Transcript The Synapse - University of Toronto

Strategy 2: Make the tissue
more resilient to poor plumbing.
Pros:
-Likely a pharmacological treatment
-Can be administered more quickly by 1st
response team
-Can extend therapeutic time window.
-May be of benefit to a large number of
people.
Cons:
- Does not exist.
How to treat stroke
1. Prevent excitotoxicity
2. Block excitotoxicity
3. Block downstream consequences of excitotoxicity
4. Treat non-excitotoxic mechanisms.
5. Treat white matter damage
AND
Maybe, just maybe, it’ll work…
Prevent excitotoxicity
Prevent glutamate release
• Block action potentials
• Block neurotransmitter release
Blocking action potentials
1. Na Channel Blockers
2. Potassium channel openers
Advantages:
Reduce need for energy (ATP), reduce synaptic glutamate
release.
Disadvantages:
“Shut the patient down”, do not prevent non-synaptic
glutamate release, systemic toxicity (cardiovascular).
Blocking action potentials
1. Na Channel Blockers
2. Potassium channel openers
Na channel blockers currently not in use. Clinical trials have
shown no utility. Quaternary local anesthetics may be of
utility, however currently experimental
K+ channel openers have found utility in chronic spinal
cord injury. Phase III trials ongoing for stroke treatment.
Na channel blocker
Potassium channel agonist
Blocking NT release:
Block presynaptic calcium entry
SNX-111
Presynaptic calcium channel blocker
Blocking NT release:
Buffer presynaptic calcium ions
- Prevents the rise of calcium concentrations to levels that
cause neurotransmitter release
- Experimental.
Interfere with vesicle fusion/docking/release
- Tetanus toxin
- Botulinum toxin
Obviously not an
immediate
solution.
Blocking NT release:
Hypothermia.
First used in neuorlogical
diseases by Dr. Temple
Fay, in the mid-late
1930’s
Hypothermia
Blocking Excitotoxicity:
Agents that block postsynaptic
receptors.
General anesthetics are
considered by some to be
neuroprotective.
Inhalational anesthetics may
confer protection during
neurosurgery (controversial).
Blocking Excitotoxicity:
Most commonly used are the IV
anesthetics Barbiturates
(activate GABA), propofol
(activates GABA, blocks NMDA),
ketamine (blocks NMDA).
Barbiturates and propofol
commonly used in neurosurgery
for brain protection.
Blocking excitotoxicity:
Blockers of
1. Postsynaptic Ca channels
2. NMDA receptor antagonists
3. AMPA/kainate receptor antagonists
4. GABA agonists
Calcium channel blocker
NMDA antagonist
AMPA antagonist
GABA agonist
Prevent Consequences of
Glutamate Receptor Activation
Free radical scavengers
Nitric Oxide Synthase antagonists
Calpain Inhibitors
Inhibitors of other intracellular enzymes (protein kinases,
phosphatases)
Calcium buffers
NO and ROS antagonism
MnTBAP
-. SOD
.
O2-
O2
Mitochondria
ME
A
L-N
[Ca2+]
NO
ca
tal
as
e
H 2O
H 2O 2
Fe 2+
2
12
3
U7
Arachidonic acid
.
lo x
o
r
T
OONO -
NOS
Ca 2+-CaM
PLA 2
OH
I DE
S
IN
ROS
COX
Ca2+
IDE
S
T
OU
Ca2+
Free radical scavenger:
NOS antagonists
Partial
list of
stroke
drugs
so far
Complete list of effective
drugs so far:
tPA
Pro-Urokinase
Hypothemia
Back to our patient
Operated under
hypothermic circulatory
arrest.
- Placed on cardiac
bypass
- Temperature dropped to
15C
- Pump turned off:
EEG flat, BP = 0
PostOp
Pre-Op:
Glia
Glia
Astrocytes
Microglia
Oligodendroglia
Schwann cells
Glia
There are a few ways in which glia cells are different from neurons:
1. Neurons have TWO "processes" called axons and dendrites....glial
cells only have ONE.
2. Neurons CAN generate action potentials...glial cells CANNOT.
However, glial cells do have a resting potential.
3. Neurons HAVE synapses that use neurotransmitters...glial cells do
NOT have chemical synapses.
4. Neurons do not continue to divide...glial cells DO continue to divide.
5. There are many MORE (10-50 times more) glial cells in the brain
compared to the number of neurons.
Glial Cells
More numerous than neurons
Have many different functions
Nutritive
Electrical Insulators
Scavengers (immunological role)
K+ buffers
Cell guidance
Tight junctions (Blood-Brain Barrier)
Recently, glial cells have been
shown to be much more “active”
1. Glia communicate to each other via gap junctions
2. Glia communcate with neurons via gap junctions
3. Gap junctions permit the diffusion of calcium ions and
IP3. The latter causes calcium release from internal
stores.
4. Glial communication may underlie a number of
pathological conditions
Glial activity may underlie
pathological conditions:
1. “Spreading depression” – propagating waves of negative
DC potential that are believed to spread the ischemic
penumbra
2. Migraine (?)
Calcium waves in astrocytes
Glia recently recognized as
targets of excitotoxicity
Oligodendroglial cells
express AMPA subtype of
glutamate receptors.
Oligodendroglia are the
white matter cell most
susceptible to excitotoxicity
in anoxic injury.
From:
Li S, Mealing GA, Morley P, Stys PK
J Neurosci 1999 Jul 15;19(14):RC16