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Adenosine: Key to Blood Brain Barrier Regulation Health Science Symposium ( 5 /6/14) Special thanks to the Organizers for the Invitation. Margaret Bynoe, Ph.D. Associate Professor, Director of Graduate Studies Cornell University, College of Veterinary Medicine Ithaca, NY. Adenosine.

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slide1

Adenosine: Key to Blood Brain Barrier Regulation

Health Science Symposium (5/6/14)

Special thanks to the Organizers for the Invitation

Margaret Bynoe, Ph.D.

Associate Professor,

Director of Graduate Studies

Cornell University, College of Veterinary Medicine

Ithaca, NY

Adenosine

adenosine is a purine nucleoside regulates inflammation immune cell migration
Adenosine is a purine nucleoside: regulates inflammation, immune cell migration

CD73

Four adenosine receptors:

A1

A2A

A2B

A3

CD39

Ado

10 Sec

Extracellular adenosine regulates the blood- brain barrier (BBB)

slide3

What is the blood brain barrier (BBB)?

The BBB: is a semi-permeable barrier that consists of a single layer of endothelial cells that line cerebral vasculature

Blood vessel

Astrocytes

WEB OF VESSELS: The brain is replete with blood vessels—some 500 miles of them—. By Megan Scudellari | November 1, 2013

By Marta Toran

The blood to brain barrier refers to a lack of direct communication between the blood and peripheral tissues and the brain

slide4

Adenosine receptors (ARs) are expressed on BBB cells

  • Ecto-enzymes, CD39 and CD73 are expressed on BBB cells

CD73 and CD39 expression on

mouse brain endothelial cells

A1 and A2A ARs are expressed on

mouse brain endothelial cells

CD39

CD73

4

slide5

The Scientific Problem

The blood brain barrier (BBB) hinders the delivery of therapeutic drugs into the central nervous system (CNS).

The Challenge

To safely and effectively modulate the BBB to permit the entry of therapeutic drugs into the CNS.

slide6

Modulation of adenosine receptor signaling alters

blood brain barrier permeability

DMSO

Mice treated with 10 mg/kg FITC-dextran and

DMSO or adenosine receptor modulator for 1 hr.

NECA: (general AR agonist)

SCH58261: (A2AAR antagonist)

slide7

AR facilitates anti-beta amyloid antibody entry into the brain of Alzheimer’s transgenic mice

Lexiscanvs NECA in Rats

  • FDA-approved A2A agonist is more potent than NECA
slide8

30

60

90

Adenosine receptors are highly expressed on primary human brain endothelial cells

150

Control

Relative TEER Changes (%)

LEX 1uM

130

NECA 1uM

VEGF

110

S1P

90

A1 AR

70

50

0

10

20

30

Minutes post

-

treatment

How do we Test whether Adenosine Receptor Signaling operates the human Blood Brain Barrier?

A2A AR

8

Control

**

6

Trans-endothelial electrical

resistance

An in vitro human BBB

Concentration

Relative FITC-Dextran

T cell

4

*

*

*

*

*

GAPDH

Endothelial

Cell

2

*

Tight Junction

Molecule

0

HBMVEC

HCMEC-D3

AR Agonist

Porous

membrane

slide9

Could Activation of A2A Adenosine Receptor permeabilize human

BBB to Gemcitabineextravasation and kill Glioblastoma cells

Lexiscan or NECA

Gemcitabine

Brain endothelial

cell monolayer

Porous membrane

Glioblastoma cells

Incubation of receiver chamber

for 4 days at 37 °C

15

5

30

60

Removal of donor chamber

(Minutes post treatment)

slide10

A2A AR activation permeabilized primary human brain endothelial cell barrier to Gemcitabine passage

slide11

Modifications often result in loss of drug activity

Approaches to CNS drug delivery technologies

  • Pro-Drug

Current approaches are either

-too invasive

-painful

-result in permanent

brain damage

-loss of drug efficacy

  • Lipidization
  • Drug Modification to Cross BBB
  • Fusion Protein

Modulation of BBB

  • CNS Delivery
  • Collodial
  • Endogenous Control
  • Invasive
  • Costly
  • Non-patient friendly
  • High probability of causing permanent brain damage
  • Disruption
  • BBB Modification/ Bypass
  • Mechanical pump
  • Intercranial
  • injection
slide12

Approaches to CNS drug delivery technologies

The use of adenosine signaling to modulate BBB permeability has many advantages over other approaches to deliver therapeutics to the CNS:

1) It makes use of an endogenous mechanism for BBB control

2) It has the potential for precise time dependent control of BBB permeability

3) The process is reversible

4) ARs are located directly on BBB endothelial cells

5) Over 50 commercial reagents for ARs are available; some FDA-approved

6) Use of in vivo and in vitro model systems, there is great potential to gain molecular mechanistic understanding; can lead to other targets

Adenosine

  • Endogenous Control
  • CNS Delivery

Modulation of BBB

Disadvantages of adenosine as a facilitator of BBB permeability:

-drug-drug interaction

-multifunctional properties of adenosine

slide13

Conclusion/s

We propose that blood brain barrier permeability is mediated by A2A AR signaling

  • The BBB, mediated by the A2A receptor operates as a DOOR - “blood brain door”. Local adenosine concentration is the “key”.
  • Differential modulation of adenosine receptor signaling represents a “tunable” system that can be exploited for therapeutic purposes.

Opening the BBB to therapeutics:

Closing the BBB to

damaging inflammatory cells:

Alzheimer’s disease

Parkinson’s disease

Cancers of the CNS

Neurological manifestation of HIV-AIDS

Mental disorders

Multiple sclerosis

slide14

Work Presented today by Past and Present members of the lab:

Dr. Aaron Carman

Dr. Jeff Mills

Dr. Dogeun Kim (DVM)

Cindy Meuller

Special thanks to Philip Owhfor many encouraging conversation