الفهرس 
Structure of the Blood-Brain BarrierOnly 14 pages are availabe for public view
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Abstract
The BBB is an anatomical and mechanical barrier that separates the brain from the blood-borne substances, to protect the neuronal milieu and function. The BBB exist at the level of the TJ, which present between the BECs; endothelia cells, have a low transcytosis and endocytosis as compared with other endothelial cells else were. TJ in conjunction with AJ are responsible for the barrier property.
The functional unit of the BBB is the neurovascular unit. It`s a construct formed by neurons, BECs, pericytes “engulf vascular lumen, contractile, and share the same BM with the BECs”, astrocytes “connect with its multiple foot processes to the BECs, pericytes, and neurons”, microglia “represent the immune system in the neurovascular unit”. Neurovascular unit control the bloof flow to the neurons, through the interaction of these cells, ans TJ. TJ compose of proteins, interact together to form a tight seal, limiting the paracellular diffusion of molecules.
So, transport systems are needed to allow passage of certain molecules across BBB. These transport systems exist on luminal and abluminal wall of BECs, to allow a bidirectional passage of nutrients, electrolytes, and vitamins into the BECs and xenobiotics back into the blood. Then, prevent potentially harmfull substances from entering the neuronal milieu.
Despite that number of transporters are ever expanding, the transport systems could be classified as iron transporters, Na dependent transporters, Na independent transporters, and active transport.
Through forming a tight seal arround the neuronal environment, the BBB controls entry of nutrients into the brain, not only through the transport systems, i.e., carrier mediated transport “responsible for transport of glucose, amino acids, and several water soluble vitamins”, but also, by the enzymatic function, as evidenced by the presence of cytochrome P540 and monoamine oxidase.
One role of the BBB is the signaling function, through it TJ integrity is regulated and activation of microglias is mediated by interleukin-6 receptor on BECs. The old notion that the brain is an immune privalleged area had turned out tobe false. Normal brain undergoes limited routine immune surviellance, by the immune cells that enter the CSF throuh the post-capillary venules, and cluster in the Virchows-Robbins spaces.
Another function is the formation of new blood vessels, what`s termed angiogenesis, when exposed to periods of hypoxia.
BBB dysfunction results from a diverse of mechanisms. Altered residual leakiness as a result of BBB disruption or dysfunctional transport systems, whether a result of long standing hypertention, inflammatorty mediators, alchol, opiates, or chronic infection. Disruption of the barrier function leads to changes in disrupted ionic balance in the neuronal milieu and cause exposure of proteins and membranes to toxic effect of ionic imbalance and the consequent ROS formation.
Another disturbed function of BBB is its nutreitive function, with the resultant low glucose transport across BBB. Disruptio results in exposure of neurons to the putative toxins which form free radicals and ROS, causing degeneration of neurons. The high concentration of mitochondria in cerebrovascular endothelium might account for the sensetivity of the BBB to oxidative stressors.
Aging doesn`t disrupt the BBB, but makes it vulnerable to subsequent pathological insults.
BBB dysfunction causes neuronal degeneration, and the resultant neurodegenerative diseases.
Neurodegenerative disorders are chronic progressive neurologic disorders associated with neuronal loss of specific neuronal populations in the brain, spinal cord, or both. The most common NDs are Alzheimer`s disease, and Parkinson`s disease. The clinical presentation of NDs is largely determined by the destripution of pathology, not type of pathology. They start insidiously after long period of normal nervous system functioning.
AD is one of the most frequent NDs in old age, characterized by marked cognitive decline. The pathological hallmark is Aβ. Aβ showed increased influx and decreased efflux across BBB, causing abbarrent angiogenesis, and vasoconestriction, as Aβ is a potent vasoconestrictor, that causes increased vascular permeability, and hypervascularization, resulting in atrophy in frontal, temporal, and parietal lobes, and marked more in the hippocampus. Also in parahippocampal gyri, amygdala, nucleus basalis of myenert, and locus ceruleus.
PD is another common NDs characterized by involuntary tremulous motion with lessened muscular power, with propensity to bend the trunk forward. It`s pathologically characterized by neuronal death in several cell groups in dopaminergic neurons in substantianigra pars compacta, ventral tegmental area andretrorubral field, noradrenalinergic neurons in locus coeruleus, serotonergic neurons in dorsal raphe nucleus, and acetylcholine neurons in edinger wistphal nucleus. The pathology is marked by α synuclein containg lewy body.
ALS is characterized by loss of upper and lower motor neurons in primary motor cortex, brainstem, and spinal cord.
Early detection and diagnosis of BBB dysfunction and NDs have allways been a challenge. Recent modalities have been introduced to allow more accurate and early diagnosis of BBB dysfunction, and the resulting NDS.
CSF biomarkers could be used due to its proximity to the CNS, which gives it advantage over serum biomarkers. It could be used to detect, follow-up, and assess response to treatment in CNS disorders. Biomarkers either determine presence of CNS defect; determine type of disrupted cells and type of the specific CNS disease. Biomarkers are either product of metabolism, CNS specific, of axonal pathology, or for oxidative stress.
CSF Aβ biomarker, and ABP decrease in AD, S100B increases in PD, and decreases in ALS, Mn-SOD increases in PD, AD, and ALS, and NFL increases in ALS.
Neuroimaging is another modality for NDs and BBB dysfunction diagnosis. It`s used to detect BBB permeability by dynamic MRI, cell death by PET and SPECT scans either alone or in conjunction with apoptosis biomarkers, rCGM and rCBF by PET and SPECT scans with Technecium, and glucose uptake by FDG PET and SPECT.Introduction of radiolabeled compounds as Pittsburgh Compound-B showed advances in detection of AD, and differantiating AD from dementia with Lew body. Finally, Tesla 7 T2* MRI used to detect iron in leaking RBCs from BBB.
Nanomedicine offered revolutionary advances in diagnostic modalities, because of its ability to magnify the biomarkers detected in CSF, making earlier diagnosis of NDs possible. Several tehniques is used, and others are under research for providing a more reliable and applicable nanodiagnostic tools. Nanotechnology allowed detection of Aβ as low as 10fg/ml, Tau protein as low as 1pg/ml, and RNA aptamers with PET scan is under reasearch for diagnosis of PD.
Understanding BBB helped in designing alternative therapeutic approaches for drug targeting to the brain. it`s difficult to pass the tight seal made by the BBB, to allow more availability of drugs in the CNS. So, ultrasound induced disruption of BBB was introduced to make it possible.
It depends upon microbubbles, which is a small (3μ in diameter) gas filled bubbles, injected intravenously. FUS MB causes the BBB tobe disrupted only in the transducer focal volume. It could be used either MRI guided, or MRI free, and allows for delivering antibodies for AD treatment.
Nanomedicine again used in treatment of NDs by making it possible to cross BBB by nanocarriers, to transport drugs for treatment of AD and/ or PD as rivastigmin, tacrine, curcumin, acetylcholine, estradiol, Mifepriston, EGCG, MAEHP, d-penicillamine, ferulic acid, DNA, and dopamine. Another nanomedicine approach in treatment of NDs is the neuroprotechtive agents as nanogels, fullerene, dendrimers, nanoceria, gold nanoparticles, diamondoid derivatives, dopamine using nanosystems, and non-viral vectors. Offering not only better symptomatic improvement, but also, stops the disease progression.
The next approach for NDs treatment is the active and passive immunotherapy. In AD active immunization with Aβ aggregates, results in antibodies formation against n-terminus of Aβ. In ALS, familial type showed good results when treated with IgG-SOD1, which forms antibodies against mutant-SOD1. In PD, PD01A, and mannan have been studied as a potential immunotherapy against αsyn in PD.
Stem Cells are yet another revolutionary therapeutic modality in medicine with potentials in offering an applicable treatment of NDs. The main challenge in Stem Cells therapy is the need to renew specific cell type in a specific location in the brain for each neurodegenerative disease. Several researches have been undertaken for treating PD, AD, and ALS, with promising results. Making replacing the lost neurons and glial cells, and by mediating remayelination, trophic action, and modulationof inflammation.
Other molecules have shown a prophylactic charachteristic as DHA in animal researchs showed that it partially counteract cognetive decline in AD, and protect dopaminergic neurons in PD. Caffeine, when adminestered chronically has benificial effects against PD, and AD.