Strategy 2: Make the tissue more resilient to poor plumbing. Pros: -Likely a pharmacological treatment -Can be administered more quickly by 1 st 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

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

Post- Op Pre-Op:

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