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101 Cards in this Set

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What are the Neuroprotective Agents? (9)
My Good Neighbor Pablo Can 4 C Cunts Rising
1. Methylprednisolone
2. Gacyclidine
3. P2X7R antagonists
4. Carboxy buckyballs
5. 4-Aminopyridine
6. Carbamylated EPO
7. cAMP
8. NMDA
9. Rolipram
What Neuroprotective agents eventually Have to do w/Ca?
Gacyclidne
NMDA
P2X7R antagonists
cAMP
Rolipram
Methyprednisolone
Neuroprotective Agent: Steroid

Stabilizes Cell membranes
Gacyclidine
Neuroprotective Agent

NMDA Antagonist --> Inhibits Ca influx
NMDA
Neuroprotective Agent
Glu receptor

--> Inhibits Ca influx
P2X7R antagonists
neuroprotective agents: OXATP, PPADS

inhibits Ca influx by antagonizing P2X7R (ATP receptor)

Can't cross Bl. Brain Barrier, but Brilliant Blue G can--> rats w/Spinal injuries have reduced inflammation, better stepping motion, & bladder control
Carboxy Buckyballs
Neuroprotective Agent

neutralizes free radicals
4-Aminopyridine
Neuroprotective Agent

Improve Conduction in spared demyelinated axons by opening K+ channels
Carbamylated EPO
Neuroprotective Agent

Reduces Inflammation via Unknown receptor
cAMP
Neuroprotective Agent

Restores normal Ca balance by closing Ca channels
Rolipram
Neuroprotective Agent

Resortes normal Ca balance by degrading PDE 4
how are cAMP, PDE, & Ca linked in neurons?
cAMP closes Ca channels, restoring normal Ca balance

Injured axons have high Ca --> upregulates PDE, which breaks down cAMP & stops cAMP from closing Ca channels, leading to Toxic intracellular Ca levels
Rho A in neurons
Rho A: small GTPase
bound to GTP Rho A depolymerizes actin cytoskeleton (growthcone)

NoGO, MAG, Ompg all signal through NoGo Receptor --> Activating Rho A
these are ligands for the NoGo Receptor
Cause GC collapse
NoGo
MAG
Ompg
soluble molecules that inhibit Rho A pathway --> inhibits Growth Cone collapse (9)
BDNF, GDNF, NGF, NT-3
NoGo 66
NoGo Ab + injection of NTF-3
Bac C3 transferase
Inhibitors of Rho Kinase
myelin Ab
Promotes Axon elongation

Inhibits GC collapse
What are the targets for agents that promote axon elongation & NSC survival
inhibit Rho A pathway
inhibit EGFR kinase activity (internal domain)
Myelin inhibitory proteins
Agents that limit Glial Scar
Minocycline

CM101
Minocycline
Agent that limits Glial Scar: (Antibiotic)

limit cavitation & glial scar by targeting Inflammatory Cells
CM101
Agent that limits Glial Scar: (polysccharide from Stretococcus B)

limit glial scar by targeting Inflammatory cells
Agents that allow traverse or bypass Glial Scar
Chondroitinase ABC
Fetal Spinal Cord (into newborn rats)
Intercostal nerves in FGF-1 loaded fibrin matrix
Collagen 1 + Ln or 4-Aminopyridine
Chondroitinase ABC
Agent that allow traverse or bypass of glial scar

Targets CS-GAGs of PGs
-->increases adhesivity of scar suface
Fetal Spinal Cord into newborn rats
Agents that allow traverse or Bypass of the Glial Scar

Promotes axon elongation via adhesion molecules & soluble factors
Targets Axon surfaces
Intercostal nerves in FGF-1 loaded fibrin matrix
allows tranverse or bypass of glial scar

Mice not people
use axon tubes --> adhesive guidance of axons
Targets: axon surfaces
Collagen 1 + Ln or 4-axons
Adhesive guidance of Axon Surfaces

Targets aminopyridine
Cat
Cell transplants
Schwann cells (2)
OECs (Olfactory Ensheathing Cells)
Splenic dendritic cells
Cord Blood
Fibroblasts
Ways that Topical Agents are used for Acute wounds
Enhance Hemostasis
Reduce Inflammation
Enhance structural repair
Acute Wound: Enhance Hemostasis
QuikClot

Hem Con Bandage
QuickClot
Over the Counter
hydrous aluminum silicate (zeolite) & Ca++
Absorbs water FAST < min
Hem Conn Bandage
Enhance hemostasis
chitosan (+)
pulls neg charged RBCs into bandage --> tight fitting plug over wound
3 ways of Reducing Inflammation in Acute wounds
Debriding agents
Antibacterials
Anti-inflammatories (anti scarring)
Debriding agents
Vibrolysin
Papain/urea
Medical Maggots
Vibriolysin
Debriding Agent: Reduces Inflammation

Enzyme
Papain/urea
Debriding agent: Reduces Inflammation
Medical Maggots
Debriding Agent: Reduces Inflammation

green blowfly (Phaenicia sericata)
liquefy necrotic tissue
antibiotic
amps helaing of EGF & IL-6
Acute Wound
Reduce Inflammation: Antibacterials
oleic n-9 FA
HB-107 cecropin B peptide
honey
Topical Agents for Re-Epithelialization of Acute Wounds
HA/CS hydrogel

Epiregulin (thicker epidermis)
Topical Agents for Angiogenesis of Acute Wounds
Fentanyl (Narcotic, colonoscopy)
Pig Enamel matrix
Ketanserin (blocks serotonin R-hypertension)
Angiotensin (proliferates endo)
VEGF (proliferates endo)
Topical Agents for FB migration/proliferation of Acute Wounds
Extract of C. agentia (cockscomb/quail grass)
NA/CS hydrogel
EGF
FGF-2
TGF Beta 1,2
hGH
Vanadate (more collagen-thicker)
Oxandrolone (Anabolic Steroid --> mature & dense collagen
Regen Templates for Acute Wounds
Alloderm
Integra
DeVries
Alloderm
Scafold for Acute Wound
Human Dermal Matrix
works best if
+ keratinocytes
+ Meshed Split Thick Skin Grapht MSTSG
ESC need this factor to proliferate in an undifferentiated state
Mouse: LIF

Human: FGF-2
Directs ESC to become Neurons
Retinoic Acid
Who ASC --> ESC
Takahasahi et al 2007 (Sinya Yamanka)

Yu et al 2007 (James Thompson)
Sinya Yamanka TF
Oct4
Sox2
Klf4 (cell division)
c-Myc (cell division)
James Thompson TF
Oct4
Sox2
Lin28
Nanog
What TF are found in blastem & used for iPSC
Sox2
Lin28
Nanog
Klf
problems w/iPSC
1. direct differentiation not fully understood (100%) Teratomas
2. how robust? Last how long?
3. Function
4. Cost - testing for Efficacy & Safty
5. Feasibility --> Rejuvination/Ethics
Goals of Chemical Induction
1. Enhance repair by scar tissue
2. Stimulate Cell growth (axons)
3. Stimulate resident ASC
4. Dedifferentiation --> ASC
5. transdifferentiation
6. Compensatory Hyperplasia
Integra
Acute Scaffold
Bovine Col1 + Chondrotin 6 sulfate
Clinical use for burns
DeVires
Acute Scaffold
Collagen + elastin
Netherlands 1994
Not in US yet
Why don't cell transplants work for Acute wounds (burns)
damaged dermis can't produce GF needed for epidermis
Bioartificial Skin Equivalents
living wound dressings
scaffold + keratinocytes (allogeneic --> rejected)
allows skin to heal
Re-Epithelialization for Chronic
KGF-2 (Repifermin)
Beta-NGF
PDGF-BB; better/w TGF-alpha
What neurprotective agents inhibit Glu's action --> Ca influx
NMDA
Gacyclidine
Neuroprotective Agent that's an ATP receptor Antagonist
OXATP
PPADS

(P2XR7)
prevent GDP --> GTP on Rho A
BDNF
GDNF
NGF
NT-3
inhibits NoGo R by binding to it
NoGo66
inhibits end result of RhoA pathway
Inhibitors of Rho Kinase (ROCK)
how is the Glial scar limited?
targeting inflammatory cells

Minocycline (Antibiotic)
CM101 (Strep B polysac
cell transplant that produced partial recovery from SCI
OEC
APC
Cell transplant for SCI that produce paracrine & Juxtacrine
APC
Splenic dedritic cells (Rat)
APC
in vivo
in vitro
vivo: paracrine, NSC --> partial functional recovery

vitro:dendritic cells --> Juxacrine --> NSC survival & proliferation
Androgenetic Alopecia
test --> 5 alpha reductase --> DHT
Telogen (rest) elongates
Anagen (grow) shortens
Catagen (destroy) same
Androgenetic Alopecia: topical treatments
Rogaine (minoxidil)
Propecia (finasteride)
Rogaine (minoxidil)
--> minoxidil sulfate
K+ channels
slows hair loss, but don't regrow
Propecia (finasteride)
blocks 5-alpha reductase
restores anagen length
Future Androgenetic Alopecia
inject bulge & Dermal papilla
--> dermal papilla Wnt restores anagen
Most prevalent Neurodegen Disease
Multiple Sclerosis
MS
T cells attack myelin
Autoimmune, demyelinating disorder
Can lead to sensory, motor, cognitive Defects
Alzheimer's Disease
Beta Amyloid aggregation
tau protein
Hippocampal degeneration
intrafiliment inhbits synapses
Huntington's Disease
loss of Multi striatal neurons
b/c repeats of Glu (CAG-CAG-CAG)
--> can't move BDGF
ALS stands for
Amyotrophic: lack of muscle nourishment
Lateral : location of motor columns in spinal cord
Sclerosis: scaring (motor neuron death)
ALS: types
Sporadic - 90%
Familial - 10%; of which 20% mutated SOD-1
ALS molecular abnormalities
Neurofiliment bulidup in motor neurons
low retinoid pathway enzymes
high Glu in CSF b/c astrocytes downreg GLT1 --> influx Ca
G93A mouse model
mouse model of ALS
SOD1 mutant (not 95% of cases)
2O2- + 2 H2O --> O2 + H2O2 + 2 OH—
G93A Culture Experiment
cultured w/WT neurons --> 1/2 Apop
Paracrine Factors
- Inflammation b/c Prostaglandins --> NOS ->
G93A secretions
Upped Prostaglandins --> Upregulated Prostaglandins --> NOS1 (nitric oxide synthase) --> NOX2
ALS research Q's
1. what initiates

2. Progression: Astro toxic to Motor N ?
3. same Initation & progression in familial & Sporadic?

iPSC- any good- Epigenetic;
- Compare Familial & sporadic
- screen for initiating factors
ALS: have tried the following factors
delayed initiation
- siRNAs for G93A
- IGF-1, FGF, CNTF, VEGF
- Caspase inhibitors (Cas --> Apop
- COX2 inhibitors (b/c inflammation
- Antibiotics (increase Glu1
bioartifical pancrease
Cadaver Islet cells mixed into Alginate
spread over CaPO4 --> cross links Alginate
microsphere w/pores
Bioartifical Chin
Ti Cage + MSC
- BMP7 (drives MSC into osteoblasts)
- Bovine Bone Matrix (accelerates process)

Made pocket underskin to get it vascularized (Body as a bioreactor)
Bioartifical Bladder
polyester matrix seeded w/
- epithelial, fibroblasts, smooth muscle
Esophagus (Tracea)
Had TB
Decellularized
autogenetic MSC --> Fibro, Chondro, & muscle
Bioartifical Bone
frogs
MSC + BMP4 --> Chondrocytes
vascular
Satellite --> MI heart
increased LVEF 8-9% 6months
Augment Contraction
Paracrine factors that
-cardiomyocyte survival
- Promoting angeiogenesis
- Inhibiting scar formation
Fetal Cardiomyocytes
dog, pig
differentiated but remained immature
Cardiac SC --> Rat
Regen: 31% decrease infarct size
but remained immature
BM into MI
Wollert 2004
6.7% increase LVEF
= 42% improvement
G-CSF + BM
Granulocyte colony stimulating factor
Zohlnhofer et al (2006)
G-CSF upped HSC
6.2% decrease Infarct
.5% increase LVEF (less than placebo)
MSC transfected w/Akt
Mangi (2003)
Akt gene --> Protein Kinase B- inhibits Apop

LVEF --> Norm
Healed Infarct

--> MSC NO diff into Cardio
--> b/c more paracrine factors, upped Cardio survival & angiogenesis, dropped fibrosis
Akt cardiomyocytes under hypoxic
Gnecchi (2005) Thymosin B-4 (TB4)
regular Cardio Apop
Akt Cardio 41% survived
Media --> MI upped survival 60%, Infarct droped 40%
Thymosin B-4 (TB4)
binds actin monomers
TB4 is upped after MI
--> Activated (P-late) Akt
--> Expands heart tissue
TB4 expands Heart tissue
TB4 caused migration EndoCardial --> MyoCardium

(AcSDKP) TB4 self cleaved tetrapeptide that caused differentiation into Sm muscle & endothelium
TB4 --> MI mouse
reduced Apop, Scarring, & upped Angio
LVEF 21--> 44, but Norm=75
HSC transplant Experiment
Donor: P-CRE-GFP
Host irradiated ROSA26: Promoter-FSC-LaxZ(reporter)
FSC: Flox Stocked Cassette- LoxP removes FSC, FSC protects LaxZ
GFP in blood, Beta-gal found b/c fusion in Hepatocytes, Cerebellum, Heart
Fussion naturally occurs in
Osteocyte
Muscle
Zygote
HSC 2
Donor: Promotor-FSC-GFP, male (Y)
Host: leathally irradiated, P- CRE
found Y+ cells lung, liver, wounded Epidermis
No GFP --> no Fussion
Old Don't heal well
less Delta expression (maintains Notch intracellular signaling)
Old Cells in young serum
upped Delta --> Notch --> SC proliferation

Young in old was opposite
Cenegenics
MGF & Growth Hormone w/strength training can retard loss of muscle due to aging

GH & train increases endogenous MGF