nerve injury & motoneurons
DESCRIPTION
Nerve injury & Motoneurons. Core concepts : Loss of trophic support Excitotoxicity. Causes of motoneuron death. NOCD. Early postnatal injury. Disease SMA ALS PMN. ~5000 affected in UK 1-2/100,000 new cases p.a. Affects men > women Onset >40 years of age - PowerPoint PPT PresentationTRANSCRIPT
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Nerve injury &
Motoneurons
Core concepts:•Loss of trophic support•Excitotoxicity
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Causes of motoneuron death
NOCD Early postnatal
injury
DiseaseSMAALSPMN
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Motoneuron disease• ~5000 affected in UK
– 1-2/100,000 new cases p.a.
• Affects men > women• Onset >40 years of age
– 55-65 yrs old most commonly affected
• Genetic– Not possible to prevent
onset
Symptoms
• Progressive muscle weakness & wasting
• Hands, arms & legs usually affected first
• May get spasticity, painful cramps & loss of balance
• Affects vocal & respiratory muscles
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Clinical syndromes:
Spinal Muscular Atrophy• Hereditary condition defect
in SMN gene
(Chromosome 5q12.2-q13)• Insufficient peripheral motor
sprouting• Increased motoneuron
activity – excitotoxicity?
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Clinical syndromes:Age related motoneuron loss
Senile Muscular Atrophy• Affects 15% of elderly population
• 10-20% motoneuron loss
• Motoneurons show signs of damage CGRP, GAP43, p75 trkB, trkC;
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ALS
• Affects UMN/LMNs• Mechanisms
– 10% Hereditary (SOD1)– Oxidative stress– EAA toxicity
• Glial EAAT2 abnormal Glutamate in CNS Glutamate in CSF
• NOS, Cox 2 induced• Defect in RA pathway
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Goals of neuromuscular disease research
1. Prevent death
2. Maintain phenotype
3. Repair neuronal damage
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BDNF, NT3, NT4GDNFLIF, CNTFFGF5, bFGFIGF1, IGF2
BDNF, NT3, NT4GDNF, NTN, PSNLIF, CNTF, CT1FGFs RAHGFIGF1
Trophic factors and motoneuron
survival
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NOCD & trophic factor knockoutNGF- trk A No motoneuron lossBDNF/NT4 - trk B No motoneuron lossNT3 - trk C No motoneuron lossp75 No motoneuron lossBDNF-NT4 double KO No motoneuron losstrk B/C double KO No motoneuron loss
CNTF No motoneuron lossCNTFR 40-50% LOSSLIFR LOSSgp130 40% LOSS
GDNF- GFR1 20-40% LOSSGFR2 No motoneuron lossc-RET Significant loss
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Motoneuron survival depends on age
and post-operative survival time
P0 90%P3 80%P4 30%P5 0%
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YES
YES
Neonatal motoneuron deathdepends on lesion site
Yes
Motoneuron loss also depends on duration of deprivation•P0 axotomy: 1% survival•P0 crush: 10-30% survival•Delayed reinnervation P5 & P10 crush 60% survival
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Is motoneuron death due to axon damage per se or target deprivation?
Motoneuron loss is regulated by target deprivation
can be induced by NMJ blockade at birth (maintains MN immaturity)
injury induced release of glutamate (kills immature MNs)
Can be mimicked by NMDA injection
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Muscle induced neuro-
transmitter release
Motoneuron death is regulated by target contact
Growing mode Transmitting mode
Ach
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Prevention of neuromuscular
interaction
No induced neuro-
transmitter release
Motoneuron death is regulated by target contact
Growing mode Preserved immature state
Deathby
glutamateexcito-toxicity
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Motoneuron maturationGrowing neurone transmitting neurone
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Neonatal axotomy: effects on surviving neurons
Biochemical expression, Reg2,
HSP27, GFR1, p75, CGRP, CB, gp130, trkC, CNTFR
expression GAP43, c-Jun, NOS, NR1, NR2B, GAL, mRNAs for LIF, trkB, c-RET
Physiological neuronal activity• abnormal reflex
patterns dendrite number,
altered morphology
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Pharmacological manipulations that rescue dying motoneurons
1. Neurotrophic support
2. Preventing excitotoxicity
Important Outcomes
1. Permanent survival2. Rescued motoneurons
must reinnervate muscles
3. Muscles must develop adequate force on reinnervation
4. Spinal circuits must be re-established
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Neurotrophic support1 week 2 weeks combination
nerve + s.c
P3 sciatic cut + single dose NTF treatment to injury site
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Neonatal neurotrophic support
Transient rescue• BDNF < 3 weeks• NT3 < 2 weeks• NT4 < 1week• CNTF < 2 weeks• LIF < 2 weeks• GDNF• combinations • Restore ChAT levels
Permanent rescue• GDNF (AAV)
Deleterious• NGF (activity dependent)
• High dose BDNF– receptor desensitisation or
activity dependent
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NO/
YES -delayed
YES
Adult motoneuron death
NO
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Adult nerve injury
Loss of normal function• Loss of reflex function• Soma atrophy• Motor c.v. ChAT transmitter receptors
• No cell death*– VRA– Repeated nerve injury
Regeneration GAP43, c-Jun CGRP, GAL, REG2 HSP27 c-Ret, GFR1,
LIFR, p75, CNTFR, trkB
gp130, trkC
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trkBGFR1
p75
NGF, BDNF, GDNF, NT4
***
CNTF, NT3RegenerationGAP43, CGRP
Tubulinp75 apoptosis in Schwann cells
regeneration
Exogenous NTFs reverse effects of injury & aid
regeneration
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trkBGAP43
p75
BDNF, GDNF, NT4
***
or Schwann cell derived trophic factors
Regeneration mode
Adult injuries that kill:Repeated nerve injury
EAAtoxicity
SA
Immature state
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trkBGFR1
p75NOS
Exogenous
BDNF, GDNF prevents death
***
Regeneration possible GAP43, CGRP, Tubulin
Adult injuries that kill: Avulsion
EAAtoxicity
No transport of Schwann cell derived
NTFsNo access to
Schwann cells
Activation of p75 death pathway?
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Rescuing dying motoneurons Preventing excitotoxicity
• Riluzole
• NOS inhibitors
• Glutamate inhibitors MK801
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Clinical trials in ALS• CNTF severe side effects: fever, chest pains, muscle
weakness, herpes virus activation
• BDNF – Major side effects. Pain.
• IGF1 – data not conclusive; drug well tolerated
• GDNF, NTN – not tested
• TCH346 (anti apoptotic) – failed phase 2 trial
• Riluzole – activity blocker
• Retinoic acid – RALD2 & RAR
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References
• Lowrie MB & Vrbova G 1992 TINS 15: 80-84
• Greensmith L & Vrbova G 1995 Neuro-muscular Disord 5: 359-69
• Vejsada R et al 1995: EJN 7:108-115
• Ma J et al. 2001 139: 216-223