|Disease||Bbb effect||Disease||BBB effect|
|Alzheimer||Disruption/breakdown||Multiple sclerosis (immune system deficiency)||Breakdown|
|Brain abscess||Unknown mechanism||Neuromyelitis optica (Devic's disease)||Breakdown|
|Cerebral edema||Opening (due to hypoxia)||Prion and prion-like diseases (Parkinson, Alzheimer)||Unknown penetration mechanism|
|De Vivo||Unknown mechanism||Progressive multi-focal leuko-encephalopathy||Disruption|
(latent hiv crosses the BBB)
|Damage (inflammatory)||Systemic inflammation (sterile, infectious)||Disruption?|
|Meningitis||Disruption||Tripanosomasis (sleep thickness)||Disruption|
Table 1: Some brain diseases and their corresponding effects on the BBB.
Figure 1: Increasing interest in research in epilepsy and the blood brain barrier.
The brain has five protective barriers (BPB) that hinder the delivery of therapeutic drugs. They describe the five main interfaces between the central nervous system (CNS) and the periphery.
Oby and Janigro  have proposed links between the BBB and epilepsy. Drug resistance, which affects ~ 30% of patients, and the possible role of the BBB, obviously remain an important focus of epilepsy research. Additionally, a compromised BBB has been associated with seizures in a number of disorders. Not only congenital defects, such as GLUT1 deficiency, but acquired deficiencies, like those resulting from brain tumors, head trauma, etc., often result in seizure disorders. More recently systemic and immune triggers have been implicated in a leaky BBB and neuroinflammation. Understanding the nature of the role of BBB in these disorders is imperative in the treatment of the disease, but the fundamental question of whether the compromised integrity of the BBB is a component of the etiology of epilepsy or a consequence of seizures remains unanswered.
Figure 2: Increasing interest in research in epilepsy and the blood brain barrier.
Permeability of the BBB is one of the factors determining the bioavailability of therapeutic drugs and resistance to chemically different AEDs. It becomes particularly relevant in drug resistant patients. There are two main theories describing drug resistance in epilepsy: (1) the target (or pharmacodynamic) hypothesis of pharmacokinetic resistance and (2) the transporter or pharmacokinetic hypothesis. The former hypothesis is based on a modification of the molecules targeted by the AED, thus reducing the efficacy of the drug. Changes in known AED targets include:
- Altered subunit expression in sodium channels [7-10];
- Expression of AED sensitive sodium channels in interneurons [11, 12];
- Increased expression of T-type calcium channels [13-14];
- Decrease of GABA-A receptor α1 subunits and increase of GABA-A receptor α4 subunits . Recently, the possibility that GABA currents are kinetically altered in drug resistant epileptic brain has been proposed .
- Overexpression of P-glycoprotein (MDR-1) [17-19];
- Overexpression of MRP-1 [20,21];
- Overexpression of MRP-2 ; and
- Overexpression of MVP .
BBB disruption after acute head trauma is a well-known pathologic finding in human (and also animal) studies and [humans (24-25)]. This disruption may persist for weeks to years after the injury and may be associated with abnormal EEG activity . Whether this abnormal activity develops into epilepsy is currently unknown, but observations have suggested BBB disruption in conjunction with a slowing in EEG activity may be a precursor to seizures . Others have observed persistent BBB disruption in the absence of any evidence of active epileptic foci .
The heightened interest in osmotic opening of the BBB as a viable mechanism of increased drug delivery to the brain provides an opportunity to explore the connection between BBB disruption and seizures in a more controlled environment [29-32]. Osmotic opening of the BBB by intracarotid infusion of a hypertonic mannitol solution is mediated by: (a) vasodilatation, (b) shrinkage of cerebrovascular endothelial cells, (c) modulation of the contractile state of the endothelial cytoskeleton, and (d) junction proteins by increased intracellular calcium, with widening of the inter-endothelial tight junctions to an estimated radius of 200 Å. The marked increase in apparent BBB permeability to intravascular substances (10-fold for small molecules) following the osmotic procedure is due to both increased diffusion and bulk fluid flow across the tight junctions. The permeability effect is largely reversed within minutes to hours.
In addition to iatrogenic BBB disruption, other medical procedures or conditions implicating BBB failure and linked to seizure disorders exist. For example, between 6 and 36% of transplant patients experience seizures, commonly caused by drugs, metabolic derangements or hypoxic-ischemic injury [34-41]. Although the seizures are usually transient and easily treated, it has been hypothesized that the focal loss of BBB induced by immunosuppresants may play a significant role in the development of partial seizures in a subpopulation of transplant recipients.
The development of new drugs against CNS disorders has not kept pace with progress in molecular neurosciences. Thus, new drugs discovered are unable to cross the BBB, the culprit being the lack of appropriate delivery systems. Further, localized and controlled delivery of the drugs at the desired sites is preferred because it reduces toxicity and increases treatment efficiency/efficacy. Here, LDLRP/Epic, a low density lipoprotein/related protein with engineered peptide compound, is a new effective therapeutics. It improves the transcytosis capacity of specific receptors expressed across the BBB.
These delivery systems include:
- Lipid-mediated transport;
- Pro-drug approach; and
- Lock-in systems.
The pharmaceuticals are re-engineered to cross the BBB via specific endogenous transporters located within the brain capillary endothelium.
- Receptor-mediated transport systems that enable drug molecules to cross the BBB in vivo. Such systems exist for certain endogenous peptides (insulin, transferin);
- Solid lipids;
- Mesoporous silica; and
One of the most promising applications of nanotechnology is in clinical neuroscience and multiple tasks can be carried in a pre-defined sequence [42-52].
The various NPs include:
- Radiolabeled polyethylene glycol-coated: HexaDecylCyanoAcrylate; (HDCA); PolyAlkylCyanoAcrylate (PACA); PolyLacticCoGlycolic Acid (PLGA); Peptidomimetic Monoclonal Antibodies; (PMA);
- Magneto-Electric Nanoparticles (MENs) for targeted delivery and drug release across the BBB + wireless stimulation of cells deep in the brain;
- Bioavailability-improved nanoscale particles and molecules: Nanoscale particles and molecules can also be developed to improve drug bioavailability, i.e., the presence of drug molecules where they are needed in the brain and where they will do the most good. Drug delivery focuses on maximizing bioavailability both at specific places in the body and over a period of time. It can be achieved by molecular targeting by nano-engineered devices targeting the molecules and delivering drugs with cell precision. The basic process to use drug delivery involves at least three steps: (i) Encapsulation of the drugs; (ii) Successful delivery of said drugs to the targeted region of the brain; and (iii) Successful release of that drug there. Several NPs are employed, including: nutshells (that can be targeted to bond to cancerous cells by conjugated antibodies or peptides to anopheles' surface); platelet-coated NPs (that can deliver higher doses of medication drugs to targeted sites in the body, thus greatly enhancing their therapeutic effects); biocompatible and biodegradable gelatin NPs (that can deliver multiple drugs to the brain bypassing the blood brain barrier (BBB) to treat a variety of brain injuries and neurological diseases in stroke and other victims); and shape-shifting engineered NPs (that can be tailored to deliver drugs to specified tumors and nowhere else); and
- Nanogels: They were previously discarded because they stick together with their neighbors (lost colloidal stability) when trying to “upload” the drugs within them. This made delivery impossible or ineffective. However, a solution to the stickiness was developed by Prof. Potemkin at the University of Florida. Figure 3 is an illustration of multi-shell nanogels with responsive shell permeability.
Figure 3: Multi-shells nanogels with responsive shell permeability.
- Peptides : A peptide is a compound of 2 or more amino acids in which the alpha carboxyl group of one is united with the alpha amino group of the other with the elimination of a molecule of water, thus forming a peptide bond. A polypeptide is a peptide formed by the union of an infinitely (usually large) number of amino acids. Peptides are able to cross the BBB through various mechanisms providing new diagnostic and therapeutic avenues. Various mechanisms are under study. To help in this effort, the “brainpeps” database has been developed. It includes transport information, prioritization of peptide choices for evaluating different BBB responses, study of quantitative BBB behavior, etc. For example, casomorphion (a heptapeptide) is able to pass the BBB (16);
- HexaDecylCyanoAcrylate (HDCA): Although these have been used against sarcomas in rats, they are not yet ready for clinical trials because the NPs accumulate in the surrounding healthy tissue;
- PolyAlkylCyanoAcrylate (PACA);
- The more promising PolyLacticCoGlycolic Acid (PLGA) coated with polysorbate 80 or poloxamer 188. Loaded with Doxorubicin, it can be employed in the treatment of glioblastomas (phase I); and
- Magneto-Electric Nanoparticles (MENs).
Nanoscale devices can be engineered to aid the delivery of life-saving drug treatments (including cancer) at the affected sites. Such minute devices have the potential to be engineered to efficiently and more safely deliver drug treatments directly to the location of diseased cells while helping avoid harm to healthy cells that fall victim to toxic drugs administered by conventional means. Engineered NDs include:
- Improved pharmacokinetic strategies of drug molecules (biodistribution, bioavailability, controlled and site-specific drug release);
- Decreased peripheral toxicity;
- Influenced manufacturing factors (type of polymers and surfactants, particle size and size distribution, drug molecules); and
- Limitations of drug amount delivered, and physiological factors [phagocytic activity of the reticulo-endothelial system (RES), protein opsonization].
Several "nano-carriages" for drug delivery to the right address have been created but many challenges remain, chief among them being how not to let the medicine act before it gets to the right place in the brain. The carriers usually encapsulate drugs through long-range electrostatic interactions wherein the carrier attracts oppositely charged medicine. Other tools are available to trigger the release of drugs, for example, an external magnetic field, different pH values, etc.Such systems, loaded with life-saving drugs, may revolutionize the way in which cancer is treated with chemotherapy, reducing the debilitating side effects of the therapy, making medications more effective, and all the while preserving the healthy living cells. These include: (a) Protein Cages (containing the anticancer drug daunomycin, a small amount of acid and set at a pH below neutral), which slightly open to let the drug jump inside the tumor, stay in until it came in contact with cancer cells. They can kill more than 70% without attacking healthy cells; (b) Microbubbles (microscopic balls of gas enclosed in an ultra-thin layer of fat which can be injected into the blood stream). Theoretically, upon reaching the unhealthy part of the brain, they are burst with ultrasound waves, releasing the drug exactly where it is needed. Because the entire blood stream is not being flooded with the drug, side-effects from chemotherapy can be greatly reduced; and (c) Multi-shell hollow nanogels with responsive shell permeability described above.
- Circulate throughout the bloodstream without being attacked by the immune system;
- Preferentially bind to cancerous areas allowing them to deliver and release their drug payloads specifically there;
- Are non-toxic as the platelet membranes are nanoparticle cores made of a biodegradable polymer that can be safely metabolized by the body; and
- Can be packed with many small drug molecules that diffuse out of the polymer core and through the platelet membrane onto their targets.
Glioblastoma multiform (GBM), a cancer of the brain also known as "octopus tumors" because of the manner in which the cancer cells extend their tendrils into the surrounding tissue, is virtually inoperable, resistant to therapies, and always fatal, usually within 15 months of onset. Each year, GBM kills approximately 15,000 people in the United States. One of the major obstacles to treatment is the blood brain barrier (BBB), the network of blood vessels that allows essential nutrients to enter the brain but blocks the passage of other substances. What is desperately needed is a means of effectively transporting therapeutic drugs through this barrier.
Figure 4: New 3HM nanocarriers for effectively delivery of therapeutic drugs to brain cancer tumors.
The complex pattern of MDR-1 expression in epileptic patients does not directly support a significant pharmacokinetic role in human epilepsy [54-57]. While localization of the drug extrusion pump in the BBB is consistent with the pharmacokinetic explanation for drug resistance, it is still unclear if or how the presence of MDR-1 in the parenchyma affects drug delivery and distribution or whether it is involved in other cellular functions. In a recent study [58-60], brain: plasma AED ratios were determined intra-operatively during lobectomies performed to alleviate drug-resistant seizures. The brain: plasma ratio of carbamazepine was 1.48 when therapeutic serum levels (15–34 μM) were achieved. When concentrations of carbamazepine found in multiple drug resistant brain were directly applied to human cortical slices from drug resistant patients made hyperexcitable and hypersynchronous by Mg2+-free media, bursting frequency was not significantly affected, but overall excitability was reduced by 40%. Similar results were obtained for phenytoin. At higher AED concentrations (60–200 μM), a dose-dependent decrease of bursting frequency and amplitude was observed. These 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.
- Presence at the anatomical interface between brain and blood;
- Transport of AEDs;
- Functional expression in brain microvascular endothelial cells but not in parenchymal glia or neurons; and
- Increased CNS accumulation of phenytoin in RLIP76−/−mice.
The BBB has developed a sophisticated mechanism to carry glucose efficiently into the brain. This sodium- and insulin-independent transport depends on endothelial expression of glucose transporter-1 (GLUT1), which mediates glucose transport across the BBB and is thus essential for brain energy metabolism [63,64]. First described in 1991, the GLUT-1 causes impaired transport of glucose across the BBB, interfering with cerebral energy metabolism and brain function, ultimately leading to seizures. While the resulting seizures do not generally respond to common AEDs, they can be controlled by strict adherence to a ketogenic diet [65-67]. Understanding the mechanism of action of the ketogenic diet may perhaps provide insight into how other types of seizures can be controlled.
Traditionally, neuroinflammation has been seen as a CNS-specific branch of immunology. Thus, a great deal of effort has been made to find immunocompetent or inflammatory cells in the brain (or spinal cord) parenchyma. A schematic representation of the cells and molecules involved in cerebral inflammation is shown in Figure 5, which provides a summary of events that may link intravascular inflammatory events to pro-epileptogenic events in the brain parenchyma.
Figure 5: Summary of events linking intravascular inflammatory events to pro-epileptogenic events in the brain parenchyma.
Not all the blood vessels in the brain constitute a BBB: only capillary vessels are endowed with a full-blown BBB phenotype. Vessels of increasing diameter have comparably increasing levels of leakiness and thus superficial vessels of large diameter are the leakiest, while penetrating pial vessels and descending penetrating vessels tend to have an intermediate barrier function. Since most animals, including vertebrates, have some form of barrier separating their blood circulation from the brain or the central nervous system, it has been speculated that profound evolutionary pressure existed to create such a complex organ. The CNS of vertebrates lacks lymphatic drainage; thus, passage of molecules or ions across the capillary wall will result in a net gain of water into the brain compartment, soon leading to an increase in intracranial pressure. This is a most damaging situation since the brain is contained within a rigid skull. Thus, the combination of a restricted volume and the lack of effective drainage for solutes leaving the blood for the brain parenchyma is probably one of the leading implications for the necessity of a tight barrier between the blood and the brain. The relationship between various BBB compartments (Virchow-Robin space; venules; penetrating pial vessels) has been reviewed in detail elsewhere ).
Our understanding of the cellular mechanisms that initiate changes in BBB permeability is limited. Several vasoactive or inflammatory compounds, which include bradykinin, complement 3a, ATP, histamine and serotonin from mast cells, interleukins, arachidonic acid and its metabolites, interferon alpha and beta, prostaglandins, and tumor necrosis factor, have all been shown to alter BBB permeability [69-73]. A subsequent rise in intracellular calcium may stimulate cyclic nucleotide production, which in turn leads to pinocytosis and vesicular transport. It has been proposed that the rise in intracellular calcium also triggers a contraction of the endothelial cells, which increases permeability by deforming or opening the intercellular tight junctions. The role of vasoactive agents in the control of BBB permeability, edema formation, and leukocyte infiltration is a key field of study. Given the prominent role of BBB integrity in the control of brain homeostasis and neuronal excitability, it is simple to predict that inflammatory changes affecting BBB integrity may have a profound impact on brain function.
Clinical evidences link inflammation of the CNS to the development of seizures. In Rasmussen's syndrome, a very rare form of brain malfunction which may occur at any time in childhood, it is known that brain cells usually in only one hemisphere are inflamed. Rasmussen's encephalitis was originally thought to be a chronic form of viral encephalitis but is now considered to be an autoimmune disease of the brain and is more properly termed Rasmussen's syndrome. Starting in one area of one side of the brain, the disease appears to gradually and progressively involve that side of the brain causing progressive and intractable focal seizures, a hemiparesis, and expressive aphasia when the left hemisphere is involved. Immune therapy with steroids, immunoglobulins, or plasmaphoresis provides only temporary relief from seizures.
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