Group 5 Presentation

Question 1

Blood brain barrier?

Answer 1

Tight junctions that connect endothelial cells
- Composed of cerebral micro-vessels blocks passage for macromolecules, small organic drugs and ions
Permeability: inversely related to size and directly related to lipophilicity

Question 2

What is P=glycoprotein?

Answer 2

ATP drive effluc pump
BBB transporter that is a major obstacle
Provides cross resistance to multiple classes of chemotherapeutics
High level of expression in barrier and excretory tissues and multidrug resistant tumor and non-tumor cells

Question 3

What are ligand activated nuclear receptors?

Answer 3

Pregnane X receptors is the regulatory structure for ligand activated nuclear receptors

• Activated by endogenous steriods, glucocorticoids and xenbiotics
• DNA binding is conserved but ligand binding is not
• Patient variation to treatment could be due to polypharmacy

Question 4

P-gp and Innate immunity?

Answer 4

Variable expression of P-glycoprotein is observed depending on the state of inflammation

• EX: treatment of hepatocytes with LPS reduces expression of P-gp mRNA
• IL-6, IL-beta, and TNF-alpha can all reduce the expression of many drug efflux proteins but chronic exposure can increase expression

Question 5

P-gp and the BBB?

Answer 5

Inflammation in the brain initially decreases P-gp expression, but chronic inflammation can increase P-gp

• Initial decrease is a mechanism by which the brain can preserve ATP in the even of an acute injury
• Increase in P-gp expression in chronic inflammation is protective

Question 6

Define oxidative stress

Answer 6

Due to exposure to heavy metals, ROS’s and even some chemotherapeutics can upregulate P-gp expression

Question 7

How does P-gp impact seizures?

Answer 7

Induced seizures upregulated P-gp expression
Pharmacoresistance in AEDs due to overexpression of P-gp, Mrp1/2 and BCRP
– Uptake of several AEDs increased by P-gp inhibitors, thus reducing seizure severity

Question 8

What is the glutamate hypothesis?

Answer 8

Glutamate accumulates during seizures

Glu signaling via NMDA receptors activates COX2 which upregulates P-gp

Question 9

Brain cancer?

Answer 9

Brain P-gp contributes to multidrug resistance in certain tumors and inaccessibility of drugs to these tumors –> inhibition is necessary to get drugs to the brain

Question 10

HIV-1?

Answer 10

Highly active anti-retroviral therapy (HAART): combination therapy using multiple antiretrovirals to control HIV

• Most HIV drugs do not penetrate the BBB
• Tat (HIV transactivator protein) enhances HIV transcription and can upregulate P-gp and Mrp1 expression
• Microglia and astroglia cells harbor the HIV and inflammation strengthens the glial barriers

Question 11

Alzheimer’s disease?

Answer 11

Association btwn P-gp gene halotypes and disease incidence

- Pgp plays a role in movement of beta-amyloid from brain to blood (increase amyloid, increase Pgp degradation)