Spinal Cord Damage and Repair Flashcards
SCI statistics
affects ~27mil worldwide
change in demographics (more elderly SCI patients)
burden to healthcare (£1 bil UK/ ASIA A $2.3 mil)
no cure
lose sensory/motor function below injury site causing defects in thermoregulation/defecation
Spinal cord anatomy
C8/T12/L5/S5/1Coccygeal
cervical division - neck (least protected area of SC)/arms/hands/speech&swallow
thoracic division - muscles
lumbar division - leg/foot
sacral - bladder/bowel
no cognitive decline
SCI symptoms
paralysis (paraplegia-L/T, tetraplegia, quadriplegia-C)
loss of movement/muscle function/loss of sensation
loss of bladder/bowel control
sexual dysfunction
secondary dysfunction: bladder infection/lung infection/pressure sores/pain/spasticity/depression/social exclusion
what is the aim of therapies
therapies which promote neuroplasticity/regeneration means patients can breathe without a ventilator/have hand movements etc
recent advances
epidural spinal stimulation combined with high intensity rehabilitative training
caveats of regeneration
neuromodulation does not equal regeneration (no tissue repair)
better recovery in SCI patients with most remaining residual function (ASIA C/D)
regeneration which promotes growth can promote recovery, SC is more open to rehabilitation protocols
2 approaches for tissue repair/neuroplasticity
1) regenerative therapies which enhance poor regenerative response of the CNS neurons (cellular transplanation-NSC/OPC/OEC/Schwann, PTEN/KLF7 regeneration gene overexpression, transcriptome screening/bioinformatics which discover regulators of axon regenerators (cama2d2)
2) regeneration which modifies the growth-inhibitory environment (targetting scar-ECM around scar/enzyme therapies/inhibit CSPGR signalling/CSPG synthesis/fibrotic scar, targetting myelin associated inhibitors- anti-Nogo antibodies, Nogo R inhibition)
PNS response to injury
-good regenerative ability
-less abundant myelin inhibitors
-rapid wallerian degeneration (myelin debris is cleared from the distal stump by schwann cells and macrophages)
-no glial scar at injury site
-abundant growth factors (upregulated during injury)
-minimal secondary damage (responsible for non-resolving pathology/lack of regeneration)
CNS response to injury
-poor regenerative capacity (no long distance regeneration, some neurons grow in adulthood)
-myelin inhibitors present (Nogo/MAG/netrin-1/sema4d/ephrinB3)
-slow wallerian degeneration(incomplete myelin debris clearance)
-glial scar in days, inhibits regeneration, high density of CSPGs
-no GF expression in temporal/spatial gradients
-extensive secondary damage (tissue destruction)
neuropathology of SCI
immediate: bleeding/axon injury
hours: necrosis/neutrophil invasion/macrophage B+T cell activation/cytokine release
days: wallerian degeneration/apoptosis/demyelination/debris/ECM scarring/ongoing inflammation
weeks/months: muscle atrophy/ongoing cell death/cyst/cavities/axons die back
2 classes of CNS growth inhibitors
scar-associated inhibitors
CNS myelin-associated inhibitors
adult rat model of contusion injury
force-defined impactor device to create spinal contusion injury/loss of SC neurons (NeuN) GFAP (astrocyte)
classical pathology: cystic cavitation/predominant grey matter degeneration/WM spared rim/wallerian degeneration/focal demyelination/scar
causes: permanent sensory/motor/autonomic impairment/walk despite damage
SCI targets for repair
prevent secondary injury (acute hrs)
repair damage (chronic)
maximise function in spared tissue (acute & chronic)
glial scar
reactive glial cells surround the injury site and seal in the injury, prevent regeneration
adv: barrier which seals in injury (isolates damage and prevents further infection)/scar ECM contains growth promoting molecules (laminin) /molecules for glial limitans formation (if not properly formed, increases damage)
dis: prevents neuronal growth/physical barrier(dense gap junctions)/molecule barrier (ECM contains CSPG/Ephrin/Slit/Sema)
Chondroitin sulphate proteoglycan (CSPG)
increased CSPGs in scar tissue after injury
limits regeneration and plasticity
sugar components (CS-GAGs) inhibit neuronal growth - chondroitinase breaks down CS-GAGs and promotes growth/neuroplasticity
chondroitinase ABC (ChABC)
bacterial enzyme which degrades CS-GAGs (from core CSPG component)
ECM is more permissive
in-vitro neurite growth (Zuo et al., 1998) vs in vivo regeneration, increases neuroplasticity, immune modulation (decreased cavitation/cell death), used in combination therapies
degrades at 37 degrees Celsius
best time for chondroitinase administration
Warren et al., 2018
acute (immediate) treatment: minimal respiratory recovery
chronic (1.5yrs after injury) activates phrenic MNs, 100% animals showed recovery
respiratory recovery via growth of serotonergic neurons
cell based therapies
clinical trials
autologous human schwaan cell (ahSC) The Miami Porject
human neural stem cells (HuCNSSC) trasnplant
human embryonic stem cells (hESCs) derived oligodendrocyte progenitor cells (GRNOPC1)
G Raisman/Tabakow clinical study - olfactory bulbar cells+nerve grafts+intensive rehabilitation
pharmacology
clinical trials
riluzole (sodium channel blocker/glutamate antagonist)
cethrin (rho/rockA inhibitor)
nogo-A antibodies
7 therapeutic targets for improving secovery after SCI
limit secondary damage
tissue/cell transplants
removal of inhibitory molecules (CSPG)
regeneration though neuron-intrinsic mechanisms
resupply of trophic support
remyelination of demyelinated axons
rehabilitation for circuit remodelling
modulation of scar inhibition
-indirect modification (MT stabilising antimitotic agents Taxol/Epothilone B suppreses fibrotic scarring - cancer)
-targetting biosynthesis of inhibitory ECM components (target CSPG sulfation, neutralising antibodies, synthetic sulfotransferase inhibitors,disrupt CSPG GAG chain assembly using XT-1)
**-inhibiting CSPG signalling (receptors: PTP sigma/LAR - use ISP to block interaction)
PTEN/mTOR intracellular signalling
mTOR - activates protein translation and ribosome biogenesis via phosphorylation (of S6 ribosomal protein) increases protein synthesis and cell growth
AKT - phosphorylates substrates/role in cell proliferation/growth/glucose metabolism = survival promoting factor
PTEN deletion (desired) activates mTOR/RGC axon regeneration after optic nerve injury/corticospinal tract regeneration (Park et al., 2008)
cell types transplanted in SCI experimental models
ESC
adult neural precursor cells
OPC
fibroblast
fetal tissue
glial restricted progenitor
bone marrow stromal cell
cells derived from pluripotent SC
olfactory tissue
peripheral nerve graft
biomaterials
NSC transplation of SCI
Lui et al., 2012
method: 14 days post injury add to fibrin gel: GFs(BDNF/GDNF/a-TNF), calpain inhibitor, human/rat ESC - inject rats with complete spinal transection, fill ~2mm gap
results: after 7 wks, NSCs differentiated into neurons (~20% grafted cells), projected over multiple spinal segments (connects cervical and lumbar SC)
considerations: only minor effects/multiple tumours//uncontrolled growth in brain
considerations for transplantation in SCI
poorly understood
few clinical trials despite >1000 patients
lots of data in private NOT public domain
small labs make big claims - not independently reproduced
risk of tumours and pain
low methodological quality for rodent data/ few primate studies
