BBB

what aids the transcellular route of transport through the BBB?

-an efflux transporter embedded in the PM -metabolizing enzymes that reside on the endothelial cells

what are the three stages of embryogenesis in which the BBB develops?

1. angiogenesis 2. Differentiation 3. Maturation

why does the nature of the BBB when it is dysfunctional make treatment of CNS diseases difficult?

1. pathologic disruption of the tight junctions cause the inappropriate passage of therapeutic drugs leading to adverse effects/drug interactions 2. pathologic BBB impairment can cause increased drug efflux which will reduce the amount of drug the cells actually uptake, leading to a decreased drug efficacy

what things make maturation distinct?

1. the pericytes and astrocytes that were just recruited help to make the BBB mature 2. BBB mechanism is not yet fully defined 3. Agrin (a protein) defines the polarity of the astrocytes

how do astrocytes contribute to the BBB?

1. they seal the BBB structure 2. regulate ECM space components 3. induce neurite growth/diff/survival by secreting neurotrophic factors

what is used to treat epilepsy?

AV-101

what is used to treat Schizophrenia?

CYP-1020

what is used to treat depression?

Neurotrophin antagonists

if there's one thing to remember exists in each phase of embryogenesis development of the BBB, what is it?

angiogenesis: tight junctions differentiation: N-cadherin maturation: junction points

with regards to the BBB, what is the correlation b/t how complex the meshwork is compared to the stage of development and/or the permeability?

complexity directly correlates to stage of development complexity inversely correlates with permeability

what are the CVOs?

discrete organs in the brain that are highly penetrated by solutes/ions: -hypothalamus -pineal gland -area postrema (controls vomiting)

what are the components that make up the BBB?

endothelial cells pericytes astrocytes interneurons

how do we know that tight junctions modulate BBB?

inflammatory mediators influence both paracellular tight junctional and transcellular routes of passage; if BBB's integrity is damaged by inflam agents, endothelial permeability will increase, vessels will dilate, and things will leak across the BBB

what is the biggest challenge in treating CNS diseases with drugs?

the difficulty of making small molecule drugs that are actually able to cross the BBB

how do interneurons contribute to the BBB?

they interact with the astrocytes to form the BBB and relay info to neurons

what controls transport via the paracellular route thru the BBB?

tight junctions

what are the three methods by which a drug can gain access to the CNS?

1. Carrier-mediated transport (CMT) 2. Active-efflux transport (AET) 3. Receptor-mediated transport (RMT)

what is meningitis?

inflammation in the CNS due to bacteria/virus/microbacteria that causes disruption of the BBB ---> headache, neck stiffness, high fever, spots on body, photophobia, altered mental status, etc

what is used to treat chronic pain?

N-type Ca2+ channel blockers

what things make angiogenesis distinct?

1. VEGF-A binds tyrosine kinase 2. vascular sprouts of endothelial cells begin invading the neuroectoderm 3. Incomplete tight junctions cause the BBB to be leaky due to increased MEDCA-32 4. GLUT1 is evenly expressed 5. the Wnt signaling/Beta Catenin pathway

what is the mechanism of infection of Rabies?

1. animal bite causes entry of virus into human 2. virus replicates in muscle at bite site 3. virus infects peripheral nervous system and moves via retrograde transport to spine 4. it replicates in the dorsal root ganglion and moves retrograde up spinal cord to brain 5. infects brain 6. travels from brain to peripheral tissues/organs to infect all of that

what are some other non-specific things about the BBB that make it selectively permeable?

1. endothelial cells' lipid nature 2.carriers 3. ion channels

what are the consequences of pathophysiological damage to BBB integrity?

1. passage of antibiotics & inflamm agents to fight infections 2. exposure of CNS cells to harmful [ ]'s of substances that can disrupt brain homeostasis and screw up neuronal signaling 3. it increases the potential infiltration by bacteria and viruses 4. an increased amount of salt/water movement into the brain can cause Cerebral Edema and raise intracranial pressure

what are the physiological responsibilities of the BBB?

1. regulate solute/blood passage b/t CNS & blood 2. act as a highly dynamic (not inert/rigid) barrier 3. homeostasis!!!! 4. restrict

what physical properties allow the BBB to restrict solutes from entering?

1. the vascular endothelial barrier 2. the epithelial barrier in the choroid plexus 3. tight junctions

what things make differentiation distinct?

1. there is a change in the expression profiles of the endothelial cell surface molecules: -increase Claudin3/5 -decrease MECA-32 -increase GLUT1 -increase N Cadherin -Ang-1 binds Tie-2 2. more complex tight junctions make the BBB less leaky 3. pericytes and astroglia are recruited to the site

what pathways do blood-borne substances use to enter the CNS?

1. water & other small things are allowed through via residual leakiness 2. membrane diffusion 3. saturable transport 4. diapedesis

where does the BBB exist?

In ALL parts of the brain except Circumventricular Organs (CVOs)

are full BBBs present in fetuses yet?

YES

how do pericytes contribute to the BBB?

they regulate capillary blood flow/permeability/and phagocytosis of cellular debris

how do the endothelial cells contribute to the BBB?

they restrict paracellular transport thru TGs regulates transcellular transport