Damir Janigro

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..Because of a significant overlap in substrates between P-glycoprotein and RLIP76, present studies were carried out to determine the potential role of RLIP76 in AED transport in the brain...

..The aim of the present study is to test the hypothesis that permeability of several MDR1 over-expressing tumor cell lines to the chemotherapic agent doxorubicin is enhanced by low frequency, low intensity AC stimulation...

..This hypothesis is supported by the fact that the ketogenic diet is the treatment of choice for the glucose transporter protein syndrome and pyruvate dehydrogenase deficiency, both associated with cerebral energy failure and seizures...

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..Pretreatment with ibuprofen (0.125 mmol/L) prevented BBB failure by decreasing the inflammatory response after flow cessation/reperfusion...

..However, a confounding factor was the presence of BBB changes due to cerebrovascular disease...

..We have evaluated the cerebrovascular CYP expression and function, hypothesizing possible implication in drug-resistant epilepsy...

..Our data suggest that neither acute-induced nor chronic seizures correlate with WBC brain parenchymal migration while albumin and IgG brain leakage is a hallmark of acute and chronic seizures...

..However, evidences also suggest that BBB failure may be an etiological factor contributing to the development of seizures...

..We tested the hypothesis that lipophilic and hydrophilic drug distribution is differentially affected by BBB damage...

..We have evaluated the pattern of expression of the specific enzyme CYP3A4 and studied its co-localization with MDR1. We also determined whether an association exists between CYP3A4 expression and cell survival...

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..We also observed abluminal extravasation of monocytes but only when the BBB was breached. In conclusion, the DIV-BBBr represents the most realistic in vitro system to study the immune cell trafficking across the BBB...

..In conclusion, loss of flow (flow cessation/reperfusion) independent of hypoxia-hypoglycemia plays a significant role in blood-brain barrier failure by stimulating leukocyte-mediated inflammatory mechanisms...

..Animals pre-treated with IL-1ra exhibited significant reduction of SE onset and of BBB damage. Our data support the concept of targeting systemic inflammation and BBB for the prevention of status epilepticus...

..Our data suggest that a drug resistant BBB not only impedes drug access to the brain but may also allow the formation of neurotoxic metabolites...

..Secondary, massive elevations in S100beta are indicators of prior brain damage and bear clinical significance as predictors of poor outcome or diagnostic means to differentiate extensive damage from minor, transient impairment...

..We tested the hypothesis that immunosupression by splenectomy or lack of perforin, a downstream factor of natural killer (NK) and cytotoxic T cells, could reduce seizure onset...

..Since various antiepileptic drugs (AEDs) can act as substrates for MDR1, the enhanced expression/function of this protein may increase their active extrusion from the brain, resulting in decreased responsiveness to AEDs...

..Brain stimulators currently used for the treatment of neurological disorders may thus also be used for the treatment of brain (or other) tumors...

..We conclude that, in addition to proinflammatory changes, BBB failure may also trigger protective release of alpha2M by perivascular astrocytes as well as peripheral source...

..With the use of a well established humanized dynamic in vitro BBB model and cDNA microarrays, we have profiled the effect of SS in the induction/suppression of ECs genes and related functions...

..A promising approach is the use of corticosteroids that may have a dual beneficial effect. Resective brain surgery remains the ultimate and highly successful approach to multiple drug resistance in epileptic patients...

..This second line of defense for xenobiotics may have profound implications for the pharmacokinetic properties of antiepileptic drugs and their capacity to reach neuronal targets...

..We will present clinical and laboratory evidence supporting the use of these markers as modern neurodiagnostic tools...

..Transcranial Doppler was used to monitor cerebral blood flow. EEG recordings were used to detect seizures. Immunocytochemical detection (Cresyl Violet, anti-human CD8 for TALL-104, Evans Blue for BBB damage, GFAP and NEUN) was performed...

..The extent of such peripheral events and the contribution to SE are unknown and the possibility that pilocarpine also induces SE by peripheral actions is yet untested...

..Further experiments will confirm the efficacy of this treatment in vivo and elucidate the pathways that lead to BBB repair after exposure to GPI...

..Others reported a possible link between inflammation, a microgliosis and the blood-brain barrier (BBB) in suicidal patients. Serum S100B is a marker of BBB function commonly used to study cerebrovascular wall function...

..Maintenance of BBB function during and following NNFC appears to depend on intact NO signaling and IL-6 release...

..Finally, a link between P450 and MDT expression in the diseased brain and cell survival is discussed...

..Taken together, our results support the hypothesis that multiple drug resistance to AEDs involves cerebrovascular changes that impede the achievement of appropriate drug levels in the central nervous system...

..These data indicate that blood leukocytes and loss of flow are major factors in the activation of MMP-2, and that cytokine-mediated differential regulation of TIMP-1 and TIMP-2 may contribute significantly to BBB failure...

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..The mechanism encompasses improvement of BBB integrity. Our results also suggest that add on GCs could be of efficacy in controlling pediatric drug resistant seizures...

..In this article we will review the relationships between BBB function and epilepsy. In particular, we will illustrate consensus and divergence between clinical reality and animal studies...

..We also present BBB neuroimaging as a tool to correlate BBB restoration to seizure mitigation. Add-on cerebrovascular drug could be of efficacy in reducing seizure burden when used in association with neuronal antiepileptic drugs...

..The fact that the BBB plays an etiologic role in other neurological diseases will be discussed in the context of a more "holistic" approach to the patient with epilepsy, where comorbidity variables are also encompassed by drug therapy...

..This review summarizes the most recent data related to cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in blood-brain barrier homeostasis and pathophysiology...

..We also discuss the potential toxicity of recently marketed "potential-reduced exposure products"...

..NR2B may constitute a target for new diagnostic and pharmacotherapeutic approaches...

..Because TTR is localized primarily in choroid plexus and, as a soluble monomer, in CSF, we concluded that although S-100beta is a marker of BBB integrity, TTR instead may be a peripheral tracer of blood-to-cerebrospinal barrier...

..Herein we provide a detailed review and discussion of currently employed in vitro BBB models along with probable future developments...

..These techniques for both "reading" and "writing" the BBB will help new and old medications to reach their pharmacological targets in the CNS...

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..We aimed to determine if the presence of small vessel ischemic disease (SVID) of the brain is protective against the development of brain metastases in lung cancer patients...

..The data on the roles of the glutamate, GABA, acetylcholine, and adenosine receptors is discussed. The recent information on the role of glial cells in the expression of epileptogenicity is reviewed...

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..The correlation of serum S100B, auto-antibodies and DTI changes support a link between repeated BBBD and future risk for cognitive changes...

..These preliminary results demonstrate that APOE epsilon4 is associated with an increased risk of postictal confusion in patients with medically intractable TLE, suggesting possible dysfunction in neuronal recovery mechanisms...

..TSP-4 had not previously been implicated in vascular pathology, and very little information is available on its expression and functions...

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..Collectively, this mini review surveys investigations of head trauma involving altered mechanisms of synaptic plasticity and how trauma may be related to increased risk for dementia...

..Studies have reported an increased risk for suicide in adults with schizophrenia, but limited data on younger populations are available...

..These changes may explain longevity and antioxidant efficiency of ECs and may provide insight in mechanisms leading to pathological conditions such as arteriosclerosis...

..CONCLUSIONS: Complex MDR expression changes may play a role in AEDs pharmacoresistance by altering the permeability of AEDs across the BBB...

..We conclude that glucose transport at the CNS/blood interface appears to be dependent on and regulated by a serial chain of membrane-bound and intracellular transporters and enzymes...

..These morphological abnormalities gradually disappeared at adult stages. Although the adult MAM-THAL rats showed normal cortical morphology, abnormal hippocampal connectivity and mossy fiber sprouting persisted well into adulthood...

..We conclude that in addition to neuronal and glial heterogeneity, cortical structures are also endowed with region-specific vascular patterns characterized by distinct pathophysiological responses...

..Serum S-100beta increased significantly after mannitol infusion (P<0.05) while NSE did not. This suggests that S-100beta is an early marker of BBB opening that is not necessarily related to neuronal damage...

..As discussed here, the field is replete with controversies and false starts, in particular as it concerns the existence of genetic predisposition to inadequate pharmacological seizure control...

..Other apoptotic markers were also absent in epileptic glia.Our results suggest a possible link between loss of p53 function and expression of multiple drug resistance in non-tumor CNS cells...

..In conclusion, TS is a strong vascular inflammatory primer that can facilitate the loss of BBB function and viability in pathological settings involving a local transient loss of cerebral blood flow such as during ischemic insults...

..P-gp may play a role in the pharmacoresistance to OXC by determining the attainment of insufficient concentrations of its active metabolite at neuronal targets...

..This complicates interpretation of drug resistance in epilepsy, and therapeutic strategies...

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..These studies indicate that SIV can persist in MVEC without overtly compromising BBB function, and suggest that the DIV-BBB will be a highly valuable and suitable model for studies of HIV neuropathogenesis...

..Objectives of this study were (1) to quantify S100 beta levels in serum and pericardial cavity during coronary artery bypass grafting (CABG), and (2) to identify proteins recognized by standard immunodetection as S100beta...

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..In the present study, the authors explored the effect of adenosine on EAA transport across the BBB...

..Larger prospective studies may better determine the true specificity of S100beta as a marker for BBB function and as an early detection or follow-up marker of brain tumors...

..In conclusion, these data indicate that in addition to inhibiting nucleoside efflux across the barrier, dipyridamole can also improve blood-brain barrier function in this model...

..In particular, we are investigating how changes in blood-brain barrier function may drive glia and neurons into an "epileptic" phenotype. ..

..Finally, we will validate the usefulness of these markers in the early detection of recurrent brain tumors or metastases, to specifically address one of the mandates of this PA. ..

..g. Alzheimer's, demyelinating diseases, brain tumors). ..

..The outcome of the proposed experiments may be useful for further extrapolations applicable to other physiological aspects of glia(c)neuronal interactions. ..

..2) To elucidate the mechanisms of potassium-mediated dilations in vivo. These studies will allow better understanding on neuronal-vascular interactions and will open new perspectives for the treatment of neurological diseases. ..

..Finally, we will validate the usefulness of these markers in the early detection of recurrent brain tumors or metastases, to specifically address one of the mandates of this PA. ..