pharmacological inhibition of Na/H exchange also suppressed the seizure activity associated with the brain-specific alkalosis. Our findings show that the post-asphyxia seizures are attributable to an enhanced Na/H exchange-dependent net extrusion of acid equivalents across the blood-brain barrier and to consequent brain alkalosis. These results suggest targeting of blood-brain barrier-mediated pH regulation as a novel approach in the prevention and therapy of neonatal seizures.
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ABSTRACT: Objective: To evaluate the significance of circulating tight-junction (TJ) proteins as predictors of hemorrhagic transformation (HT) in ischemic stroke patients. Methods: We examined 458 consecutive ischemic stroke patients, 7.2% of whom had clinically evident HT. None of the patients was treated with thrombolytic drugs. Serum levels of standard markers of blood-brain barrier (BBB) breakdown (S100B, neuron-specific enolase), TJ proteins (occludin [OCLN], claudin 5 [CLDN5], zonula occludens 1 [ZO1]), and molecules involved in BBB disintegration (matrix metalloproteinase 9 and vascular endothelial growth factor [VEGF]) were assessed upon admission to the emergency department. A clinical deterioration caused by HT (cdHT) was defined as an increase of ≥4 points in the NIH Stroke Scale score in combination with a visible HT on a CT scan performed immediately after the onset of new neurologic symptoms. Results: Patients with cdHT had higher concentrations of OCLN, S100B, and the CLDN5/ZO1 ratio, and a lower level of VEGF than those without cdHT. CLDN5 levels also correlated with cdHT occurrence when estimated within 3 hours of stroke onset. We also demonstrated correlations between the levels of circulating TJ molecules and the level of S100B, which is a previously established marker of BBB disruption. Conclusions: Analyzing serum levels of TJ proteins, like CLDN5, OCLN, and CLDN5/ZO1 ratio, as well as S100B and VEGF, is an effective way to screen for clinical deterioration caused by HT in ischemic stroke patients, both within and after the IV thrombolysis time window.
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