badaut, jerome
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J. Badaut1,2, D. Ajao2, J Kamper3, V Pop1, S Ahswal1, R Hartman3, A Obenaus1,4,5,6
Departments of 1Pediatrics, 2Physiology, 3Psychology, 4Radiation Medicine, 5Biophysics & Bioengineering, and 6Radiology
Inhibition of the JNK pathway improves the longInhibition of the JNK pathway improves the long--term term
functional recovery after juvenilefunctional recovery after juvenile
traumatic brain injurytraumatic brain injury
NIH RO1 HD061946
JNK-
signalosomes:
1) JNK1, JNK2
ubiquitous and JNK 3
in Heart, Brain and
testis
2) the outcome of JNK
signaling depends of
several factors
Adapted from Waetzig & Herdegen, TIPS Vol. 26, 2005
Apoptosis
Regeneration
JNK in TBI: Contradictory resultsModel of TBI JNK
activationJNK
inhibitorReferences
FPI n.a. Raghupathi et al., 2003
FPI n.a. Otani et al. 2002
Role of JNK in Juvenile TBI?
CCI SB203580 Mori et al., 2002
Human TBI n.a. Ortolano et al., 2009
CCI PeptideD-JNKI
Ortolano et al., 2009
JNK is potentially activated in juvenile TBI
and
DJNKI is a potential therapeuticaldrug in Juvenile TBI
JNK
JIP
P P
Activation of JNK
P
+
PP
JNK
SubstrateSubstrate
Phosphorylation
D-JNKI: Inhibitor Peptide acting on JNK binding domain
1)
S S
JNK
JIP No access of JNK to JIP or substrate
Adapted from Waetzig & Herdegen, TIPS Vol. 26, 2005Adapted from Borsello & Bonny Trends Mol. Med. Vol10, 2004
TAT Peptide acting on JBDForm LL-JNKI
D-JNKITATPeptide acting on JBDForm D
2)
S
Experimental protocol
JuvenileTBI: CCI in Rat-P17
Ajao et al., 2011, submitted
sham
3d-TBI
NeuN-GFAP
D-JNKI improves motor ability: Rotarod
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*
*
Increased time on rotarod for D-JNKI treatedrats at 7 and 60 days
**
D-JNKI improves motor ability: Foot-faults
*
Decreased number of foot faults for D-JNKI treated rats after 3 days
**
D-JNKI improves motor ability: Turn Bias
**
*
Reduced asymmetry of movement in D-JNKI treated rats at 30 and 60 days
Counting of left and right turns on swim path
**
D-JNKI decreases anxiety: Zero Maze
**
*
*
D-JNKI treated rats spent less time in the dark arms at 60 days
*
D-JNKI improves spatial learning: MWM
30d 60d** *
Block 1 Block 5
Reduced cumulative distance in D-JNKI treated rats
*
*
*
***
*
*
D-JNKI improves spatial memory: MWM Probe test
*
Saline
*
*
Increased number of entries to platform in D-JNKI-treated rats
D-JNKI
Summary & PerspectivesSummary & Perspectives
�IP injection of D-JNKI 3h after jTBI:�Improved motor functions�Reduced development of Anxiety�Improved spatial learning�Improved spatial memory�Improved spatial memory�Decreased the lesion volume
�Molecular and cellular changes sustaining behavioral improvements?
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